BOROX CATALYSIS: A NEW FRONTIER IN CHIRAL BRØNSTED ACID CATALYSIS DERIVED FROM CHIRAL BORATE ANIONS By Anil Kumar Gupta A DISSERTATION Submitted to Michigan State University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Chemistry 2012 ABSTRACT BOROX CATALYSIS: A NEW FRONTIER IN CHIRAL BRØNSTED ACID CATALYSIS DERIVED FROM CHIRAL BORATE ANIONS By Anil Kumar Gupta In this doctoral research, focus has been on the development of the new chiral Brønsted acid catalysts, large-scale synthesis, novel reaction methodologies and understanding their mechanisms by experimental/computational analysis. In due course of time, a pool of unprecedented chiral Brønsted acid catalysts known to be “BOROX” catalysts, were prepared and characterized by NMR spectroscopy and X-ray analysis. These Wulff’s BOROX catalysts were then employed on a variety of asymmetric reactions. In particular, the long-lasted problem of the alkyl aziridination has been solved by the development of the first multi-component aziridination reaction using the IMINO-BOROX catalyst. Out of the investigations regarding alkyl aziridination, a novel multi-component asymmetric [3+2] cycloaddition has also been developed. Additionally, an asymmetric epoxidation of aldehydes utilizing an unprecedented 1 chiral SULFOX-BOROX catalyst has been successfully realized. By means of H, 11 B NMR and computational analysis, the catalytic cycle of a Brønsted acid catalyzed reaction and its intermediates have been characterized using the Wulff aziridination reaction as the template. Interestingly, during this doctoral research, it has been found that the Brønsted acid catalysts derived from chiral borate anions are generated only upon the addition of a base. This was further supported by NMR spectroscopy, computational chemistry and X-ray analysis. Lastly, a new mechanism has been examined for the imino-aldol reaction using computational chemistry. This mechanism supports the idea of a Lewis acid assisted Brønsted acid catalyzed reaction. COPYRIGHT By ANIL KUMAR GUPTA 2012 To, My Family, Friends and Teachers v ACKNOWLEDGEMENTS A life of a graduate student is full of experiences and mine is no different. A PhD degree is a result of the hard work, the dedication, and foremost the passion for the subject. However, it is impossible to discount the fact that it is one of the perfect examples where continuous support of several people contributes to the progress of one being and the science. I am really blessed in this regard. I would start my acknowledgement by thanking Professor Wulff, my research advisor, for providing an opportunity to work under his guidance. To me, he has always been one of the most simple person, I ever met. I could not have asked for a better person to be my mentor. His intellect, vision and desire to do different from others always inspired me to work hard. When I joined the group, the senior members of the group were in the process of graduating. Hence, I had to go to Dr. Wulff for any problems I had and I was really surprised to see how patiently he used to listen and always had some valuable suggestions to offer. One of the most important things in the Wulff group is the freedom offered by him. The freedom to pursue my own ideas and dreams has allowed me to learn a lot many things in different research areas. I really liked his approach as it provides an opportunity to grow as an independent researcher and to enhance one’s creative thinking. Also, his thrust on the minute details about the experimental information has helped me to become a skillful scientist. I would like to thank him for all his teachings about life and chemistry during the last six years. Not only he taught chemistry, but also how to celebrate success and enjoy life in the graduate life. Further, he introduced me to one of the interesting additions to my life i.e. wine. connoisseur He is real wine and loves to share with others. He also introduced me to the Sex, the sparkling vi wine. I think, no words can suffice my gratitude to him for being an amazing advisor and a person. My other committee members were also quite supportive throughout my PhD life. Specially, Dr. Babak Borhan has been very helpful on many occasions. I think, it’s the ease with which he let others to interact with him makes him a different person altogether. And, he is such kind of a person who always has a solution irrespective of the problem. I learnt a lot from him thorough personal interactions and of course his spectroscopy course. His continuous support has provided much needed inspiration to keep going at crucial phases of my PhD. Hence I would like to thank him for all his inputs. Although I did not get a chance to interact a lot with Prof. Maleckza, I still found him one of the best teachers and I really enjoyed his course CEM 956. I really appreciate him for his suggestions and recommendations. Also, I would like to thanks Prof. Odom for his suggestions during my second year oral and final oral exams. Although Dr. Jackson is not in my committee, he has been really phenomenal in passing the passion for the understanding the mechanisms of organic reactions to me. I am really thankful to him. I would like to thank Dr. Baker for his smile whenever I met him in the hallway. I owe special thanks to Dr. Dan Holmes for his time during my NMR studies. He has been really nice to me all the time. I have really bugged him a lot and I dedicate all my NMR studies to him. I also thank Dr. Richard Staples for his efforts towards the determination of the structure and absolute stereochemistry of some of my compounds. Additionally, I thank Ms. Chen Lijun and Dr. Jones for the excellent service they provided at Mass facility at Michigan State University. A special thank to my friend and my collaborator Carmin Burrell. It was really fun working with her and she was phenomenal in finishing up the collaborative project in a short span of time. Also, I would like to thank Jeanne Basnight, staff in Department of vii Chemistry at Michigan State University, for her care for me. It was always refreshing to talk about many things including her grandson’s funny stories. I would like to take this opportunity to thank Dr. G. B. Bhattacharjee, my advisor in my Masters, for his teachings and guidance. Also, I would like to thanks Dr. Chad Lewis, professor at Cornell University, for being patient and giving me ample time to finish my thesis and giving me an opportunity to work with him as a postdoctoral associate. I believe that the lab environment is very important for a healthy PhD life. I was fortunate enough to be part of a wonderful group. All past group members were awesome, especially Dr. Zhenjie Lu. She taught me many things during my initial time in the group. Dr. Alex Predesus and Dr. Kostas Rampalakos were really awesome lab mates. Dr. Zhensheng Ding was always the funniest face of the group. Also, I would like to thank Dr. Gang Hu for his suggestions and ideas about research. In the current group, I interacted a lot with Dr. Li Huang and Dr. Dymtro Berbasov. We had so many fruitful and not so fruitful discussions about chemistry, life, and many other silly things. I shared some very good moments with Dr. Li Huang and found her an exceptional chemist and human being. Dr. Dymtro Berbasov is one of the few people who are immensely talented and very nice at the same time. I would like to thank him for teaching me driving and for the parties we had together. Also, I owe a special thanks to Victor Prutyanov for his valuable teachings about computational chemistry. He taught me the minute details of theoretical chemistry. I really had good time with other current group members like Hong Ren, Wenjun Zhao, Xin Zhang, Dr. Yong Guan and Dr. Nilanjana Majumdar in the group meeting and the post-group meeting parties. Hong Ren is one of the most hard working persons, I know. The smile of Wenjun Zhao is always soothing. I really like the simplicity of Xin Zhang. Dr. Yong Guan has been a very good lab mate and very friendly in nature. I am viii really grateful to all of them for making a great atmosphere in the lab. It was also wonderful to work with Dr. Mathew Vetticatt, postdoctoral associate, in the Wulff group. I would like to thank him for his help in the KIE studies and his suggestions regarding calculations. I am also thankful to Yubai Zhou and Xiaopeng Yin, new Wulff group members, for their enthusiasm. Dr. Munmun Mukherjee and Wynter E. Osminski certainly deserve special thanks. Wynter Osminski, a fun person to talk, has always been a quiet admirer of all my silly jokes. She has been a wonderful person to work with and to have long discussions. Especially, I would like to thank her for celebrating my last birthday in East Lansing and for her time during HRMS analysis. I wish her all the best for everything. In the end, I would like to thank Dr. Munmun Mukherjee for everything she did for me for last six years. We moved from Indiana University together and since then she has been always there for me. She is exceptional lab mate, a very close friend and of course, a wonderful human being. I used to have so many long discussions about chemistry and there are many inputs from her in my dissertation. In her defense talk, she mentioned that I helped her even if she did not need it. But, I can say very easily that she always helped me as I always needed her help. I was fortunate to work with Dr. María Pascual and Dr. Roberto Morán-Ramallal, postdoctoral research associates from Spain, during their brief visit. I learned a lot from them. I am also thankful to my undergraduate students Charlie Najt and Leslie Bateman for their help in my research and for the wonderful time we spent together. I am also fortunate to have lot of friends outside the Wulff Group. Dr. Aman Kulshrestha has been a long time friend and has helped on numerous occasions. Its hard to mention every occasion, yet, she was there for every time I needed her. Specifically, she gave a lot of time during my postdoctoral search. So a big thank to her for all she did for me in last six years. Also, I am thankful to my other friends, Kumar Ashtekar, Carmin Burrell, Camille Watson, Ipek ix Yapici, Tanya Berbasova, Atefeh Garzan, Roozbeh Yousefi, Arvind Jaganathan, Dr. Mercy Anyika, Dr. Rahman Saleem, Dr. Luis Mori-Quiroz, Dr. Luis Sanchez and Damith Parera for making my life pleasant by their presence. Specifically, Kumar Ashtekar helped me on many occasions, be it my car related issues or research problems. I am also thankful to him for patiently listening to my crap even if he was busy. I am sure that I am going to miss the big smile of Camille Watson. Her smile has always been the source of inspiration especially in tough times during PhD. Dr. Rahman Saleem and Dr. Luis-Mori Quiroz have also been very close friends. I would like to thank my other friends, Dr. Rupinder Sayal, Puneet Kumar, Dr. Paramita Mukherjee, Krishna Chotnerru, Dr. Kelly Telu, Dr. Abhishek Singh and Dr. Vijoya Sa for their time and help. Also, I would like to thank my friend, Sara Bano for her help and support. Additionally, I am lucky to have numerous good friends from India. Dr. Manish Singh, Abhishek Singh, Sapna Gupta, Aishwarya Kar, Soumitra Kar and Dr. Aditi Singhal, have been really nice and supportive throughout these years. Additionally, I am really thankful to my close friend, Dr. Navratna Vajpai, for helping me in every possible way whenever I needed. It would have been very difficult without his support. Last but not the least, I would like to thank my family. It’s their continuous support and encouragement that helped me to travel so far in life. I owe special thanks to my dad, Ramesh Chandra Gupta and my mom, Maya Gupta. It would not have been possible without them. My brother, Sunil Gupta and sister in law, Gudiya Gupta have been always there when it mattered most. I am also thankful to Nikhil Gupta, my younger brother, for being my best buddy and for listening to all my sorrows in difficult times. Finally, I would like to thank God for being so kind and providing a chance to interact with so many nice people during my journey so far. x     TABLE OF CONTENTS LIST OF TABLES ...................................................................................................................... xvii LIST OF FIGURES .................................................................................................................... xxii LIST OF SCHEMES ................................................................................................................ xxxii CHAPTER 1 CHIRAL BORATE ANIONS IN ASYMMETRIC BRØNSTED ACID CATALYSIS AND ASYMMETRIC COUNTERANION-DIRECTED CATALYSIS 1.1 Chiral anions in asymmetric catalysis and its different classes ................................................ 1 1.2 Chiral borate anions in asymmetric Brønsted acid catalysis (Class I and II) ........................... 9 1.2.1 An introduction to asymmetric Brønsted acid catalysis .................................................. 9 1.2.2 Chiral spiroborate anions in asymmetric Brønsted acid catalysis ................................. 15 1.2.3 Chiral fused-spiroborate anions in asymmetric Brønsted acid catalysis ....................... 20 1.2.4 Chiral boroxinate anions in asymmetric Brønsted acid catalysis: BOROX catalysis ... 23 1.3 Chiral borate anions in asymmetric counteranion-directed catalysis (Classes II, III, IV, and V) ........................................................................................................................................... 30 1.4 Miscellaneous chiral borate anions ......................................................................................... 38 1.5 Conclusions ............................................................................................................................. 43 References ............................................................................................................................... 45 CHAPTER 2 A NEW ARRAY OF BRØNSTED ACID CATALYSTS DERIVED FROM CHIRAL BORATE ANIONS 2.1 B3 or BOROX catalysts .......................................................................................................... 55 2.1.1 Imines as the base: IMINO-BOROX catalyst ................................................................ 56 2.1.1.1 B(OPh)3 as the boron source ............................................................................. 60 2.1.1.2 Other boron sources ........................................................................................... 64 2.1.1.3 Temperature studies of IMINO-BOROX catalyst 190a .................................... 70 2.1.1.4 Multiplex diversity in the generation of BOROX catalyst ................................ 73 2.1.1.5 A comparison of X-ray structure and calculated structure of BOROX catalyst 79 2.1.2 Amines as the base: AMINO-BOROX catalyst............................................................. 83 2.1.3 Pyridines and quinolines as the base: PYRIDINO- and QUINOLINO-BOROX catalyst ........................................................................................................................................ 88 2.1.4 Amides as the base: AMIDO-BOROX catalyst............................................................. 98 2.1.5 Sulfoxides as the base: SULFOX-BOROX catalyst ...................................................... 99 2.1.6 Phosphine-oxides as the base: PHOSPHINOX-BOROX catalyst ............................... 106 2.1.7 Amine-oxides as the base: AMINOX-BOROX catalyst ............................................. 111 2.1.8 Aldehydes as the base: ALDO-BOROX catalyst ........................................................ 116     xi     2.1.9 Diazo as the base: DIAZO-BOROX catalyst............................................................... 118 2.1.10 Miscellaneous bases:.................................................................................................. 121 2.2 Prediction of BOROX catalysts via computational chemistry ............................................. 122 2.3 Possibility of bench-top stable BOROX catalyst .................................................................. 124 2.3.1 Substrate induced formation of the catalyst ................................................................. 125 2.3.2 Stability of the BOROX catalyst.................................................................................. 126 2.3.2.1 Base incorporated in alcohol ............................................................................ 126 2.3.2.2 Base incorporated in the boron source ............................................................. 130 2.4 B1 catalysts ........................................................................................................................... 131 2.5 Conclusions ........................................................................................................................... 132 Appendix (Experimental)...................................................................................................... 134 References ............................................................................................................................. 167 CHAPTER 3 MECHANISTIC STUDY OF THE CATALYTIC CYCLE OF A BRØNSTED ACID CATALYZED REACTION UTILIZING AZIRIDINATION AS THE TEMPLATE 3.1  Introduction ........................................................................................................................... 172   3.2  Characterization of the various stages of the catalytic cycle of a Brønsted acid catalyzed aziridination reaction ............................................................................................................ 173   3.2.1  Evidence for IMINO-BOROX complex ...................................................................... 176   3.2.2  Evidence for an AZIRIDINO-BOROX complex......................................................... 181   1 3.2.2.1  Monitoring the reaction by H NMR spectroscopy ......................................... 181   3.2.2.2  Initial attempts towards the generation of AZIRIDINO-BOROX complex using aziridine 114a................................................................................................... 187   3.2.2.3  First glimpse of an AZIRIDINO-BOROX complex using aziridine 114o ...... 189   3.2.2.4  Temperature studies of 239o and recovery of aziridine 114o .......................... 198   3.2.2.5  Dependence of the formation of AZIRIDINO-BOROX 239o on various protocols........................................................................................................... 203   3.2.2.6  Direct generation of AZIRIDINO-BOROX at room temperature ................... 205   3.2.2.7  Generation of AZIRIDINO-BOROX complexes from other alkyl aziridines . 208   3.2.3  Equilibrium studies ...................................................................................................... 211   3.2.4  Probing path II of the catalytic cycle ........................................................................... 218   3.2.5  Termination of the catalytic cycle of the aziridination reaction .................................. 223   3.2.6  Possibility of ‘free’ BOROX complex 23-H ............................................................... 229   3.3  Conclusions ........................................................................................................................... 233   Appendix (Experimental)...................................................................................................... 235 References ............................................................................................................................. 265   CHAPTER 4 CAN “FREE” PROTON BE THE COUNTER CATION OF CHIRAL BORATE ANIONS IN THE ABSENCE OFA BASE IN NON-AQUEOUS MEDIA 4.1  Introduction ........................................................................................................................... 267       xii     4.2  The case of the chiral spiroborates 20-H and 21-H .............................................................. 270   4.3  The case of the chiral fused-spiroborate 22-H ...................................................................... 285   4.4  The case of the achiral tetraphenoxyborate 262-H ............................................................... 295   4.5  Mode of catalysis: Lewis acid catalysis verses Brønsted acid catalysis ............................... 303   4.5.1  Asymmetric imino-aldol reaction and heteroatom Diels-Alder reactions catalyzed by 20-H ............................................................................................................................. 304   4.5.2  Asymmetric Pictet-Spengler reaction catalyzed by 20-H and 21-H. ........................... 305   4.5.3  Asymmetric Diels-Alder reaction catalyzed by 22-H. ................................................. 309   4.6  Conclusions ........................................................................................................................... 311   Appendix (Experimental)...................................................................................................... 313   References ............................................................................................................................. 327   CHAPTER 5 AN EXAMINATION OF VARIOUS CHIRAL DIOLS AS LIGANDS FOR ASYMMETRIC AZIRIDINATION REACTION AND THEIR IMPACT ON THE STRUCTURE OF THE BOROX CATALYST 5.1  Introduction ........................................................................................................................... 330   5.2  ISOVAPOL: a new entry to the family of vaulted biaryl ligands......................................... 331   5.2.1  Rational design of ISOVAPOL 197 ............................................................................ 332   5.2.2  Preparation of ISOVAPOL 197 ................................................................................... 335   5.2.3  Asymmetric aziridination reaction catalyzed by BOROX catalyst derived from ISOVAPOL .................................................................................................................. 338   5.2.4  NMR investigation of the BOROX catalysts 191a and 290a ...................................... 344   5.2.5  Calculated structure of BOROX catalyst 290a derived from ISOVAPOL (S)-197 .... 348   5.2.6  X-Ray crystal structure of ISOVAPOL (S)-197 and VANOL (R)-59 ......................... 349   5.3  BINOL and its derivatives .................................................................................................... 352   5.3.1  Preparation of BINOL derivatives ............................................................................... 361   5.3.2  Screening of BINOL and its derivatives on aziridination reaction .............................. 363   5.3.3  NMR studies on substrate induced BOROX catalyst formation from BINOL and BINOL derivatives by imine 209h .............................................................................. 368   5.3.4  Calculated structure of BOROX catalyst 323a derived from 3,3ʹ′-Ph2-BINOL 56a ... 384   5.4  Generation of BOROX catalyst 329 with BINOL 55 using DMSO as the base. ................. 386   5.5  TADDOL and its effect on the Wulff catalytic asymmetric aziridination reaction .............. 389   5.6  Conclusions ........................................................................................................................... 392   Appendix (Experimental)...................................................................................................... 394 References ............................................................................................................................. 439 CHAPTER 6 DIRECT IMINO-BOROX CATALYSIS: ASYMMETRIC AZIRIDINATION, [3+2] CYCLOADDITION, UGI REACTION AND KINETIC RESOLUTION OF IMINES 6.1  Catalytic asymmetric one-pot aziridination .......................................................................... 445   6.2  Racemic aziridination with various Lewis/Brønsted acids ................................................... 460       xiii     6.3  Catalytic asymmetric [3+2] cycloaddition ............................................................................ 461   6.4  Attempts towards catalytic asymmetric Ugi 3CR, Ugi-type 2CR and Ugi-type 3CR. ......... 472   6.4.1  Attempts towards catalytic asymmetric Ugi -3CR ....................................................... 474   6.4.2  Attempts towards catalytic asymmetric Ugi-type 2CR and Ugi-type 3CR .................. 476   6.5  Attempts towards catalytic asymmetric Passerini reaction ................................................... 480   6.6  Attempts towards kinetic resolution of imines ..................................................................... 481   6.7  Conclusions ........................................................................................................................... 487   Appendix (Experimental)...................................................................................................... 489 References ............................................................................................................................. 540   CHAPTER 7 INDIRECT IMINO-BOROX CATALYSIS: MULTICOMPONENT CATALYTIC ASYMMETRIC AZIRIDINATION (MCAZ) 7.1  Introduction ........................................................................................................................... 545   7.2 The real need for a true multicomponent aziridination reaction ........................................... 548   7.3  Can any or all the components of the proposed mcaz reaction generate the boroxinate catalyst?................................................................................................................................. 551   7.4  Possible complications for the five-component catalyst assembly/aziridination.................. 554   7.5  Optimization and substrate scope of aryl substrates in the MCAZ reaction ......................... 556   7.5.1  Different protocols for the multicomponent cis-aziridination (MCAZ) ...................... 556   7.5.2  Catalyst loading, N-substituent and ligand screening .................................................. 559   7.5.3  Substrate scope for aromatic aldehydes ....................................................................... 562   7.6  Optimization and substrate scope of alkyl substrates in the MCAZ reaction ....................... 565   7.6.1  Initial optimization using n-butanal and n-hexadecanal .............................................. 566   7.6.2  Substrate scope for aliphatic aldehydes ....................................................................... 569   7.7  Mechanistic study towards the five-component catalyst assembly/catalytic asymmetric aziridination .......................................................................................................................... 571   7.7.1  Effects of the order of addition on the multicomponent cis-aziridination ................... 573   7.7.2  Mode of catalysis and sequence of the final steps in the five-component catalyst assembly/aziridination .......................................................................................................... 576   7.8  Multiplex diversity: evolution of a seven-component catalyst assembly/catalytic asymmetric aziridination .......................................................................................................................... 584   7.8.1  Using BH3•Me2S as the boron source ......................................................................... 585   7.8.2  Using BH3•THF as the boron source ........................................................................... 588   7.9  Initial attempts towards a multicomponent trans-aziridination reaction .............................. 591   7.10  Determination of absolute stereochemistry of cis- and trans-aziridines using circular dichroism ............................................................................................................................. 594   7.11  Gram scale catalysis and large scale synthesis ................................................................... 599   7.12  Application of multicomponent aziridination reaction in organic synthesis ...................... 601   7.13  Future applications: multicomponent intra-molecular aziridination reaction ..................... 603   7.14  Conclusions ......................................................................................................................... 605   Appendix (Experimental).................................................................................................... 608 References ........................................................................................................................... 682     xiv     CHAPTER 8 SULFOX-BOROX CATALYSIS: CATALYTIC ASYMMETRIC EPOXIDATION OF ALDEHYDES 8.1  Introduction ........................................................................................................................... 686   8.2  Previous approaches towards catalytic asymmetric synthesis of epoxides........................... 687   8.3  Initial optimization of catalytic asymmetric epoxidation of aldehydes ................................ 693   8.4  Substrate scope...................................................................................................................... 703   8.5  Determination of absolute stereochemistry of epoxides ....................................................... 707   8.5.1  Via optical rotation ....................................................................................................... 707   8.5.2  Via X-ray structure ....................................................................................................... 708   8.5.3  Via circular dichroism .................................................................................................. 708   8.6  Mechanistic study towards the identification of the actual catalyst in epoxidation reaction 713   8.6.1  Investigating non-covalent interactions ....................................................................... 714   8.6.2  Screening of a different catalytic system ..................................................................... 716   8.6.3  Catalytic asymmetric epoxidation reaction with and without dmso ............................ 717   8.6.4  Temperature study ....................................................................................................... 719   8.6.5 NMR study ................................................................................................................... 720   8.6.6  Calculated structures of boroxinate catalysts from dmso and diazoacetamides .......... 724   8.6.7  Possible rationale for the observed stereochemical outcome of asymmetric epoxidation reaction ......................................................................................................................... 727   8.6.7.1  With DMSO ..................................................................................................... 727   8.6.7.2  Without DMSO ................................................................................................ 728   8.6.7.3  Lewis acid catalysis ......................................................................................... 729   8.6.8  Kinetic isotopic effect studies of asymmetric epoxidation reaction ............................ 730   8.7  Gram scale catalysis and large scale synthesis ..................................................................... 733   8.8  Conclusions ........................................................................................................................... 736   Appendix (Experimental)...................................................................................................... 738   References ............................................................................................................................. 786   CHAPTER 9 IS IT REALLY A LEWIS ACID CATALYED ASYMMETRIC IMINO-ALDOL REACTION? - PROBING THE NATURE OF THE ACTIVE SITE VIA NMR SPECTROSCOPY, COMPUTATIONAL STUDIES AND SUBSTRATE AND CATALYST MODIFICATIONS 9.1  Introduction ........................................................................................................................... 789   9.2  Proposed catalytic cycle of imino-aldol reaction .................................................................. 792   9.3  NMR experiments: ................................................................................................................ 796   9.4  DFT calculations ................................................................................................................... 797   9.4.1  Catalytic cycle I verses catalytic cycle II ..................................................................... 798   9.4.2  Various transition states for catalytic cycle II .............................................................. 803   9.5  Catalyst modifications .......................................................................................................... 808   9.6  Imine modifications .............................................................................................................. 810   9.7  Examination of the catalytic cycle III for (S)-VAPOL 58 .................................................... 815   9.8  Case of BINOL derivative 459 ............................................................................................. 816       xv     9.9  Conclusions ........................................................................................................................... 828   Appendix (Experimental)...................................................................................................... 830   References ............................................................................................................................. 836       xvi     LIST OF TABLES   Table 1.1 Different classes of catalysis involving chiral counter-anions ....................................... 2   Table 1.2 The addition of N-methyl indole 145 to an iminium ion 146 ...................................... 31   Table 1.3 The ring-opening of an aziridinium ion 150 with benzylamine 151 ............................ 32   Table 1.4 Asymmetric aziridination reaction with spiroborate ion-pair 147e ............................. 34   Table 1.5 Asymmetric cyclopropanation reaction with spiroborate ion-pair 147e ...................... 35   Table 1.6 Asymmetric cyclopropanation with spiroborate ion-pair 166 ..................................... 35   Table 1.7 Asymmetric hydrogenation with spiroborate ion-pair 147d ........................................ 38   Table 2.1 Asymmetric aziridination with different boron sources and (S)-VAPOL 58 .............. 64   Table 2.2 NMR Analysis of mixtures of (S)-VAPOL 58, imine 111a and various boron sources ...................................................................................................................................... 68   Table 2.3 Catalytic asymmetric aziridination with different alcohols and (S)-VAPOL ............. 74   Table 2.4 Catalytic asymmetric aziridination with different ligands .......................................... 75   Table 2.5 Catalytic asymmetric aziridination with imines from different protecting groups ..... 77   Table 2.6 Comparison of distances in computed structure 190a using different levels of theories ...................................................................................................................................... 82   Table 2.7 NMR Analysis of a mixture of (S)-VAPOL, B(OPh)3 and amines 126 as bases ....... 83       xvii     Table 2.8 Comparison of distances in computed structure 215c using different levels of theories ...................................................................................................................................... 88   Table 2.9 NMR Analysis of a mixture of (S)-VAPOL, B(OPh)3 and pyridine derivatives, pyrrole, imidazole and quinoline derivatives as bases .............................................. 91   Table 2.10 NMR Analysis of a mixture of (S)-VAPOL, B(OPh)3 and sulfoxides as bases ....... 99   Table 2.11 NMR Analysis of a mixture of (S)-VAPOL, B(OPh)3 and phosphine-oxides as bases ................................................................................................................................. 107   Table 2.12 NMR Analysis of a mixture of (S)-VAPOL, B(OPh)3 and amine-oxides as bases 112   Table 2.13 Crystal data and structure refinement for BOROX complex 217b: ......................... 164   Table 2.14 Hydrogen bonds [Å and °] ....................................................................................... 165   1 Table 3.1 Monitoring aziridination reaction by H NMR spectroscopy ................................... 182   Table 3.2 Generation of AZIRIDINO-BOROX 239o with different boron sources ................ 204   Table 5.1 Screening of ISOVAPOL 197 with different N-protected imines ............................. 339   Table 5.2 AZ reaction with imines 78 using (S)-ISOVAPOL and various solvents .................. 341   Table 5.3 AZ reaction with imines 78 using (S)-ISOVAPOL AND (R)-VANOL .................... 342   Table 5.4 AZ reaction with the catalysts derived from various ligands (Chen’s work) ........... 360   Table 5.5 Asymmetric aziridination with the catalysts derived from various BINOL derivatives .................................................................................................................................... 364       xviii     Table 5.6 Aziridination with different N-protected Imines using (R)-55 and (R)-56a as ligands .................................................................................................................................... 367   Table 6.1 One-pot aziridination reaction of N-DAM imines 110 using procedure II ................ 450   Table 6.2 Asymmetric Aziridination with Aryl DAM imines 110 ............................................ 455   Table 6.3 Asymmetric Aziridination with Alkyl DAM imines 110 .......................................... 458   Table 6.4 Effect of various additives on the aziridination reaction ........................................... 459   Table 6.5 Racemic Aziridination with various Lewis/Brønsted acids ....................................... 460   Table 6.6 Initial optimization of the [3+2] cycloaddition reaction ............................................ 469   Table 6.7 Preliminary results towards the Ugi-3CR reaction .................................................... 475   Table 6.8 Preliminary results towards the Ugi-2CR and Ugi-3CR ............................................ 477   Table 6.9 Matched and mis-matched aziridinations of the phenylneopentyl imine (S)-378...... 482   Table 6.10 Kinetic resolution of phenylneopentyl imine rac-378 furnishing amine (S)-384 .... 485   Table 6.11 Kinetic resolution of phenylneopentyl imine rac-378 furnishing amine (S)-385 .... 486   Table 7.1 Protocol dependence of the multicomponent aziridination ....................................... 558   Table 7.2 Catalyst Loading, N-substituent and Ligand Screening ............................................ 560   Table 7.3 Multicomponent aziridination of aryl and hetero-aryl aldehydes .............................. 562   Table 7.4 Optimization of the multicomponent aziridination reaction of n-butanal ................. 566       xix     Table 7.5 Optimization of the multicomponent aziridination reaction of n-hexadecanal 127p 568   Table 7.6 Multicomponent aziridination of alkyl aldehydes...................................................... 570   Table 7.7 Effect of order of addition on the multi-component aziridination reaction .............. 573   Table 7.8 Multicomponent aziridination with a deficiency of benzaldehyde ........................... 579   Table 7.9 Aziridination reaction of pre-formed imine 78a with added bases ........................... 582   Table 7.10 Multicomponent aziridination using BH3•Me2S as the boron source .................... 587   Table 7.11 Multicomponent aziridination using BH3•THF as the boron source ...................... 590   Table 7.12 Multicomponent trans-aziridination of aldehydes .................................................. 592   Table 8.1 Initial screening of various BOROX catalysts for asymmetric epoxidation reaction 694   Table 8.2 Initial screening of various diazoacetamides for asymmetric epoxidation ................ 696   Table 8.3 Screening of diazoacetamides at different concentrations, solvents and temperatures .................................................................................................................................... 698   Table 8.4 Varying the equivalents of aldehydes and boron sources and sequence of events .... 700   Table 8.5 Screening of the one-pot procedure for asymmetric epoxidation .............................. 702   Table 8.6 Catalytic asymmetric epoxidation of aryl and alkyl aldehydes ................................. 704   Table 8.7 N-H verses N-Me and O in the catalytic asymmetric epoxidation reaction .............. 715   Table 8.8 Catalytic asymmetric epoxidation with and without SULFOX-BOROX catalyst..... 717       xx     Table 8.9 Screening of various temperatures for asymmetric epoxidation ................................ 719   Table 9.1 Imino-aldol reaction between imine 457/458 with ketene acetal 460 using various ligands. ...................................................................................................................... 791   Table 9.2 Imino-aldol reaction between imine 457a with keten acetal 460 using various ligands. ................................................................................................................................... 810       xxi     LIST OF FIGURES   Figure 1.1 Chiral counter-anions used in asymmetric catalysis (blue: asymmetric Brønsted acid catalysis; red: asymmetric counteranion-directed catalysis). For interpretation of the references to color in this and all other figures, the reader is referred to the electronic version of this dissertation. ........................................................................................... 3   Figure 1.2 Chiral borate anions used in (A) asymmetric Brønsted acid catalysis (B) asymmetric counteranion-directed catalysis ..................................................................................... 7   Figure 1.3 A list of various (A) chiral phosphoric acids, phosphorodiamidic acid, phosphoramides, imidodiphosphoric acids, disulfonamides, carboxylic and sulfonic acids. (B) chiral thioureas and chiral diols.................................................................. 11   Figure 1.4 Chiral borate ion-pairs used for resolution of racemic compounds............................ 39   Figure 1.5 Chiral borate ion-pairs used as chiral NMR shift reagents. ........................................ 40   Figure 1.6 Chiral borate ion-pairs used as chiral ligands. ............................................................ 40   Figure 1.7 Chiral borate anions existing in nature ....................................................................... 42   Figure 2.1 Brønsted acid catalysts derived from chiral borate anions and imines as the base ... 55   Figure 2.2 Generation of the BOROX catalysts 190a and 191a .................................................. 59   Figure 2.3 Imine induced boroxinate catalyst formation using commercial B(OPh)3 ................ 61   Figure 2.4 Imine induced boroxinate catalyst formation using other boron sources. ................. 66   Figure 2.5 Generation of a BOROX catalyst from (A) trialkyl/triaryl borates 187 (B) boroxines 191 (C) B(OH)3 193 (D) BH3•Me2S complex 192a ................................................ 70       xxii     1 Figure 2.6 H NMR spectra of the bay region of 190a in CDCl3. ............................................. 71   Figure 2.7 Imine induced boroxinate catalyst formation (See Table 2.5 for structures of different imines used) ............................................................................................................... 78   Figure 2.8 Calculated structure of IMINO-BOROX catalyst 190a using Gaussian ʹ′03. ............ 81   Figure 2.9 Amine induced boroxinate catalyst formation............................................................ 84   Figure 2.10 Calculated structure of AMINO-BOROX catalyst 215c (derived from MEDAM amine 126c) using Gaussian ʹ′03 ............................................................................. 87   Figure 2.11 Pyridine induced boroxinate catalyst formation. ..................................................... 89   Figure 2.12 Pyridine and quinoline derivatives in the induction of boroxinate catalyst formation. ................................................................................................................................ 92   Figure 2.13 Solid state structure of the LUTIDINO-BOROX 217b visualized by the Mercury Program.................................................................................................................... 95   Figure 2.14 Amide induced boroxinate catalyst formation.......................................................... 98   Figure 2.15 Sulfoxide induced boroxinate catalyst formation. ................................................. 100   Figure 2.16 Calculated structure of SULFOX-BOROX catalysts 222a and 222b using Gaussian ʹ′03. ......................................................................................................................... 105   Figure 2.17 Phosphine-oxide induced boroxinate catalyst formation........................................ 108   Figure 2.18 Amine-oxide induced boroxinate catalyst formation ............................................. 113   Figure 2.19 Aldehyde induced boroxinate catalyst formation ................................................... 117       xxiii     Figure 2.20 Diazo induced boroxinate catalyst formation.. ....................................................... 119   Figure 2.21 Miscellaneous bases induced boroxinate catalyst formation .................................. 121   Figure 2.22 Calculated structures of boroxinates (A) 228b (base = PhCHO 127a), (B) 217d (base = pyrrole 216d), (C) 222h (base = Me2SO2 221h), (D) 222i (base = (CH2)4SO2 221i), (E) 224c (base = (BuO)3PO 223c) and (F) 233b (base = THF 232b) using Gaussian ʹ′03....................................................................................... 123   Figure 2.23 Bases (with pre-installed alcohols) induced boroxinate catalyst formation ........... 126   Figure 2.24 Aniline induced boroxinate catalyst formation ...................................................... 129   Figure 2.25 Attempt to generate dimer catalyst 238. ................................................................. 131   Figure 2.26 The Schlenk flask was prepared from a single-necked 25 mL pear-shaped flask that had its 14/20 glass joint replaced with a high vacuum threaded Teflon valve. ..... 137   Figure 2.27 Natural charges on the oxygen atoms of the boroxinate anion............................... 163 Figure 3.1 Chemical shift of the bay proton of (S)-VAPOL 58 and its different derivatives .... 177   Figure 3.2 Imine induced boroxinate catalyst formation ........................................................... 179   1 Figure 3.3 H NMR spectra in CDCl3 with Ph3CH as internal standard .................................. 183   Figure 3.4 Aziridine 114a induced boroxinate catalyst formation ............................................ 188   Figure 3.5 Aziridine 114o induced boroxinate catalyst formation ............................................ 189   Figure 3.6 Calculated structure of AZIRIDINO-BOROX complex 239o using Gaussian ʹ′03 .. 195   1 Figure 3.7 H NMR spectra of the bay region of boroxinate 239o in d8-toluene ..................... 199       xxiv     Figure 3.8 Treatment of 239o with water .................................................................................. 201   Figure 3.9 Direct generation of aziridine-boroxinate complex at room temperature ................ 205   Figure 3.10 Examination of alkyl aziridines for boroxinate formation ..................................... 208   Figure 3.11 Aziridine induced boroxinate formation and its subsequent dilution studies ........ 211 Figure 3.12 Aziridine induced boroxinate formation and its behavior with excess aziridine ... 214   Figure 3.13 (A) Equilibrium between boroxinate 239o, (S)-VAPOL 58, aziridine 114o and various borate species. (B) Plot corresponding to Figure 3.11 (C) Plot corresponding to Figure 3.12 ............................................................................... 217   Figure 3.14 Probing Path II of the catalytic cycle (part i).......................................................... 219   Figure 3.15 Probing Path II of the catalytic cycle (part ii) ........................................................ 221   Figure 3.16 Probing path X for the generation of the adduct 230 ............................................. 225   Figure 3.17 Probing path Y for the generation of 230 ............................................................... 227   Figure 3.18 (A) Calculated structure of BOROX anion 23 (B) Calculated structure of the neutral BOROX catalyst 23-Ha resulting from protonation of 23 on O1. (C) Calculated structure of the neutral BOROX catalyst 23-Hb resulting from protonation of 23 on O2. ......................................................................................................................... 229   Figure 3.19 Design of the experiment to observe the free neutral BOROX 23-H ..................... 231   Figure 4.1 (A) Free BOROX 23-H (B) Spiroborates 20-H and 21-H and Fused-spiroborate 22-H ................................................................................................................................. 268   Figure 4.2 11 B NMR chemical shifts of B(OPh)3 187a, triphenoxy boroxine 191a, various achiral and chiral borate anions. .............................................................................. 269       xxv     Figure 4.3 Calculated structures of 20-H, 72 and 72ʹ′ obtained using Gaussian ʹ′03 at B3LYP/631g* level of theory.. ............................................................................................... 274   Figure 4.4 NMR Analysis of a mixture of (R)-55 with B(OPh)3 and imine 78a or DMAP ...... 277   Figure 4.5 Bronsted acid 74a and Brønsted acid assisted Lewis acid 71a or 73a (imine = 78a) ................................................................................................................................. 280   Figure 4.6 Schematic drawing of imine (S)-139a, Yamamoto’s structure 248 and Gang Hu’s structure 249 ............................................................................................................ 281   Figure 4.7 Calculated structures of 251 and 251-H obtained using Gaussian ʹ′03 at B3LYP/631g* level of theory. ................................................................................................ 284   Figure 4.8 Calculated structures of 22, 91 and 91ʹ′obtained using Gaussian ʹ′03 at B3LYP/6-31g* level of theory .......................................................................................................... 288   Figure 4.9 NMR Analysis of a mixture of 89 with various boron sources and imine 78a. ....... 291   Figure 4.10 Brønsted acid 92 and Brønsted acid assisted Lewis acid 90 .................................. 295   Figure 4.11 (A) tetraphenoxyborate anion 262 (B) proposed structure for 262-H (C) common tetraphenoxyborates 244 (D) piperdine-B(OPh)3 244dʹ′ (Lewis acid-Lewis base + – adduct) (E) proposed structure for [imine-H] [B(OPh)4] complex 263/264...... 296   Figure 4.12 Calculated structures of 262 and 262-H obtained using Gaussian ʹ′03 at B3LYP/631g* level of theory ............................................................................................... 297   Figure 4.13 NMR Analysis of a mixture of PhOH 194a with B(OPh)3 187a and DMAP 216c. ............................................................................................................................... 299   Figure 4.14 Solid state structure of the tetraphenoxyborate 244e.............................................. 302       xxvi     Figure 4.15 (A) Asymmetric imino-aldol reaction of imine 78a catalyzed by 20-H (B) Diagrammatic representation of TS-263 and TS-264 for BA and BLA type mechanism respectively. ........................................................................................ 305   Figure 4.16 (A) Asymmetric Pictet-Spengler reaction of nitrone 83a catalyzed by 20-H (B) Division of layers for the ONIOM(B3LYP/6-31g**:AM1) level of calculations (C) 3D structures and relative energies of TS-S-265 and TS-R-265 for BA type mechanism. The relative energies given in italics are the energies computed from the full DFT B3LYP/6-31g* (D) 3D structures and relative energies of TS-S-266 and TS-R-266 for BLA type mechanism. .............................................................. 306   Figure 4.17 (A) Asymmetric Diels-alder reaction of 94a catalyzed by 22-H (B) Diagrammatic representation of TS-267 and TS-268 for BA and BLA type mechanism respectively. ........................................................................................................... 310   Figure 5.1 (A) Different chiral diols from vaulted biaryl ligands. (B) Different BOROX catalysts derived from VAPOL and VANOL. (C) Diagrammatic representation of X-ray structure of the BOROX catalyst 190a. ........................................................ 333   Figure 5.2 (A) Possible orientation of the imine over the boroxinate core. (B) Rational design of the new vaulted ligand ISOVAPOL 197 ................................................................. 334   Figure 5.3 Treatment of (S)-59 and (S)-197 with B(OPh)3 and imine 111a .............................. 345   Figure 5.4 Calculated structure of IMINO-BOROX catalyst 290a using Gaussian ʹ′03 ............ 349   Figure 5.5 (A) ORTEP drawing of X-ray crystal structure of (S)-197 and ORTEP drawing of crystal packing of (S)-197 along b-axis. (B) ORTEP drawing of X-ray crystal structure of all three conformations (in the unit cell) of (R)-59 and ORTEP drawing of crystal packing of (R)-59 along b-axis. ................................................................ 350   Figure 5.6 (A) Vaulted biaryl ligands (B) Linear biaryl ligands (C) Location of major and minor groove in vaulted and linear biaryl ligands. .............................................................. 353   Figure 5.7 Treatment of (R)-55 and (R)-56a with commercial B(OPh)3 and imine 111h ......... 370       xxvii     Figure 5.8 Treatment of (R)-56e and (R)-56i with commercial B(OPh)3 and imine 111h ........ 376   Figure 5.9 Treatment of (R)-56f and (R)-56j with commercial B(OPh)3 and imine 111h ........ 379   Figure 5.10 Treatment of (R)-53 and commercial B(OPh)3 and imine 111h ............................. 382   Figure 5.11 Calculated structure of IMINO-BOROX catalyst 323a using Gaussian ʹ′03 .......... 385   Figure 5.12 Treatment of BINOL (R)-55 and DMSO with different boron sources ................. 387   Figure 5.13 Treatment of (R,R)-61a and commercial B(OPh)3 with imine 111h...................... 390   Figure 7.1 (A) Catalytic asymmetric aziridination of imines. (B) three-component catalytic asymmetric aziridination. (C) five-component catalyst assembly/catalytic asymmetric aziridination. ........................................................................................ 546   Figure 7.2 (A) Biologically important alkyl aziridines. 387: antimicrobial activity against Grampositive bacteria. 388 and 389: cytotoxic and antimicrobial activity. 390: inhibitor of arachidonate epoxygenase. (B) Sphinganine family (391-394) of biologically important compounds resulting from the ring-opening from alkyl aziridines. ....... 550   Figure 7.3 Chemoselectivity in the five-component catalyst assembly/catalytic asymmetric aziridination ........................................................................................................... 572   Figure 7.4 Products from the reaction with procedure VIII in Table 7.7 .................................. 576   Figure 7.5 Time course of events in the five-component catalyst assembly/aziridination reaction. (A) Time zero. (B) Assembly of AMINO-BOROX 215a/215b. (C) Start of formation of imine 78/111 (78a/111a when R = Ph) in presence of AMINO-BOROX 215a/215b. (D) Formation of IMINO-BOROX catalyst 188/190 (188a/190a when R = Ph). (E) Catalytic asymmetric aziridination. ......................................................... 577   Figure 7.6 Determination of absolute stereochemistry of cis-aziridines 124 and 130. (A) Observed ECCD amplitudes for chiral cis-aziridines. All measurements were     xxviii     performed with 1µM tweezer in hexanes at 0 ºC. (B) Proposed mnemonic explaining the signs of the observed ECCD signals. ............................................. 595   Figure 7.7 Determination of absolute stereochemistry of trans-aziridines 125, 125ʹ′, 129 and 400. (A) Observed ECCD amplitudes for chiral trans-aziridines. All measurements were performed with 1µM tweezer in hexanes at 0 ºC. (B) Proposed mnemonic explaining the signs of the observed ECCD signals. ............................................... 597   Figure 8.1 ORTEP drawing of cis-epoxides (A) (S,S)-135g and (B) (S,S)-435a ...................... 708   Figure 8.2 Determination of absolute stereochemistry of cis-epoxides 135, 426a and 436a .... 709   Figure 8.3 Determination of absolute stereochemistry of trans-epoxide (R,S)-135g ................ 712   Figure 8.4 DMSO 221a and diazoacetamide 128a induced boroxinate formation ................... 721   Figure 8.5 Calculated structure of SULFOX-BOROX catalyst 432, DIAZO-BOROX catalyst 448a and 448ʹ′a using Gaussian ʹ′03 ......................................................................... 724   Figure 8.6 Proposed models (I and II) for the mechanisms involving (S)-SULFOX-BOROX catalyst (derived from (S)-VANOL) leading to (A) cis-epoxide (B) trans-epoxide 728   Figure 8.7 Proposed model III for the mechanism involving (S)-DIAZO-BOROX catalyst (derived from (S)-VANOL) leading to both cis-epoxide and trans-epoxide. ......... 729   Figure 8.8 Proposed model IV for the mechanism involving chiral Lewis catalyst (derived from (S)-VANOL) leading to both cis-epoxide and trans-epoxide. ................................ 730   Figure 9.1 Ligands and imines used in the imino-aldol reaction. .............................................. 790   Figure 9.2 Division of layers for the ONIOM calculations ONIOM (B3LYP/LanL2DZ:HF/ STO-3G) and ONIOM(BHandHLYP/DGDZVP:HF/STO-3G) level. ................... 799       xxix     Figure 9.3 Calculated 3D structures and relative energies of the imine-catalyst complexes 466a and 470a at ONIOM(B3LYP/LanL2DZ:HF/STO-3G) level and ONIOM (BHandHLYP/DGDZVP:HF/STO-3G) level. .......................................................... 800   Figure 9.4 Free Energy diagram for the transition states TS0-477-Si and TS1-478-Si at ONIOM (B3LYP/LanL2DZ:HF/STO-3G) level. Energy in parenthesis is enthalpy............. 802   Figure 9.5 Calculated 3D structures of the TS0-477-Si and TS1-478-Si at ONIOM (B3LYP /LanL2DZ:HF/STO-3G) level. ................................................................................ 803   Figure 9.6 (A) Different conformations and orientations of silyl ketene acetal 460 used for calculations. (B) Calculated 3D structures and relative free energies of TS1-478 to TS4-481 at ONIOM(BHandHLYP/DGDZVP:HF/STO-3G) level. ........................ 804   Figure 9.7 Various ligands used for imino-aldol reaction. ........................................................ 809   Figure 9.8 Calculated 3D structures and relative free energies of (A) TS-483-Si and (B) TS-483Re at ONIOM(BHandHLYP/DGDZVP:HF/STO-3G) level. ................................... 811   Figure 9.9 Free Energy diagram of transition states for imines 457a and 458a at ONIOM (BHandHLYP/DGDZVP:HF/STO-3G) level for catalytic cycle II. Energy in parenthesis is enthalpy............................................................................................. 814   Figure 9.10 Calculated 3D structures and relative free energies of TS-484-Si and TS-484-Re at ONIOM(BHandHLYP/DGDZVP:HF/STO-3G) level. ......................................... 815   Figure 9.11 Division of layers for the ONIOM calculations ONIOM(B3LYP/LanL2DZ: HF/ STO-3G) and ONIOM(B3LYP/DGDZVP:B3LYP/LanL2MB) level. ................. 818   Figure 9.12 (A) Different conformations and orientations of silyl ketene acetal 460 used for calculations. (B) Calculated 3D structures and relative free energies of TS1-485 to TS4-488 at ONIOM(B3LYP/LanL2DZ:HF/STO-3G) level. ................................ 820   Figure 9.13 Calculated relative free energies of TS1-485-Si, TS1-485-Re, TS3-487-Si and TS3487-Re, at ONIOM(B3LYP/DGDZVP: B3LYP/LanL2MB) level. ...................... 822       xxx     Figure 9.14 (A) Different conformations and orientations of silyl ketene acetal 460 used for calculations. (B) Calculated 3D structures and relative free energies of TS1-489 to TS4-492 at ONIOM(B3LYP/LanL2DZ:HF/STO-3G) level ................................. 824   Figure 9.15 (A) Calculated relative free energies of TS1-489-Si, TS1-489-Re, TS3-491-Si and TS3-491-Re, at ONIOM(B3LYP/DGDZVP:B3LYP/LanL2MB) level. (B) Calculated 3D structures and relative free energies of TS1-489-Si and TS3-491-Re at ONIOM(B3LYP/DGDZVP:B3LYP/LanL2MB) level. ..................................... 826       xxxi     LIST OF SCHEMES   Scheme 1.1 Brønsted acid catalysis verses asymmetric counteranion-directed catalysis ............ 14   Scheme 1.2 Different proposals about catalytic activity of 20-H (LB = Lewis base).................. 16   Scheme 1.3 Asymmetric imino-aldol reaction catalyzed by 20-H ............................................... 17   Scheme 1.4 Asymmetric heteroatom Diels-Alder reaction catalyzed by 20-H or 74 .................. 18   Scheme 1.5 Asymmetric Pictet-Spengler reaction catalyzed by 20-H or 21-H ........................... 19   Scheme 1.6 Asymmetric aziridination reaction catalyzed by (R,R)-74a...................................... 19   Scheme 1.7 Proposed catalytic activity of 22-H .......................................................................... 20   Scheme 1.8 Asymmetric Diels-Alder reaction of dienes and enals catalyzed by (A) 22-H (B) 98100 ............................................................................................................................. 21   Scheme 1.9 Formal [4+3] cycloaddition catalyzed by 22-H ........................................................ 22   Scheme 1.10 Asymmetric Diels-Alder reaction of dienes and alkynals catalyzed by 22-H or 9822   Scheme 1.11 Asymmetric aziridination reaction catalyzed by (R)-92a ....................................... 23   Scheme 1.12 Generation of BOROX catalyst 104 and 105 ......................................................... 24   Scheme 1.13 The Wulff asymmetric cis-aziridination reaction ................................................... 25   Scheme 1.14 The Wulff asymmetric trans-aziridination reaction ............................................... 26   Scheme 1.15 Asymmetric multicomponent aziridination reaction catalyzed by 104a or 105a ... 27       xxxii     Scheme 1.16 Asymmetric aza Diels-Alder reaction of imine and Danishefsky diene 80 ............ 28   Scheme 1.17 Asymmetric aza-Cope rearrangement catalyzed by 105a ...................................... 28   Scheme 1.18 Asymmetric [3+2] cycloaddition reaction catalyzed by BOROX catalyst 104a .... 29   Scheme 1.19 Asymmetric epoxidation reaction catalyzed by BOROX catalyst 105d ................ 29   Scheme 1.20 Catalytic asymmetric reduction of quinolines ........................................................ 29   Scheme 1.21 Double stereodifferentiation in catalytic asymmetric aziridination ........................ 30   Scheme 1.22 The ring-opening of an aziridinium ion 150 and 154 with catalysts 147d and 153 33   Scheme 1.23 Asymmetric cyclopropanation reaction with spiroborate ion-pair 166b ................ 37   Scheme 1.24 Chiral reaction medium made of spiroborate ion-pair 174 ..................................... 39   Scheme 2.1 The Wulff asymmetric cis-aziridination reaction with benzhydryl imines 78 ......... 57   Scheme 2.2 The Wulff asymmetric cis-aziridination reaction with benzhydryl imines 78 ....... 125   Scheme 2.3 Boroxinate formation using BH3•Et2NPh 192d ..................................................... 131   Scheme 3.1 Catalytic cycle of a Brønsted acid catalyzed reaction ............................................ 173   Scheme 3.2 Brønsted acid catalyzed aziridination reaction ....................................................... 174   Scheme 3.3 Catalytic cycle of a Brønsted acid catalyzed aziridination reaction ....................... 176 Scheme 3.4 Different procedures used to perform and monitor the aziridination reaction ....... 181       xxxiii     Scheme 3.5 Termination of the catalytic cycle and the aziridination reaction ........................... 224   Scheme 4.1 Asymmetric reactions reported to be catalyzed by 20-H ........................................ 271   Scheme 4.2 Proposed catalytic activity of 20-H ........................................................................ 273   Scheme 4.3 Common borate esters of catechol 250 ................................................................... 282   Scheme 4.4 Asymmetric reactions reported to be catalyzed by 22-H ........................................ 286   Scheme 4.5 Proposed catalytic activity of 22-H ........................................................................ 287   Scheme 4.6 Preparation of BINOL derivative 89 ...................................................................... 290   Scheme 4.7 Current understanding of the catalytic activity of 20-H ......................................... 309   Scheme 4.8 Current understanding of the catalytic activity of 22-H ......................................... 311   Scheme 5.1 (A) Preparation of the monomer 272 of VAPOL. (B) Proposed mechanism ......... 336   Scheme 5.2 Preparation of the ISOVAPOL monomer 285 ........................................................ 338   Scheme 5.3 Preparation of the rac-197 and (S)-ISOVAPOL (S)-197........................................ 338   Scheme 5.4 Common borate esters of (A) BINOL 55 and (B) BINOL derivatives 55 and 89 .. 355   Scheme 5.5 BOROX catalysts from (A) (S)-VAPOL 58 and (B) (R)-BINOL 55 ..................... 358   Scheme 5.6 Preparation of dimethoxy-BINOL 258 ................................................................... 361   Scheme 5.7 Preparation of BINOL derivatives 56d (R = Br) and 56e (R = I)........................... 361   Scheme 5.8 Preparation of BINOL derivative (A) 56a (R = Ph) and (B) 56f (R = TRIP) ........ 362       xxxiv     Scheme 5.9 Preparation of BINOL derivative 56i (R = 9-phenanthryl) .................................... 363   Scheme 5.10 (A) One-pot aziridination with imine 78a using (R)-55 and (R)-56a as the ligands. (B) aziridination with B1 catalysts. ...................................................................... 374   Scheme 5.11 NMR study of the BOROX catalysts using (R)-56 as the ligand ......................... 375 Scheme 5.12 Aziridination with imine 78a using (R,R)-61a as the ligand. ............................... 389 Scheme 6.1 Catalytic asymmetric aziridination of imine 78a using procedure II ................... 450   Scheme 6.2 Catalytic asymmetric aziridination of imine 110g (R = 4-Br-C6H4) using (A) procedure IIʹ′ (B) procedure IV (C) procedure Vʹ′ (D) procedure V .................... 452   Scheme 6.3 (A) Reaction between EDA and different imines (B) Reaction between diazoacetamide and different imines (C) Possible products from the reaction between EDA and conjugated imine 335 .............................................................. 462   Scheme 6.4 (A) Reaction between EDA and unsubstituted acroleins (B) Reaction between EDA and β-substituted acroleins (C) Reaction between di-substituted aryldiazoacetate and β-disubstituted acroleins ................................................................................. 465   Scheme 6.5 (A) Reaction between 348 or EDA and α-substituted acroleins 347 (B) Reaction between EDA and α,β-substituted acroleins 352 (C) Reaction between disubstituted aryldiazoacetate and α-substituted acroleins 347 ................................ 466   Scheme 6.6 [3+2] cycloaddition reaction between EDA and imine 328o ................................ 468   Scheme 6.7 Multicomponent [3+2] cycloaddition reaction. ..................................................... 470   Scheme 6.8 Attempts towards the (A) hydrolysis of adduct 360a (B) reduction of adduct 360a. ............................................................................................................................... 471   Scheme 6.9 (X) Ugi-4CR reaction (Y) Proposed mechanism ................................................... 472       xxxv     Scheme 6.10 Proposed Ugi-3CR ............................................................................................... 473   Scheme 6.11 Proposed Ugi-type 2CR ........................................................................................ 477   Scheme 6.12 Catalytic Ugi-type three-component reaction ....................................................... 478   Scheme 6.13 (X) Passerini reaction (Y) Attempts towards the asymmetric Passerini reaction. 480 Scheme 6.14 (A) Proposed Kinetic resolution of imine rac-378. (B) Equation for the calculation of s factor ............................................................................................................ 483 Scheme 7.1 (A) Self-condensation of imine 110o during aziridination. (B) Self condensation of 1 imine 111t during imine formation. (C) H NMR spectra of the formation of imine 111t at t = 4 h and 21 h .......................................................................................... 549   Scheme 7.2 Generation of IMINO-BOROX catalysts 190a and 188a ...................................... 552   Scheme 7.3 Generation of AMINO-BOROX catalysts 215a and 215b ..................................... 553   Scheme 7.4 (A) Alkylation of the VAPOL by EDA. (B) Common products obtained from the reaction between benzaldehyde and EDA. ............................................................ 554   Scheme 7.5 (A) Preparation of Imine 111l (B) Synthesis of aziridine 114l via two-step method ............................................................................................................................... 565   Scheme 7.6 An equilibrium between (A) AMINO-BOROX catalyst 215a/b and (B) IMINOBOROX catalyst 188/190 ...................................................................................... 581   Scheme 7.7 Various protocols for multicomponent aziridination reaction using BH3•Me2S. ... 586   Scheme 7.8 Various protocols for multicomponent aziridination reaction using BH3•THF ..... 589   Scheme 7.9 Gram scale asymmetric catalysis ............................................................................ 599       xxxvi     Scheme 7.10 Large scale synthesis of MEDAM amine 126c .................................................... 601   Scheme 7.11 Application of MCAZ reaction in organic synthesis ............................................ 602   Scheme 7.12 Proposed intramolecular aziridination reaction via (A) Traditional aziridination (B) Multicomponent aziridination reaction ................................................................ 604   Scheme 8.1 Different approaches towards catalytic asymmetric epoxidation ........................... 688   Scheme 8.2 Catalytic asymmetric Darzens reaction .................................................................. 689   Scheme 8.3 Catalytic asymmetric epoxidation using sulfur ylides ............................................ 689   Scheme 8.4 Catalytic asymmetric epoxidation using diazoacetamides ..................................... 691   Scheme 8.5 B(OPh)3 catalyzed reaction between benzaldehyde and (A) diazoester 85 (B) diazoacetamide 123a (C) diazoacetamides 128a and 128c.................................. 692   Scheme 8.6 Tri-substitute epoxidation reaction between benzaldehyde and (A) diazoacetamide 439a (B) diazoacetamide 439b .............................................................................. 706   Scheme 8.7 Comparison of the optical rotation values of epoxide (S,S)-426a obtained from the current work and from the literature ...................................................................... 707   Scheme 8.8 Epoxidation reaction with catalyst 432 and 447 ..................................................... 716   Scheme 8.9 (A) General mechanism of the epoxidation reaction of aldehydes and diazoacetami13 des catalyzed by our catalyst. (B) Equation used for the calculation of the C KIE values. .................................................................................................................... 732   Scheme 8.10 Gram scale asymmetric catalysis .......................................................................... 734 Scheme 8.11 Large scale synthesis of diazo compounds 454 and 128a .................................... 735       xxxvii     Scheme 9.1 Proposed catalytic cycles of imino-aldol reaction using (S)-VAPOL 58 (A, B, C) and (R)-6,6ʹ′-Br2-BINOL 459 (D) as the ligands. (A) Catalytic cycle I (B) Catalytic cycle II (C) Catalytic cycle III (D) Catalytic cycle IIIʹ′ ......................................... 793 Scheme 9.2 Proposed catalytic cycles of imino-aldol reaction using (R)-6,6ʹ′-Br2-BINOL 459 as the ligand. (A) Catalytic cycle II' (B) Catalytic Cycle III' ..................................... 817       xxxviii CHAPTER 1   CHIRAL BORATE ANIONS IN ASYMMETRIC BRØNSTED ACID CATALYSIS AND ASYMMETRIC COUNTERANION-DIRECTED CATALYSIS You should never be ashamed of any reaction you did. A publication is like a movie. A classic movie is not understood completely the first time. -William D. Wulff 1.1 Chiral anions in asymmetric catalysis and its different classes Chiral compounds have always an immense impact on every aspect of chemistry. In organic synthesis, there are primarily three ways of synthesizing chiral compounds: chiral pool derived synthesis; chiral auxiliary mediated synthesis and asymmetric catalysis. 1 Nowadays, there are many different kinds of asymmetric catalysis using transition-metal complexes (organometallic catalysis), organic acids or bases/nucleophiles (“organocatalysis”), and enzymes (biocatalysis). 1e Chiral induction is typically achieved through strongly directional chiral catalyst-substrate interactions. Mostly, these interactions are operating via covalent bonds or coordination bonds. They could also be the result of simple Lewis acid/base interactions. However, many reactions might proceed via charged intermediates. In these cases, chirality induction can be achieved either by employing the salt of a chiral cation and an achiral anion or vice versa. The former type of catalysis has been used in organic synthesis for a very long time in the form of phase transfer catalysis. 2 The latter type, which involves the usage of chiral counter-anions, has emerged more recently. Over the past few years, there has been amazing advance in the field of asymmetric catalysis mediated by chiral counter-anions. 1 3 Asymmetric catalysis mediated by chiral counter-anions can be classified into five different classes based on the counter-cation and mode of catalysis (Table 1.1). The very first class (I) belongs to the field of asymmetric Brønsted acid catalysis (sometimes called as asymmetric Hydrogen-bond catalysis). The second class (II) comprises chiral counter-anions along with protonated achiral or chiral bases (mostly amine) as the cation. This class can either be included in asymmetric Brønsted acid catalysis or asymmetric counteranion-directed catalysis (sometimes called as asymmetric ion-pairing catalysis or anion binding catalysis) depending upon their catalytic function (see section 1.2). The remaining three classes can be brought under the asymmetric counteranion-directed catalysis. In class III, the ion-pair catalysts consist of chiral anions with achiral or chiral bases with no protons (for instance: tetra-alkylammonium ion). The remaining two classes (IV and V) consist of chiral counter-anions with a) metal only or b) metal with achiral or chiral ligands. The first example of chiral counteranions utilized in 4 5 transition metal catalysis and organocatalysis were reported in 2000 and 2006 respectively. Table 1.1 Different classes of catalysis involving chiral counter-anions Class Anion I X* – II X* – [B1-H] or [B1*-H] III X* – [B2] or [B2*] IV X* – V X* – a Counter Cation H + + + + M (L) or M (L*) Brønsted acid catalysis Brønsted acid or Ion-pair Brønsted acid catalysis and/or ACDC Ion-pair ACDC Ion-pair + Mode of Catalysis Brønsted acid + + Catalyst + M a ACDC in metal catalysis Ion-pair ACDC in metal catalysis – X* = Chiral anion; B1 or B2 = Base; B1* or B2* = Chiral base; M = Metal; L = Ligand; L* = Chiral ligand; ACDC = Asymmetric Counteranion-Directed Catalysis 2 These chiral anions differ in structure and reactivity. As discussed above, they have been used in both asymmetric Brønsted acid catalysis and asymmetric counteranion-directed catalysis. A list of some of the chiral anions used in asymmetric catalysis is shown in Figure 1.1. The list includes 6 carboxylate, 10 phosphoramidate, 6c,7 sulfonate, tetracoordinated hexacoordinated phosphate 11 5,8 phosphate, and cobaltate 12 are reports showcasing the concept of supramolecular chiral anions. 9 disulfonimidate, anions. More recently, there 13 Figure 1.1 Chiral counter-anions used in asymmetric catalysis (blue: asymmetric Brønsted acid catalysis; red: asymmetric counteranion-directed catalysis). For interpretation of the references to color in this and all other figures, the reader is referred to the electronic version of this dissertation. Ph CO2– NHAc 1 Milstein J. Organomet. Chem. 2004, 689, 751 Carboxylate anions CO2– CO2– 2 Maruoka J. Am. Chem. Soc. 2007, 129, 10054 J. Am. Chem. Soc. 2008, 130, 14380 CF3 CF3 SO3– SO3– O SO3– 4 3 Milstein Isihara J. Organomet. Chem. J. Am. Chem. Soc. 2008, 130, 16858 2004, 689, 751 Synlett 2011, 1247 Sulfonate anions 3 SO3– SO3– CF3 5 CF3 Toste Angew. Chem. Int. Ed. 2010, 49, 598 iPr Figure 1.1 cont’d Ph Ph iPr iPr O O P O O– O O P – O i O Pr 6 Antilla J. Am. Chem. Soc. 2007, 129, 5830 J. Am. Chem. Soc. 2005, 127, 15696 iPr 7 iPr List Angew. Chem. Int. Ed. 2006, 45, 4193 List J. Am. Chem. Soc. 2006, 128, 13368 Toste Science 2007, 317, 496 List Angew. Chem. Int. Ed. 2010, 49, 628 List Aldrichimica Acta 2008, 41, 31 iPr iPr O iPr O O– O iPr O O P O O– P 8 9 List Chem. Commun. 2011, 47, 10022. Ding Eur. J. Org. Chem. 2011, 110-116. iPr iPr List Chem. Commun. 2011, 47, 10022. List J. Am. Chem. Soc. 2010, 132, 17370 Tetracoordinated Phosphate anions CF3 CF3 SO2 N– SO2 Disulfonimidate anion CF3 10 CF3 List Angew. Chem. Int. Ed. 2009, 48, 4363 List Angew. Chem. Int. Ed. 2011, 50, 754 Lee J. Org. Chem. 2011, 76, 7141 4 Figure 1.1 cont’d O O O P S O O N CF 3 – O O O P S O O N CF 3 – 11 12 Rueping Angew. Chem. Int. Ed. 2008, 47, 593 Rueping Chem.–Eur. J. 2010, 16, 13116 Rueping J. Am. Chem. Soc. 2011, 133, 3732 Rueping Chem.–Eur. J. 2010, 16, 13116 Phosphoramidate anions Cl Cl Cl Cl Cl O Cl O Cl Cl O P O Cl O O O O P Cl Cl Cl Cl 13 Cl Lacour Tetrahedron Lett. 2002, 43, 8257 Nelson Tetrahedron Asymmetry. 2003, 14, 1995 14 O O N O Co O O N O R H 15 Tetrahedron Asymmetry. 2008, 19, 822 Cobaltate anion 5 O O Cl Cl Cl Lacour Chem. Commun. 2008, 829 Hexacoordinated Phosphate anions R H Cl O O Cl Cl Figure 1.1 cont’d CF3 H11C5 tBu S N N H O tBu S N H N Cl – O N Ph O CF3 Cl – tBu S S N H N H 17 F Jacobsen J. Am. Chem. Soc. 2008, 130, 7198 16 Jacobsen J. Am. Chem. Soc. 2007, 129, 13404 Ph N H N H N Cl – HO O N N H N H N – CN HO 19 18 tBu OPiv List Chem. Asian J. 2008, 3, 430 tBu Et3Si Jacobsen Angew. Chem. Int. Ed. 2009, 48, 6328 Supramolecular chiral anions The present discussion is focused on catalysis that involves chiral borate anions. They have been used in both asymmetric Brønsted acid catalysis (not organocatalysis as it involves boron) and asymmetric counteranion-directed catalysis (transition-metal catalysis). In the case of asymmetric Brønsted acid catalysis, there are three type of chiral borate anions: a) 14 spiroborate 15 (SB) b) fused-spiroborate (FSB) and c) boroxinate 16 (BOROX) (Figure 1.2). However, in the case of asymmetric counteranion-directed catalysis, only spiroborate type anions from BINOL, 4,11b,17 tartaric acid 18 and amino acids 6 18-19 are reported (Figure 1.2). Figure 1.2 Chiral borate anions used in (A) asymmetric Brønsted acid catalysis (B) asymmetric counteranion-directed catalysis A Br Br O – O B O O O – O B O O 20 Yamamoto, J. Am. Chem. Soc. 1994, 116, 10520 Nakagawa, Synlett 1997, 761 Nakagawa, J. Org. Chem. 1998, 63, 6348 James, Tetrahedron Asymmetry. 2003, 14, 1965 Br 21 Nakagawa Synlett 1997, 761 J. Org. Chem. 1998, 63, 6348 Spiro-borate anions O O O – B Fused-spiroborate anion O 22 Yamamoto, J. Am. Chem. Soc. 1994, 116, 1561 Yamamoto, J. Am. Chem. Soc. 1996, 118, 3049 Yamamoto, J. Am. Chem. Soc. 1998, 120, 6920 Yamamoto, J. Org. Chem. 1997, 62, 3026 Davies, Adv. Synth. Catal. 2006, 348, 2449 Ph Ph OPh O B O– B O O O B OPh Ph Ph OPh O B O– B O O O B OPh 23 24 Wulff J. Am. Chem. Soc. 2009, 131, 15615 J. Am. Chem. Soc. 2010, 132, 14669 J. Org. Chem. 2010, 75, 5643 Org. Lett. 2011, 13, 5866 Wulff J. Org. Chem. 2010, 75, 5643 J. Am. Chem. Soc. 2010, 132, 13100 J. Am. Chem. Soc. 2010, 132, 13104 J. Am. Chem. Soc. 2011, 133, 5656 7 Br Figure 1.2 cont’d R1 Ar OPh O B O– B O O O B OPh Ph Ph OPh O B O– B O O O B OPh Ar1 Ar2 OPh O B O– B O O O B OPh Ar R2 25 26 Wulff Unpublished Wulff Unpublished 27 Wulff Unpublished Boroxinate anions B EtO OEt O – O B O O O – O B O O O O O O OEt EtO 28 Arndtsen Organomettallics. 2004, 23, 2838 20 Leitner, Chem. Cat. Chem 2010, 2, 55 Nelson, Tetrahedron Asymmetry. 2003, 14, 1995 Arndtsen, Org. Lett. 2000, 2, 4165 Ph O – O B O O O O Ph Ph HN NH NH CO2Me R1 O R1 Ph O – O B O O NH O O HN R2 MeO2C R1 HN NH O O O HN R2 R2 MeO2C CO2Me R1 R2 29 30 Arndtsen Organomettallics. 2004, 23, 2838 Arndtsen Tetrahedron Asymmetry. 2005, 16, 1789 8 Figure 1.2 cont’d MeO2C Ph HN NH O O – O B O O O O O O NH MeO2C O HN NH O CO2Me Ph HN NH HN O Ph Ph CO2Me 31 Arndtsen Tetrahedron Asymmetry. 2005, 16, 1789 Spiro-borate anions 1.2 Chiral borate anions in asymmetric Brønsted acid catalysis (Class I and II) In last decade or so, there has been enormous growth in the field of asymmetric Brønsted acid catalysis (Class I). There have been a number of elegant examples demonstrating the magnificent work in asymmetric catalysis utilizing these acids. A brief introduction is given below prior to the discussion of the chiral borate anions in asymmetric Brønsted acid catalysis. 1.2.1 An introduction to asymmetric Brønsted acid catalysis A number of reviews have been published in the literature showcasing the idea of 3c,20 asymmetric catalysis via chiral Brønsted acid catalyst. The most common Brønsted acids used are chiral phosphoric acids, which has chiral tetracoordinated phosphate anions. More specifically, the phosphoric acids derived from BINOL and H8-BINOL are primarily used in 9 asymmetric catalysis. 22 catalysts. 21 In 2004, Akiyama and Terada have introduced these kinds of The binding of the substrate to the catalyst has been altered to a great deal with the help of 3,3ʹ′ or 6,6ʹ′ substituents on the BINOL ligand. Additionally, Toste and co-workers have 23 introduced thio-phosphoric acids derived from BINOL derivatives. coworkers have introduced the concept of chiral bis-phosphoric acid catalyst. 25 novel chiral phosphoric acids derived from VANOL, TADDOL 8i,28 have been employed. phosphoric acids are being used. 29 9a,9b,32 24 In recent years, 8i,27 SPINOL, and More recently, metal salts of VAPOL or BINOL In recent years, the acidity of these Brønsted acids have been increased to a great extent by utilizing phosphorodiamidic acid, bis(sufonyl)imides 8a,8b,25-26 VAPOL, Also, Terada and and bis(sulfuryl)imides 33 30 10a,10b,31 phosphoramides, 20a prepared from BINOL and H8-BINOL. More recently, List and coworkers have reported a novel class of C2-symmetric imidodiphosphoric acids. chiral disulfonic acids. 34 7,36 The other group comprises chiral dicarboxylic acids 6a,6b,35 and Also, the pKa values of these acids have been reported in DMSO 37 ranging from 1.74±0.08 to 5.74±0.05. Rueping and co-workers have recently shown asymmetric Brønsted acid catalysis in aqueous solution. 38 In the case of Brønsted acid catalysis, the mode of substrate activation is either hydrogen bonding or ion-pair formation by the complete proton transfer to the substrate. Recently, it has been demonstrated that both the activation modes are synergistically operational in case of 10 imines. 39 The population of the substrate in an activation mode would also be governed by the strength of the acid. Weak Brønsted acids are likely to operate via hydrogen bonding. 20e,20h,20j,40 Consequently, chiral thioureas like 46-47, 42 derivatives 49-54 41 TADDOL 48 have been used as Brønsted acid catalysts (Hydrogen-bond donor catalysts) 43 (Figure 1.3B). In general, diols such as BINOLs 55 and 56, 45 58, 45 VANOL 59, and chiral BINOL 46 SPINOL 60 43a,47 and TADDOL 61 44 H8-BINOLs 53 and 57, VAPOL are relatively very weak Brønsted acids when used directly as catalysts, however, they have been extensively used as chiral ligands for various asymmetric reactions. It is important to note that while the catalyst might exist as the Brønsted acid, their catalytic function could be of Lewis acid type. 25b,26a,26c,26d,48 Figure 1.3 A list of various (A) chiral phosphoric acids, phosphorodiamidic acid, phosphoramides, imidodiphosphoric acids, disulfonamides, carboxylic and sulfonic acids. (B) chiral thioureas and chiral diols A Ar Ar O O P O OH O O P O OH R O N P N OH R Ar 32a Ar Ar Ar 33 32b 11 R O O P OH O P OH O O O R 34 Figure 1.3 cont’d Ar Ar O R O P O OH R O O P O OH Ph Ph Ar O O P O OH O O Ar Ar Ar 38 37 35 (for (S)-VAPOL) 36 (for (S)-VANOL) Ar Ar O O O O P O N S CF3 H O O O O P O N S CF3 H Ar Ar 39a 39b Ar Ar O O O P O N P R R H OH O O O P P O N O Ar Ar Ar Ar 40 41 Ar Ar Ar Ar 44 43 12 SO3H SO3H Ar O SO2 Ar CO2H CO2H O SO 2 NH SO2 NH SO2 42 Ar Ar 45 Figure 1.3 cont’d B R CF3 R2 1N O S tBu S N H N H 1-Np N H H N N N H O CF3 O N 1-Np 1-Np OH OH 1-Np Ar 46 48 N 47 Ph Ph N PPh2 OH OH OH OH N OH iPr OH OH OH 49 Ph Ph 51 50 Si(m-xylyl)3 OH OH OH OH OH OH Si(m-xylyl)3 52 54 53 Ar OH OH OH OH Ar Ar Ar Ph Ph OH R O OH OH OH R O OH OH Ar Ar 55 (Ar = H) 56 (Ar ≠ H) Ar 53 (Ar = H) 57 (Ar ≠ H) Ar 58 (for (S)-VAPOL) 59 (for (S)-VANOL) 13 60 Ar 61 Ar Regarding class II type catalyst, they exist as Brønsted acid catalysts. Depending upon their catalytic function, they belong to either asymmetric Brønsted acid catalysis or asymmetric counteranion-directed catalysis. For instance; if the catalyst looses all protons at the catalytic step, then it can be included in asymmetric counteranion-directed catalysis (Scheme 1.1). In these cases, class II serves as pre-catalyst and the eventually transforms into class III type catalyst during the reaction. Scheme 1.1 Brønsted acid catalysis 49 verses asymmetric counteranion-directed catalysis iPr iPr iPr O O P – O i O Pr O iPr R1 R3 R2 CO2tBu iPr H3N iPr 63 O (5 mol%) R1 Hantzsch ester 64 Dioxane, 60 °C, 48 h 65 62 iPr iPr iPr O O P – O i O Pr O R3 R3 iPr O + N H2 iPr 67 O (20 mol%) Hantzsch ester 64 Dioxane, 50 °C, 24 h Ar Ar 68 66 14 5 Scheme 1.1 cont’d iPr iPr iPr O CO2tBu iPr O O P – O i O Pr H + N iPr iPr iPr + N O O P – O i O Pr R1 R3 iPr iPr R2 Ar 69 iPr iPr 70 Asymmetric Counteranion Directed Catalysis Asymmetric Brønsted Acid Catalysis An important class of Brønsted acid catalysts involves chiral borate anions. Catalysts 14 which belong to the class I are supposedly containing spiroborate 15 (SB) or fused-spiroborate (FSB) anions. However these are found to be class II type catalysts (see section 1.2.2 and 1.2.3). 16 Boroxinate (BOROX) anions form the Brønsted acid catalyst only in the presence of a base and hence belong to class II. 1.2.2 Chiral spiroborate anions in asymmetric Brønsted acid catalysis In 1994, Yamamoto and co-workers reported one of the early examples of chiral borate anions. They utilized spiroborate (SB) anion 20 for Mannich reactions 14a,14d heteroatom Diels-Alder reactions of imines (Scheme 1.4). 14a-14c (Scheme 1.3) and In the year 1997, the same catalyst was supposedly used for Pictet-Spengler reaction (Scheme 1.5). 14e,14f The reported structure represents the catalyst as a Brønsted acid 20-H containing a tetra-coordinate boron 15 14a,14e (Scheme 1.2). However, the mode of catalysis of 20-H was assumed to be Brønsted acid assisted Lewis acid (BLA) catalysis. The catalytic function of 20-H was proposed to be as a chiral Lewis acid where interaction with a Lewis base disrupts one of the boron-oxygen bonds to 14a,14e give Lewis acid-Lewis base complex 71 (Scheme 1.2). However, we found that there is no tetracoordinated boron atom unless a base is added (see Chapter 4). Hence, catalyst 20-H exists as Brønsted acid assisted Lewis acid (BLA) 72 with a tri-coordinate boron atom (Scheme 1.2). Scheme 1.2 Different proposals about catalytic activity of 20-H (LB = Lewis base) Catalyst Old Proposal (Yamamoto, Nakagawa) Mode of Catalysis + H LB O – O B O O LB OH OH O H O B O 20-H 2 O 71 (LB = imine) 71' (LB = nitrone) Brønsted acid assisted Lewis acid (BLA) Brønsted acid LB 55 O + O O B B(OPh)3 New Proposal (Wulff) H LB O O O 72 Brønsted acid assisted Lewis acid (BLA) O B H O 73' (LB = nitrone) Brønsted acid assisted Lewis acid (BLA) + [LB-H] O O B O H LB O 72 Brønsted acid assisted Lewis acid (BLA) 16 O – O B O O 74 (LB = imine) Brønsted acid Interestingly, we found that the mode of catalysis (catalytic function) is actually Brønsted acid or hydrogen bond catalysis for imino-aldol reaction of imines and Brønsted acid assisted Lewis acid catalysis for Pictet-Spengler reaction of nitrones (Scheme 1.2). For imino-aldol reaction of imine, the actual catalyst exists as Brønsted acid 74 and belongs to the class II type catalysts where it is formed only upon the addition of chiral or achiral bases (Scheme 1.2). A detailed discussion of this system is given in Chapter 4. In the case of asymmetric imino-aldol reaction; stoichiometric amount of catalyst 20-H 14a was utilized and enantioselectivity up to 98% was reported (Scheme 1.3). Reaction with chiral amine created the environment for matched/mismatched cases resulting in 95% diastereomeric cxcess. Yamamoto and co-workers used the asymmetric imino-aldol reaction in the total synthesis of (+)-(S)-Dihydroperiphylline. 14b,14c Scheme 1.3 Asymmetric imino-aldol reaction catalyzed by 20-H N R1 + OTMS OtBu Ph 75 76 catalyst 20-H (100 mol %) 4 Å MS, CH2Cl2 –78 °C, 20 h R1 = Ph, Bn, Bh, (S)PhMeCH 1-NpCH2 Ph OTMS N Ph + R2 78 OtBu 76 catalyst 20-H (100 mol %) 4 Å MS, CH2Cl2 –78 °C, 20 h R2 = Ph, 2-naphthyl, p-Me-C6H4, p-Cl-C6H4, p-OAc-C6H4, 2,4-Cl2-C6H4 HN Ph R1 CO2tBu 77 5 examples ee = < 5 – > 90% de = 95 (for chiral amine) Ph HN R2 Ph CO2tBu 79 6 examples yield = 35 – 58% ee = 95 – 98% 17 Yamamoto and coworkers reported the asymmetric heteroatom Diels-Alder reaction between imine 75 and Danishefsky diene 80 to give vinylogous amides 81 (Scheme 1.4). They examined different imines derived from benzaldehyde and benzylamine or (S)-αmethylbenzylamine. Excellent yields and enantioselectivities and diastereoselectivities were obtained though stoichiometric amount of catalyst used. Results with chiral amine and different enantiomers of catalyst did not show any match or mismatched cases. Our group then thought to examine benzhydryl amine derived imine 78a as it is the protecting group we utilized for the same reaction with our BOROX catalyst. 16h A slight increase in ee was observed as compared to the benzyl amine derived imine 75a although low yield was obtained when 10 mol % catalyst 50 was used instead of 100 mol % (Scheme 1.4). Scheme 1.4 Asymmetric heteroatom Diels-Alder reaction catalyzed by 20-H or 74 OMe R1 N catalyst 20-H (100 mol %) + Ph OTMS R1 4 Å MS, CH2Cl2 –78 °C, 12 h Ph 80 75 Bn (S)PhMeCH (S)PhMeCH (with ent-20-H) N Ph 81 ee/de% 78 64 49 86 99 83 Ph OMe catalyst 74 (x mol %) Ph + OTMS 78a O y% R1 Ph N 80 CH2Cl2:toluene (1:1) –45 °C, 24 h Ph N Ph 82a 10 100 18 y% ee% 39 92 Catalyst 74 (mol %) O 93 89 Regarding the Pictet-Spengler reaction, Nagakawa and coworkers had to utilize two equivalents of the catalyst 20-H in order to get the turnover as the product 84 was more basic than the reactant 83. Scheme 1.5 Asymmetric Pictet-Spengler reaction catalyzed by 20-H or 21-H catalyst 20-H or 21-H (200 mol %) + N O– N H N OH N H 4 Å MS, CH2Cl2 25 °C, 48 h R 83 R 84 6 examples yield = 39 – 94% ee = 15 – 94% R = Ph, p-OMe-C6H4, p-NO2-C6H4, Me, iBu, 1-naphthyl, Interestingly, the opposite enantiomer of aziridine 86a was obtained when (R,R)-74a was 16a,50 employed as compared to a BOROX catalyst generated from (R)-VAPOL. Low yields and moderate ees were obtained irrespective of the catalyst loading (Scheme 1.6). Scheme 1.6 Asymmetric aziridination reaction catalyzed by (R,R)-74a Ph Ph O Ph + N OEt N2 Ph 78a catalyst (R,R)-74a (x mol %) CH2Cl2 25 °C, 24 h Ph Ph N Ph 85 Ph + CO2Et 86a (Ph)H NH CO2Et Ph(H) 87a(88a) 10 100 19 y% ee % cis:trans enamines 47 8 Catalyst 74a (mol %) 40 76 2:1 50:1 24(23) 5(5) 1.2.3 Chiral fused-spiroborate anions in asymmeric Brønsted acid catalysis Another example reported is the case of fused-spiroborate (FSB) anion 22. In 1994, Yamamoto and co-workers reported this kind of catalyst for the first time. 15a They used this catalyst for asymmetric Diels-Alder reaction between dienes and enals (Scheme 1.8). The reported structure represents it as a Brønsted acid containing a tetra-coordinate boron atom 15 (Scheme 1.7). However, it was proposed to function as a Brønsted acid assisted Lewis acid (BLA) catalyst. In this case, we found that it is indeed a BLA type mechanism for aldehydes. However, we found that there is no tetra-coordinated boron unless a base is added. This work is discussed more in detail in Chapter 4. Scheme 1.7 Proposed catalytic activity of 22-H Catalyst Old Proposal (Yamamoto) OH B(OPh)3 (1 equiv) OH OH OH 89 New Proposal (Wulff) Mode of Catalysis O – + O B H O O LB 22-H Brønsted acid LB 91 Brønsted acid assisted Lewis acid (BLA) 20 LB 90' (LB = aldehydes) Brønsted acid assisted Lewis acid (BLA) LB O O B O HO O O B O HO O + – O B [LB-H] O O 92 (LB = imine) Brønsted acid Excellent yields and ees were reported for the Diels-Alder reaction of dienes 93 and enals 15a 94 giving exo isomer as the major product (Scheme 1.8A). In the years 1996 and 1998, Yamamoto and coworkers designed some modified catalytic systems for Diels-Alder reaction between dienes and enals in order to increase the enantio-induction and broaden the substrate scope (Scheme 1.8B). 15b,15c Scheme 1.8 Asymmetric Diels-Alder reaction of dienes and enals catalyzed by (A) 22-H (B) 98100 A R1 catalyst 22-H (10 mol %) R2 + R3 93 CHO 94 R1= H, CH2OBn 4 Å MS, CH2Cl2 –78 °C, 4 h exo-endo = 49 − >99:1 R2= Br,Me,Et R3= H,Me R3 R1 CHO R2 95 7 examples yield = > 99% ee = 92 – > 99% B + 96 n = 0,1,2 catalyst 98 (1-20 mol %) R1 n R2 CHO 97 R1= Br,Me,H R2= H,Me,Et, Ph,CO2Et 4 Å MS, CH2Cl2 –78 °C, 1-24 h exo-endo = 1: 3 − >99 (R1 = H) exo-endo = 7 – 9:1 (R1 ≠ H) catalyst 99/100 (5 mol%) for n=1, R1=Me, R2=H 21 n CHO R1 R2 95' 15 examples yield = 57 – > 99% ee = 75 – > 99% Scheme 1.8 cont’d F3C CF3 O B O OH OH O B O OH CF3 Ph 98 CF3 CF3 CF3 H CF3 99 O B O OH 100 Ph CF3 Ph In the year 2006, Davies and coworkers introduced a formal [4+3] cycloaddition by a tandem Diels Alder reaction/ring expansion using 22-H as the catalyst (Scheme 1.9). 15e Scheme 1.9 Formal [4+3] cycloaddition catalyzed by 22-H 1) catalyst (S)-22-H (10 mol%) CH2Cl2, –78 °C R1 R2 + CHO 97 96b 2) AlCl3 (1.1 equiv) 0 °C, CH2Cl2, 2 h R1= Me,Et, Bn R2= -(CH2)3- O R2 1 R 101 4 examples yield = 72 – 85% ee = 46 – 96% Additionally, Yamamoto and coworkers reported the first enantioselective catalytic 15d Diels-Alder reaction of dienes 96 and acetylenic aldehydes 102 with ee up to 95%. Scheme 1.10 Asymmetric Diels-Alder reaction of dienes and alkynals catalyzed by 22-H or 98 n + 96 n = 1,2 R CHO 102 catalyst 22-H or 98 (10-20 mol%) 4 Å MS, CH2Cl2 –78 °C, 3–66 h n CHO R 103 5 examples yield = 28 – 98% ee = 34 – 95% R = I,Me,CO2Et 22 Also, as a part of this doctoral work, a low ee of 48% was observed for aziridine 86a when (R)-92a was employed (Scheme 1.11). Scheme 1.11 Asymmetric aziridination reaction catalyzed by (R)-92a Ph Ph O Ph + N OEt N2 Ph 78a Ph catalyst (R)-92a (10 mol %) Ph N toluene 25 °C, 24 h Ph 85 Ph + CO2Et 86a 80%y, 48%ee cis:trans = >100:1 NH (Ph)H CO2Et Ph(H) 87a(88a) 6%(8%) O + – B [imine-H] O O O (R)-92a (imine = 78a) Brønsted acid 1.2.4 Chiral boroxinate anions in asymmetric Brønsted acid catalysis: BOROX catalysis So far we have discussed two major kinds of chiral borate anions (SB 20-H and FSB 22- H) with free proton supposedly as the cation. Both contain a spiroborate ring as a common feature. However, there is no report of a chiral boroxinate (BOROX) catalyst in literature prior to our work. In the due course of time, we have developed a universal catalytic asymmetric aziridination utilizing a chiral boroxinate catalyst derived from the vaulted ligands such as 23 16 VAPOL 58 or VANOL 59 and B(OPh)3. The catalyst consists of a chiral boroxinate anion with a protonated base as the cation. It forms only in the presence of a base and hence it belongs to class II type of catalysts (Table 1.1). It can be generated via B1 and B2 or directly from the ligands (Scheme 1.12). Since, the borate anion can be seen as a derivative of a boroxine ring, we coined a new term “BOROX catalyst” for this class of catalysts. 16 More recently, we have shown that even some BINOL derivatives form boroxinate anions of type 27 in the presence of 51 base. Scheme 1.12 Generation of BOROX catalyst 104 and 105 Ph Ph OH [ B1 + B2 ] + other boron compounds B(OPh)3 (3 equiv) OH (S)-VAPOL 58 (S)-VANOL 59 Lewis Base Lewis Base Ph Ph 104a or 105a ; LB = imines 104b or 105b ; LB = amines 104c or 105c ; LB = quinolines 104d or 105d ; LB = sulfoxides 104e or 105e ; LB = phosphinoxides 104f or 105f ; LB = aminoxides OPh O B + O– B O [LB-H] O O B OPh 104 (for (S)-VAPOL) 105 (for (S)-VANOL) B3 Brønsted acid (BOROX catalyst) Ar Ph Ph O O B OPh 106 (for (S)-VAPOL) 107 (for (S)-VANOL) B1 Ph Ph OPh B O B O OPh O 108 (for (S)-VAPOL) 109 (for (S)-VANOL) B2 24 OPh O B O– B O O O B OPh Ar 27 B3 For the past few years, a considerable effort has been given towards the evolution of a universal aziridination reaction. Utilizing BOROX catalysts, a substrate general catalytic asymmetric aziridination reaction for cis- 16a-16d,16j,16k,16m and trans-aziridination 16i,16j has been realized (Scheme 1.13 and 1.14). A unique feature of our catalytic system is that either cisor trans-aziridines can be prepared from the same imine and same catalyst 104a/105a. Recently, we accomplished a cis-aziridination for alkynyl imines. 52 In all these cases, substrate i.e. imines, acting as the base, induced the formation of the BOROX catalyst of type 104a/105a. Scheme 1.13 The Wulff asymmetric cis-aziridination reaction Ar catalyst Ar Ar 104a or 105a O Ar Ar NH (2-10 mol %) N CO2Et + Ar + OEt (R)H N toluene R N2 R CO2Et R(H) 25 °C, 24 h 85 78 (Ar2CH=Bh) 86 (Ar2CH=Bh) 87(88) (Ar2CH=Bh) 110 (Ar2CH=DAM) 113 (Ar2CH=DAM) 116(117) (Ar2CH=DAM) 111 (Ar2CH=MEDAM) 114 (Ar2CH=MEDAM) 118(119) (Ar2CH=MEDAM) 112 (Ar2CH=BUDAM) 115 (Ar2CH=BUDAM) 120(121) (Ar2CH=BUDAM) R = aryl and alkyl Ar Ar Bh 15 examples Yield = 54–91% ee = 90–98% c/t = 38–50:1 OMe Ar OMe DAM 10 examples Yield = 11–95% ee = 52–98% c/t = 33–50:1 Ar MEDAM 10 examples Yield = 67–98% ee = 90–99.5% c/t = 33–50:1 tBu OMe 25 BUDAM 11 examples Yield = 57–99% ee = 78–99% tBu c/t = > 50:1 Scheme 1.13 cont’d Ar N catalyst 104a or 105a (5 mol %) O Ar NHPh + R N CONHPh R 123a Ar O Ar OMe 124 11 examples Yield = 77–95% ee = 83–99% c/t = 4–100:1 R = aryl and alkyl N Ar Ar toluene –40 °C, 4 h N2 122 Ar OEt + catalyst 104a or 105a (10 mol %) R N CO2Et R 85 Ar Ar ether –20 °C, 24 h N2 122' Ar tBu tBu OMe 124' 8 examples Yield = 24–86% ee = 41–95% R = aryl and alkyl Scheme 1.14 The Wulff asymmetric trans-aziridination reaction Ar O Ar R N Ar NHPh + N2 111 R = aryl and alkyl catalyst 105a (5-20 mol %) toluene 0 °C, 24 h Ar Ar N R CONHPh 125 13 examples Yield = 66-98% ee = 82-98% c/t = 7-26:1 123a OMe A considerable amount of time during this doctoral research has been spent in the realization of the first catalytic asymmetric multicomponent cis- and trans-aziridination of aldehydes (Scheme 1.15). 16g Although, amine 126 induced the generation of a BOROX species, 26 it was found the reaction was catalyzed by a BOROX catalyst generated from an imine after its complete formation from amine 126 and aldehyde 127. Scheme 1.15 Asymmetric multicomponent aziridination reaction catalyzed by 104a or 105a Ar Ar NH2 O O + R 126c catalyst 104a or 105a (3-10 mol%) H + OEt N2 85 127 4Å MS, toluene 25 °C or –10 °C 24 h R = aryl and alkyl Ar Ar NH2 R 126c H + NHBu N2 128a 127p Ar Ar 4Å MS, toluene –10 °C, 24 h NH2 126c R 102 Ar catalyst 105a (10 mol%) O NHBu N2 128a N R NHBu 129p Ar Ar OMe Ar N 4Å MS, toluene –20 °C, 24 h R CONHBu 130 3 examples Yield = 70–93% ee = 88% c/t = 17–100:1 R = Ph, C5H11, TIPS OMe Ar Ar Yield = 70% ee = 93% H + + R CO2Et 114 19 examples Yield = 50–98% ee = 90–>99% c/t = 8–>50:1 R = C16H33 O Ar Ar N catalyst 105a (10 mol%) O O + Ar OMe In 2007, our group reported the catalytic asymmetric aza Diels-Alder reactions of imines and Danishefsky diene 80 using a BOROX catalyst. In that case, excess B(OPh)3 was found to be critical in improving the turnover of the catalyst. (Scheme 1.16). 27 16h Scheme 1.16 Asymmetric aza Diels-Alder reaction of imine and Danishefsky diene 80 Ph Ph N catalyst 104a (5-10 mol%) B(OPh)3 (excess) OMe + OTMS R 78 Ph Ph CH2Cl2:toluene (1:1) –45 °C, 24-50 h N R 80 O ent-82 11 examples Yield = 41–90% ee = 73–93% R = aryl and alkyl Adding to the versatility of the BOROX catalysts, our group has recently reported an example of catalytic asymmetric aza-Cope rearrangement of imines. Inspired by the multicomponent aziridination reaction, this was then performed in a multicomponent fashion. Interestingly, one equivalent of benzoic acid with respect to the catalyst was found to be synergistic in order to give useful levels of enantioselectivity (Scheme 1.17). 16l Scheme 1.17 Asymmetric aza-Cope rearrangement catalyzed by 105a Ar O R H 127 + Ar H2N 131 1 catalyst 105a (5 mol %) PhCO2H (5 mol %) 5Å MS, m-xylene 50 °C, 24 h 2 2N HCl THF/H2O, 25 °C Ar NH2•HCl R 132 20 examples Yield = 57–99% ee = 72–>96% R = aryl and alkyl During the optimization of the multicomponent aziridination reaction, a novel [3+2] cycloaddition reaction was discovered (Scheme 1.18). The absolute stereochemistry was not 53 determined. However, due to time constraints, this work has been put on hold. 28 Scheme 1.18 Asymmetric [3+2] cycloaddition reaction catalyzed by BOROX catalyst 104a Ar N O Ar + OEt toluene 25 °C, 2 h N2 133 Ar catalyst 104a (10 mol %) N NH N EtO2C Ar Ar tBu 85 tBu 134 OMe Yield = 59% ee = 50% A prominent part of this thesis will focus on the development of a catalytic asymmetric epoxidation reaction. A number of aldehydes were examined and excellent results were obtained (Scheme 1.19). 53 Scheme 1.19 Asymmetric epoxidation reaction catalyzed by BOROX catalyst 105d O O R + H N2 127 N H Bu catalyst 105d (10 mol %) toluene – 60 °C, 24 h O H N R O 135 128a Bu O + O N H R Bu 136 14 examples Yield = 60–97% ee = 78–99% c/t = 13–100:1 R = aryl and alkyl Our group has also been able to perform catalytic asymmetric reduction of quinolines (Scheme 1.20). 54 High yields with moderate ees were obtained using BOROX catalyst 104c. Scheme 1.20 Catalytic asymmetric reduction of quinolines EtO2C CO2Et + N R 137 catalyst 104c (10 mol %) benzene 60 °C, 12-18 h N H 64 N H 138 * R 2 examples Yield = >99% ee = 67–73% R = Ph, C5H11 29 Last but not the least, substrate-controlled and catalyst-controlled aziridination reactions were examined with our BOROX catalysts and chiral imines made from either chiral amines or chiral aldehydes. Both matched and mismatched cases were observed (Scheme 1.21). 55 Scheme 1.21 Double stereodifferentiation in catalytic asymmetric aziridination O Me R Ph N + OEt N2 139 R = aryl and alkyl Ar R1 + N toluene 25 °C, 24 h R CO2Et Ph N R CO2Et 141 9 examples Yield = 28-82% c/t > 50:1 140 dr (140:141) 4.9:1 to >49:1 (with (S-VAPOL) 1:1.6 to <1:3.5 (with (R-VAPOL) 4.0:1 to >49:1 (with (S-VANOL) 1:1.1 to <1:3.5 (with (R-VANOL) Ar catalyst 104a (10 mol %) OEt N2 4Å MS, toluene –10 °C, 24 h 85 R1 = aryl and alkyl R2 = OTBS, NBoc, Me etc. 1.3 Me Ph Ar H R2 142 Me 85 NH2 126 O + O catalyst 104a or 105a (10 mol %) Ar N R1 R2 Ar + CO2Et 143 Ar Ar N R1 R2 CO2Et 144 OMe 8 examples dr (143:144) Yield = 60-95% 1:1 to >99:1 (with (S-VAPOL) cis/trans > 50:1 1:20 to <1:>99 (with (R-VAPOL) Chiral borate anions in asymmetric counteranion-directed catalysis (Classes II, III, IV, and V) Nowadays, a lot of chiral anions are being used in asymmetric counteranion-directed 3 catalysis. As discussed in section 1.2, a class II catalyst can be included in asymmetric counteranion-directed catalysis if the catalyst looses all protons prior to the chirality transfer 30 step. In these cases, the class II catalyst serves as the pre-catalyst and eventually transforms itself into a class III type catalyst (see Section 1.2, Scheme 1.1). One such kind of catalyst 11b utilizing the chiral spiroborate anion 20 was reported in 2003. The addition of N-methyl indole 145 to an iminium ion 146 and the ring-opening of an aziridinium ion 150 with benzylamine 151 were studied utilizing catalyst 147. In these cases, the mode of catalysis is asymmetric counteranion-directed catalysis as depicted in Table 1.2 and 1.3. Various catalysts were generated using different chiral achiral amines as the base. The level of enantioselectivity obtained was very low (< 15%) irrespective of the base used for the generation of the catalyst. Nonetheless this was one of the early examples where chiral borate anions have been used in counteranion-directed catalysis. Table 1.2 The addition of N-methyl indole 145 to an iminium ion 146 Ph N Me + – NMe2Cl + THF 25°C, 2 h 145 # Yield 148 a,b (%) + C 1 147a Et2NH2 2 147b Et3NH + + Na 12 + (R)-PhMeCHNH3 4 147d a + 38 52 22 a 3 ee 148 c (%) –5 b –3 nd a 10 –11 b 11 nd ee 148 (%) Average yield for reactions with catalyst 147 and catalyst ent-147. 147. c N Me 148 146 Cat 3 147c * catalyst 144 (10 mol %) b Yield for the reaction with catalyst ee for the reactions with catalyst ent-147. 31 C + O – O B O O 147 NMe2 Table 1.3 The ring-opening of an aziridinium ion 150 with benzylamine 151 Ph catalyst 147 (50 mol %) Cl Ph THF-toluene 100 °C N Ph + N Ph – A1 rac-147 # H N Ph N 150 Cat + Et2NH2 2 147b Et3NH 3 147c (R)-PhMeCHNH3 4 147d + Na + + ee 152 (%) –6 ee 152 b (%) 5 25 C Ph 152 Yield 152 a (%) 18 + 1 147a a Ph 24 h Ph NH2 151 13 –15 12 3 7 12 –7 nd C + O – O B O O + – 147 (C A1) Average yield for reactions with catalyst 147 and catalyst ent-147. ent-147. b ee for the reactions with catalyst This work was then extended to a catalyst belonging to class IV (see Table 1.1 for definition of class IV type catalysts). Chiral borate anions along with a metal as the cation have been employed in asymmetric catalysis. With catalyst 147d, ring-opening of aziridinium ion was performed yielding diamine 152 in 12% yield and 7% ee. 11b However, the same reaction was reported to afford 156 in 84% yield and 94% ee utilizing TRIP-PO3Ag 153 (Scheme 56 1.22). 32 Scheme 1.22 The ring-opening of an aziridinium ion 150 and 154 with catalysts 147d and 153. catalyst 147d (50 mol %) Ph Ph Cl N rac-149 Ph THF-toluene 100 °C Ph Ph NH2 151 + N 24 h – A1 Ph Ph 150 catalyst 153 (15 mol %) Toluene 50 °C Ph Ph H N N Ph %y = 12 %ee = – 7 152 Me3C OH 155 A2 Ph 24 h + N – Ph 154 O N CMe3 %y = 84 %ee = 94 156 iPr iPr + Na O – O B O O + – Na A1 iPr O O P – + O O Ag iPr + – Ag A2 153 147d iPr iPr The following section is primarily focused on class V type catalysts (see Table 1.1 for definition of class V type catalysts). Conventionally, chiral ligands are bound to a metal along with an achiral non-coordinating counteranion. In these cases; steric information, which decides facial selectivity, lies within the coordination sphere. Recently, ion-pairs which have achiral ligands bound to the metal along with chiral non-coordinating anions have been utilized in 4,18-19 asymmetric catalysis. In these cases, the factors affecting enantioselection lies outside the coordination sphere. Moreover, a hybrid of chiral ligands and chiral anions provides the opportunity of matched and mismatched cases for catalysis. 33 4 Arndtsen and coworkers introduced class V type catalysts in the year 2000. They 4 performed asymmetric aziridination and cyclopropanation of styrene utilizing catalyst 147e. Low enantioslelectivities were observed in the case of aziridination reaction irrespective of the chiral or achiral ligands used (Table 1.4). In fact, similar results were obtained for the cyclopropanation reaction between styrene and ethyl diazoacetate. In these cases, cis isomer was found to be the major isomer (Table 1.5). Table 1.4 Asymmetric aziridination reaction with spiroborate ion-pair 147e + Cu(MeCN)4 O – O B O O + PhINTs Ph L (3.1 mol %), Benzene, 0 °C 157 L Yield 159 (%) 1 160 75 2 160 3 4 5 6 none 161 162 163 Ph 158 # a Ts N 147e (3 mol %) 85 86 43 41 78 b 159 ee 159 (%) –22 –24 7 10 10 <1 O O a N N b 160 N b 34 161 N 162 % 160. Results for the reactions with catalyst ent-147e. N Ph Ph –33% ee with 10 mol % CuPF6 and 11 mol N PhN NPh 163 Table 1.5 Asymmetric cyclopropanation reaction with spiroborate ion-pair 147e + Cu(MeCN)4 O – O B O O 147e O + Ph OEt N2 157 3 4 a Ph 164 cis/trans 1.4:1 Yield 164+165 (%) 12 0 2.2:1 20 –28 10 25 25 a Ph 85 0 a CO2Et + ent-160 (1.1 mol%), Benzene, T °C T (°C) # 1 2 CO2Et (1 mol %) ee 164 (%) 6 ee 165 (%) 21 nd nd 34 34 6 8 15 12 165 O O N N Ph Ph ent-160 Results for the reactions with catalyst ent-147e. In 2004, Arndtsen and coworkers extended the concept of chiral spiroborate counteranion by employing tartrate amides to build the framework of the counteranion. 18-19 Table 1.6 Asymmetric cyclopropanation with spiroborate ion-pair 166 166 O + Ph OEt N2 157 CO2Et (1 mol %) Benzene, 0 °C, overnight 85 + Ph Ph 164 35 CO2Et 165 Table 1.6 Cont’d. 166a 1 2 3 4 5 1.9:1 166b 166c 166d 166e # Yield 164+165 (%) 67 1.3:1 1.2:1 1.0:1 1.3:1 21 36 3 32 Cat. a trans/cis ee 165 (%) <2 ee 164 (%) <2 17 –23 –34 14 26 –19 –19 24 + Cu(MeCN)4 EtO OEt O – O B O O O O OEt O O EtO 166a a Reaction performed in dichloromethane at room temperature. + Cu(MeCN)2 MeO2C CO2Me Ph O – O B O O O O Ph Ph HN NH + Cu(MeCN)2 CyO2C CO2Cy Ph O O NH HN CO2Me O – O B O O O O MeO2C Ph Ph tBu Ph H N Ph CyO2C CO2Me MeO2C tBu Ph Ph MeO2C 36 N H + Cu(MeCN)2 O O – O B O O NH O H N O O HN 166e CO2Me Ph Ph HN NH O O O HN O Ph O NH 166d HN CO2Cy MeO2C tBu HN O – O B O O O O O 166c + Cu(MeCN)2 MeO2C CO2Me NH O NH 166b tBu Ph HN NH O Ph N H Ph CO2Me One of the important features of this approach is the availability of the large number of amino acids, thereby generating a large pool of possible catalysts. However, for cyclopropanation reaction, the maximum enantio-induction attained was 34% and 26% for transand cis-isomer respectively (Table 1.6). Interestingly, trans isomer was observed to be the major product. They carried out a limited substrate scope with catalyst 166b (Scheme 1.23). 19 Scheme 1.23 Asymmetric cyclopropanation reaction with spiroborate ion-pair 166b R1 O R2 + R3 OEt N2 85 167 catalyst 166b (1 mol %) Benzene, 0 °C, overnight CO2Et R1 R3 R2 * * 168 4 examples Yield = 10–67% ee (cis) = 2–26% ee (trans) = 17–26% t/c = 1.1–1.3:1 Recently, asymmetric hydrogenation of dimethyl itaconate 169 was reported by utilizing rhodium catalyst with rac-BINAP 171 in the presence of the chiral spiroborate ion-pair 147d (Table 1.7). 17 Enantioselectivity up to 57% ee was observed with BINAP rac-171 and 69% ee with BINAP (R)-171. Interestingly, the opposite enantiomer of 170 was observed with BINAP (R)-171 alone. 37 Table 1.7 Asymmetric hydrogenation with spiroborate ion-pair 147d + Et3NH O – O B O O 147d (x mol %) H2 [(Ligand)Rh(cod)]BF3 (0.5 mol%) MeO2C CO2Me MeO2C 169 170 # Ligand x 1 2 3 4 5 1.4 CO2Me CH2Cl2 (R)-171 (R)-171 (S)-171 rac-171 rac-171 – 5 5 5 30 ee 170 (%) –67 69 73 40 57 PPh2 PPh2 rac-171 Miscellaneous chiral borate anions There are many chiral borate anions reported in literature that are used for purpose other than asymmetric catalysis. This section will briefly touch on these aspects of chiral borate anions. In 2006, Leitner and co-workers employed chiral ionic liquid (CIL) as a medium for the aza-Baylis-Hillman reaction. 57 The chiral ionic liquid was an ion pair 174 composed of an achiral methyltrioctylammonium cation and a spiroborate anion. They were able to attain enantioselectivity up to 84% ee utilizing this ionic liquid as the chiral reaction medium (Scheme Scheme 1.24). 38 Scheme 1.24 Chiral reaction medium made of spiroborate ion-pair 174 N X Tos Tos O + 172 173 PPh3 chiral reaction medium X 174 X = Br, Me, NO2 NH O + (Octyl)3NMe O OH HO O * O–O B O O O O 175 174 4 examples ee = 71–84% chiral reaction medium Additionally, some chiral borate anions are used as the vehicle for the resolution of racemic compounds. Periasamy and co-workers reported the resolution of BINOL rac-55 by treating it with chiral amine and boric acid. The stereoselectivity is induced by the steroselective formation of the ion pair 147c comprised of the spiroborate anion 20 and a chiral ammonium 58 cation (Figure 1.4). More recently, resolution of racemic chiral diamines has been reported via an ion pair 176 consisting of a chiral diborate dianion and a protonated achiral diamine as the 59 cation (Figure 1.4). Figure 1.4 Chiral borate ion-pairs used for resolution of racemic compounds O – O B O O O O B O – O Ph CH3 147c + NH3 O – O B O O + NH3 NH3 + 176 One of the prominent uses of the chiral borate anions has been its use as chiral NMR shift reagents. Arndtsen and co-workers utilized spiroborate 147e as chiral NMR shift reagent for 60 enantiomeric copper (I) complexes with tol-BINAP and oxazoline ligand (Figure 1.5). 39 Recently, Glorius and co-workers used chiral dianion 177 as a chiral shift reagent for NMR 59 analysis of triphenylphosphonium salts (Figure 1.5). Figure 1.5 Chiral borate ion-pairs used as chiral NMR shift reagents. O – O B O O O O B O – O + Cu(MeCN)4 + C4H9NH3 C4H9NH3 + O – O B O O 147e 177 Chiral borate anions have also been used as ligands in asymmetric catalysis. Peng and coworkers developed a new class of chiral spiroborate ligands and used them in enantioselective 61 Nozaki-Hiyama allylation of alkyl and aryl ketones (Figure 1.6). Figure 1.6 Chiral borate ion-pairs used as chiral ligands. H O – N+ R N B HO O Ph N Ph O – N+ N B HO O N 178 Ph Ph 179 In quest of designing ordered materials with predicable structures and properties, considerable effort has been given to the study of chiral borate anions as a structural unit in 62 solution and in the solid state. Back-to-back twin bowls of D3-symmetry containing tris- (spiroborate) cyclophanes were recently prepared. These compounds have been prepared for 40 potential iterative host–guest interactions in an effort to generate supramolecular chain structures. 63 Finally, it is interesting to observe that there are quite a few chiral spiroborate esters exist 64 in nature (Figure 1.7). 65 boromycin 180, The first natural product containing boron to be identified was a polyether macrolide antibiotic. It was isolated from a culture of Streptomyces antibioticus which originated from a terrestrial soil sample from Ivory Coast. It is active against the Gram-positive bacteria. Boromycin affects the cytoplasmic membrane, which results in the release of potassium ions from the cell. Recent studies have suggested that boromycin has potent anti-HIV activity. coworkers. 67 66 The total synthesis has been reported by White and The second natural product, aplasmomycin 181, was isolated from a strain of Streptomyces griseus obtained from shallow sea and mud. 68 Aplasmomycin inhibits the growth of gram-positive bacteria in vitro and is active against Plasmodium berghei in vivo. 69 synthesis has also been reported by a number of groups. 68 Its total Another structurally related natural 70 product is Tartrolon B 182. It was isolated from Myxobacterium Sorangium cellulosum strain. Like other boron containing natural products, it also inhibits gram-positive bacteria and works as ion carriers. A number of syntheses of this compound have been reported in the recent past. 72 In 1994, Moore and co-workers reported borophycin 183. 71 Borophycin is the potent cytotoxin in the lipophilic extract of a marine strain of the blue-green algae (cyanobacterium) Nostoc linckia. No synthesis of borophycin has been reported yet. It showed cytotoxicity against LoVo 41 72 (MIC 0.066 µg/mL). and borophycin 72 Also, the biosyntheses of boromycin, 73 aplasmomycin, 74 tartrolon B 75 have also been elucidated. All of these natural products are polyketides and have the same boron-binding substrate C1-C7 in each half of the symmetric molecules. Further, a novel AI-2 furanosyl borate diester complex 184 and was originally identified in the bioluminescent marine bacterium Vibrio harveyi as one of the two autoinducers that regulate 76 light production in response to sell density. Later on, it has been proposed to serve as universal bacterial quorum sensing signal containing boron for inter bacteria community communication. 77 Figure 1.7 Chiral borate anions existing in nature O O O O O O O O – OH O B O OH O O O Boromycin 180 O O O O + Na – OH O B O OH O O O O O O Aplasmomycin 181 NH3 + O OH HO OH O – O + B X HO OH Autoinducer-2 AI-2 184 42 Figure 1.7 cont’d OH O O O O O – B O O + Na O OH O O O O O + Na O O O Tartrolon B 182 1.5 – B O O O O O O O O Borophycin 183 Conclusions At the end, it is quite clear that the usage of chiral borate anions has been more prominent in last decade or so. In the field of asymmetric Brønsted acid catalysis, chiral boroxinate (BOROX) anions and other borate anions have been used quite comprehensively for a number of reactions. On the other hand, a lot of work has been done in transition metal catalysis using chiral anions other than borate anions. A significant effort is still needed in order to achieve this goal. In subsequent chapters, a tale of BOROX catalysis will be told. It involves various aspects of catalysis such as designing new BOROX catalysts, novel reaction methodologies and its mechanistic understanding via NMR spectroscopy and computational chemistry. 43 REFERENCES 44 REFERENCES (1) (a) Hanessian, S. In Total Synthesis of Natural Products: The ‘Chiron’ Approach; Baldwin, J. E., Ed.; Pergamon: Oxford, UK, 1983. (b) Nugent, W. A.; Rajanbabu, T. V.; Burk, M. J. Science 1993, 259, 479-483. (c) Taylor, M. S.; Jacobsen, E. N. Proc. Nat. Acad. Sci. U.S.A 2004, 101, 5368-5373. (d) Catalytic Asymmetric Synthesis, 3rd Ed.; Ojima, I., Ed.; Wiley-VCH: Weinheim, 2010. (e) Asymmetric Synthesis: The Essentials, 2nd, Completely Revised Edition; Christmann, M.; Bräse, S., Eds.; Wiley-VCH: Weinheim, 2007. (2) Asymmetric Phase Transfer Catalysis; Maruoka, K., Ed.; Wiley-VCH Weinheim, 2008. (3) (a) Lacour, J.; Hebbe-Viton, V. Chem. Soc. Rev. 2003, 32, 373-382. (b) Lacour, J.; Moraleda, D. Chem. Commun. 2009, 7073-7089. (c) Rueping, M.; Koenigs, R. M.; Atodiresei, I. Chem.– Eur. J. 2010, 16, 9350-9365. (4) Llewellyn, D. B.; Adamson, D.; Arndtsen, B. A. Org. Lett. 2000, 2, 4165-4168. (5) Mayer, S.; List, B. Angew. Chem., Int. Ed. 2006, 45, 4193-4195. (6) (a) Hashimoto, T.; Uchiyama, N.; Maruoka, K. J. Am. Chem. Soc. 2008, 130, 14380-14381. (b) Hashimoto, T.; Maruoka, K. J. Am. Chem. Soc. 2007, 129, 10054-10055. (c) Dorta, R.; Shimon, L.; Milstein, D. J. Organomet. Chem. 2004, 689, 751-758. (7) (a) Hatano, M.; Sugiura, Y.; Akakura, M.; Ishihara, K. Synlett 2011, 1247-1250. (b) Hatano, M.; Maki, T.; Moriyama, K.; Arinobe, M.; Ishihara, K. J. Am. Chem. Soc. 2008, 130, 1685816860. (8) (a) Li, G.; Liang, Y.; Antilla, J. C. J. Am. Chem. Soc. 2007, 129, 5830-5831. (b) Rowland, G. B.; Zhang, H.; Rowland, E. B.; Chennamadhavuni, S.; Wang, Y.; Antilla, J. C. J. Am. Chem. Soc. 2005, 127, 15696-15697. (c) Martin, N. J. A.; List, B. J. Am. Chem. Soc. 2006, 128, 1336813369. (d) Liao, S.; List, B. Angew. Chem., Int. Ed. 2010, 49, 628-631. (e) Hamilton, G. L.; Kang, E. J.; Mba, M.; Toste, F. D. Science 2007, 317, 496-499. (f) List, B.; Adair, G.; Mukherjee, S. Aldrichimica Acta 2008, 41, 31-39. (g) Xu, S.; Wang, Z.; Zhang, X.; Ding, K. Eur. J. Org. Chem. 2011, 110-116. (h) Jiang, G.; List, B. Chem. Commun. 2011, 47, 1002210024. (i) Coric, I.; Mueller, S.; List, B. J. Am. Chem. Soc. 2010, 132, 17370-17373. (9) (a) Chen, L.-Y.; He, H.; Chan, W.-H.; Lee, A. W. M. J. Org. Chem. 2011, 76, 7141-7147. (b) Ratjen, L.; Garcìa-Garcìa, P.; Lay, F.; Beck, M. E.; List, B. Angew. Chem., Int. Ed. 2011, 50, 45 754-758. (c) Garcìa-Garcìa, P.; Lay, F.; Garcìa-Garcìa, P.; Rabalakos, C.; List, B. Angew. Chem., Int. Ed. 2009, 48, 4363-4366. (10) (a) Rueping, M.; Uria, U.; Lin, M.-Y.; Atodiresei, I. J. Am. Chem. Soc. 2011, 133, 37323735. (b) Rueping, M.; Nachtsheim, B. J.; Koenigs, R. M.; Ieawsuwan, W. Chem.–Eur. J. 2010, 16, 13116-13126. (c) Rueping, M.; Nachtsheim, B. J.; Moreth, S. A.; Bolte, M. Angew. Chem., Int. Ed. 2008, 47, 593-596. (11) (a) Goncalves-Farbos, M.-H.; Vial, L.; Lacour, J. Chem. Commun. 2008, 829-831. (b) Carter, C.; Fletcher, S.; Nelson, A. Tetrahedron: Asymmetry 2003, 14, 1995-2004. (c) Lacour, J.; Monchaud, D.; Marsol, C. Tetrahedron Lett. 2002, 43, 8257-8260. (12) Belokon, Y. N.; Maleev, V. I.; Kataev, D. A.; Mal’fanov, I. L.; Bulychev, A. G.; Moskalenko, M. A.; Saveleva, T. y. F.; Skrupskaya, T. y. V.; Lyssenko, K. A.; Godovikov, I. A.; North, M. Tetrahedron: Asymmetry 2008, 19, 822-831. (13) (a) Peterson, E. A.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2009, 48, 6328-6331. (b) Reisman, S. E.; Doyle, A. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2008, 130, 7198-7199. (c) Pan, S. C.; List, B. Chem.–Asian. J. 2008, 3, 430-437. (d) Raheem, I. T.; Thiara, P. S.; Peterson, E. A.; Jacobsen, E. N. J. Am. Chem. Soc. 2007, 129, 13404-13405. (14) (a) Ishihara, K.; Miyata, M.; Hattori, K.; Tada, T.; Yamamoto, H. J. Am. Chem. Soc. 1994, 116, 10520-10524. (b) Ishihara, K.; Kuroki, Y.; Yamamoto, H. Synlett 1995, 41-42. (c) Kuroki, Y.; Ishihara, K.; Hanaki, N.; Ohara, S.; Yamamoto, H. Bull. Chem. Soc. Jpn. 1998, 71, 12211230. (d) Cros, J. P.; Pérez-Fuertes, Y.; Thatcher, M. J.; Arimori, S.; Bull, S. D.; James, T. D. Tetrahedron: Asymmetry 2003, 14, 1965-1968. (e) Kawate, T.; Yamada, H.; Matsumizu, M.; Nishida, A.; Nakagawa, M. Synlett 1997, 761-762. (f) Yamada, H.; Kawate, T.; Matsumizu, M.; Nishida, A.; Yamaguchi, K.; Nakagawa, M. J. Org. Chem. 1998, 63, 6348-6354. (15) (a) Ishihara, K.; Yamamoto, H. J. Am. Chem. Soc. 1994, 116, 1561-1562. (b) Ishihara, K.; Kurihara, H.; Yamamoto, H. J. Am. Chem. Soc. 1996, 118, 3049-3050. (c) Ishihara, K.; Kurihara, H.; Matsumoto, M.; Yamamoto, H. J. Am. Chem. Soc. 1998, 120, 6920-6930. (d) Ishihara, K.; Kondo, S.; Kurihara, H.; Yamamoto, H.; Ohashi, S.; Inagaki, S. J. Org. Chem. 1997, 62, 30263027. (e) Dai, X.; Davies, H. M. L. Adv. Synth. Catal. 2006, 348, 2449-2456. (16) (a) Zhang, Y.; Desai, A.; Lu, A.; Hu, G.; Ding, Z.; Wulff, W. D. Chem. –Eur. J. 2008, 14, 3785-3803. (b) Zhang, Y.; Lu, Z.; Desai, A.; Wulff, W. D. Org. Lett. 2008, 10, 5429-5432. (c) Mukherjee, M.; Gupta, A. K.; Lu, Z.; Zhang, Y.; Wulff, W. D. J. Org. Chem. 2010, 75, 56435660. (d) Ren, H.; Wulff, W. D. Org. Lett. 2010, 12, 4908-4911. (e) Hu, G.; Huang, L.; Huang, R. H.; Wulff, W. D. J. Am. Chem. Soc. 2009, 131, 15615-15617. (f) Hu, G.; Gupta, A. K.; 46 Huang, R. H.; Mukherjee, M.; Wulff, W. D. J. Am. Chem. Soc. 2010, 132, 14669–14675. (g) Gupta, A. K.; Mukherjee, M.; Wulff, W. D. Org. Lett. 2011, 13, 5866-5869. (h) Newman, C. A.; Antilla, J. C.; Chen, P.; Predeus, A. V.; Fielding, L.; Wulff, W. D. J. Am. Chem. Soc. 2007, 129, 7216-7217. (i) Desai, A. A.; Wulff, W. D. J. Am. Chem. Soc. 2010, 132, 13100-13103. (j) Vetticatt, M. J.; Desai, A. A.; Wulff, W. D. J. Am. Chem. Soc. 2010, 132, 13104-13107. (k) Desai, A. A.; Morán-Ramallal, R.; Wulff, W. D. Org. Synth. 2011, 88, 224-237. (l) Ren, H.; Wulff, W. D. J. Am. Chem. Soc. 2011, 133, 5656-5659. (m) Desai, A. A.; Ren, H.; Mukherjee, M.; Wulff, W. D. Org. Process Res. Dev. 2011, 15, 1108-1115. (17) Chen, D.; Sundararaju, B.; Krause, R.; Klankermayer, J.; Dixneuf, P. H.; Leitner, W. ChemCatChem 2010, 2, 55-57. (18) Llewellyn, D. B.; Arndtsen, B. A. Organometallics 2004, 23, 2838-2840. (19) Llewellyn, D. B.; Arndtsen, B. A. Tetrahedron: Asymmetry 2005, 16, 1789-1799. (20) (a) Rueping, M.; Nachtsheim, B. J.; Ieawsuwan, W.; Atodiresei, I. Angew. Chem., Int. Ed. 2011, 50, 6706-6720. (b) Schenker, S.; Zamfir, A.; Freund, M.; Tsogoeva, S. B. Eur. J. Org. Chem. 2011, 2209-2222. (c) Rueping, M.; Kuenkel, A.; Atodiresei, I. Chem. Soc. Rev. 2011, 40, 4539-4549. (d) List, B.; Kampen, D.; Reisinger, C. M. Top Curr Chem 2010, 291, 395-456. (e) Sohtome, Y.; Nagasawa, K. Synlett 2010, 1-22. (f) Yamamoto, H.; Payette, J. N. In Hydrogen Bonding in Organic Synthesis; Wiley-VCH 2009, p 73-140. (g) Yu, X.; Wang, W. Chem.–Asian. J. 2008, 3, 516-532. (h) Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713-5743. (i) Akiyama, T. Chem. Rev. 2007, 107, 5744-5758. (j) Taylor, M. S. J., E. N. Angew. Chem., Int. Ed. 2006, 45, 1520-1543. (k) Akiyama, T.; Itoh, J.; Fuchibe, K. Adv. Synth. Catal. 2006, 348, 9991010. (21) (a) Terada, M. Synthesis 2010, 1929-1982. (b) Terada, M. Bull. Chem. Soc. Jpn. 2010, 83, 101-119. (c) Zamfir, A.; Schenker, S.; Freund, M.; Tsogoeva, S. B. Org. Biomol. Chem. 2010, 8. (d) Terada, M. Chem. Commun. (Cambridge, U. K.) 2008, 4097-4112. (e) Connon, S. J. Angew. Chem., Int. Ed. 2006, 45, 3909-3912. (22) (a) Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem., Int. Ed. 2004, 43, 15661568. (b) Uraguchi, D.; Terada, M. J. Am. Chem. Soc. 2004, 126, 5356-5357. (23) Shapiro, N. D.; Rauniyar, V.; Hamilton, G. L.; Wu, J.; Toste, F. D. Nature 2011, 470, 245249. 47 (24) Momiyama, N.; Konno, T.; Furiya, Y.; Iwamoto, T.; Terada, M. J. Am. Chem. Soc. 2011, 133, 19294-19297. (25) (a) Desai, A. A.; Wulff, W. D. Synthesis 2010, 3670-3680. (b) Rowland, E. B.; Rowland, G. B.; Rivera-Otero, E.; Antilla, J. C. J. Am. Chem. Soc. 2007, 129, 12084-12085. (26) (a) Senatore, M.; Lattanzi, A.; Santoro, S.; Santi, C.; Della, S. G. Org. Biomol. Chem. 2011, 9, 6205-6207. (b) Desai, A. A.; Huang, L.; Wulff, W. D.; Rowland, G. B.; Antilla, J. C. Synthesis 2010, 2106-2109. (c) Larson, S. E.; Baso, J. C.; Li, G.; Antilla, J. C. Org. Lett. 2009, 11, 51865189. (d) Della, S. G.; Lattanzi, A. Org. Lett. 2009, 11, 3330-3333. (e) Rowland, G. B.; Rowland, E. B.; Liang, Y.; Perman, J. A.; Antilla, J. C. Org. Lett. 2007, 9, 2609-2611. (f) Liang, Y.; Rowland, E. B.; Rowland, G. B.; Perman, J. A.; Antilla, J. C. Chem. Commun. 2007, 44774479. (27) (a) Xu, B.; Zhu, S.-F.; Xie, X.-L.; Shen, J.-J.; Zhou, Q.-L. Angew. Chem., Int. Ed. 2011, 50, 11483-11486. (b) Xing, C.-H.; Liao, Y.-X.; Ng, J.; Hu, Q.-S. J. Org. Chem. 2011, 76, 41254131. (c) Müller, S.; Webber, M. J.; List, B. J. Am. Chem. Soc. 2011, 133, 18534-18537. (d) Huang, D.; Xu, F.; Lin, X.; Wang, Y. Chiral spirocyclic phosphoric acid, its preparation method and application as catalyst CN102030780A Apr 27, 2011. (e) Xu, F.; Huang, D.; Han, C.; Shen, W.; Lin, X.; Wang, Y. J. Org. Chem. 2010, 75, 8677-8680. (28) (a) Akiyama, T. Preparation of cyclic erythritol phosphoric acid derivatives as catalysts for asymmetric synthesis WO2006092884A1 . (b) Voituriez, A.; Charette, A. B. Adv. Synth. Catal. 2006, 348, 2363-2370. (c) Akiyama, T.; Saitoh, Y.; Morita, H.; Fuchibe, K. Adv. Synth. Catal. 2005, 347, 1523-1526. (29) (a) Zheng, W.; Zhang, Z.; Kaplan, M. J.; Antilla, J. C. J. Am. Chem. Soc. 2011, 133, 33393341. (b) Zhang, Z.; Zheng, W.; Antilla, J. C. Angew. Chem., Int. Ed. 2011, 50, 1135-1138. (c) Larson, S. E.; Li, G.; Rowland, G. B.; Junge, D.; Huang, R.; Woodcock, H. L.; Antilla, J. C. Org. Lett. 2011, 13, 2188-2191. (d) Rueping, M.; Bootwicha, T.; Sugiono, E. Synlett 2011, 323-326. (e) Hatano, M.; Ishihara, K. Synthesis 2010, 3785-3801. (f) Klussmann, M.; Ratjen, L.; Hoffmann, S.; Wakchaure, V.; Goddard, R.; List, B. Synlett 2010, 2189-2192. (30) Terada, M.; Sorimachi, K.; Uraguchi, D. Synlett 2006, 133-136. (31) (a) Hashimoto, T.; Nakatsu, H.; Yamamoto, K.; Maruoka, K. J. Am. Chem. Soc. 2011, 133, 9730-9733. (b) Vellalath, S.; Coric, I.; List, B. Angew. Chem., Int. Ed. 2010, 49, 9749-9752. (c) Cheon, C. H.; Yamamoto, H. J. Am. Chem. Soc. 2008, 130, 9246-9247. (d) Rueping, M.; Ieawsuwan, W.; Antonchick, A. P.; Nachtsheim, B. J. Angew. Chem., Int. Ed. 2007, 46, 20972100. (e) Nakashima, D.; Yamamoto, H. J. Am. Chem. Soc. 2006, 128, 9626-9627. 48 (32) (a) He, H.; Chen, L.-Y.; Wong, W.-Y.; Chan, W.-H.; Lee, A. W. M. Eur. J. Org. Chem. 2010, 4181-4184. (b) Treskow, M.; Neudoerfl, J.; Giernoth, R. Eur. J. Org. Chem. 2009, 36933697. (33) Berkessel, A.; Christ, P.; Leconte, N.; Neudörfl, J.-M.; Schäfer, M. Eur. J. Org. Chem. 2010, 5165-5170. (34) Coric, I.; List, B. Nature 2012, 483, 315-319. (35) (a) Hashimoto, T.; Omote, M.; Maruoka, K. Angew. Chem., Int. Ed. 2011, 50, 3489-3492. (b) Hashimoto, T.; Omote, M.; Maruoka, K. Angew. Chem., Int. Ed. 2011, 50, 8952-8955. (c) Hashimoto, T.; Kimura, H.; Nakatsu, H.; Maruoka, K. J. Org. Chem. 2011, 76, 6030-6037. (d) Hashimoto, T.; Kimura, H.; Maruoka, K. Angew. Chem., Int. Ed. 2010, 49, 6844-6847. (36) Hatano, M.; Sugiura, Y.; Ishihara, K. Tetrahedron: Asymmetry 2010, 21, 1311-1314. (37) Christ, P.; Lindsay, A. G.; Vormittag, S. S.; Neudoerfl, J.-M.; Berkessel, A.; O'Donoghue, A. C. Chem.–Eur. J. 2011, 17, 8524-8528. (38) Rueping, M.; Theissmann, T. Chem. Sci. 2010, 1, 473-476. (39) (a) Fleischmann, M.; Drettwan, D.; Sugiono, E.; Rueping, M.; Gschwind, R. M. Angew. Chem., Int. Ed. 2011, 50, 6364-6369. (b) Simón, L.; Goodman, J. M. J. Org. Chem. 2011, 76, 1775-1788. (40) (a) Takemoto, Y. Chem. Pharm. Bull. 2010, 58, 593-601. (b) Yoshida, K.; Inokuma, T.; Takasu, K.; Takemoto, Y. Molecules 2010, 15, 8305-8326. (c) Rodriguez, A. A.; Yoo, H.; Ziller, J. W.; Shea, K. J. Tetrahedron Lett. 2009, 50, 6830-6833. (d) Connon, S. J. Chem. Commun. 2008. (e) Rampalakos, C.; Wulff, W. D. Adv. Synth. Catal. 2008, 350, 1785-1790. (f) Connon, S. J. Chem.–Eur. J. 2006, 12, 5418-5427. (g) Takemoto, Y. Org. Biomol. Chem. 2005, 3. (41) (a) Huang, Y.; Unni, A. K.; Thadani, A. N.; Rawal, V. H. Nature 2003, 424, 146-146. (b) Thadani, A. N.; Stankovic, A. R.; Rawal, V. H. Proc. Nat. Acad. Sci. U.S.A 2004, 101, 58465850. (c) Gondi, V. B.; Gravel, M.; Rawal, V. H. Org. Lett. 2005, 7, 5657-5660. (d) McGilvra, J. D.; Unni, A. K.; Modi, K.; Rawal, V. H. Angew. Chem., Int. Ed. 2006, 45, 6130-6133. (e) Gómez-Bengoa, E. Eur. J. Org. Chem. 2009, 1207-1213. (f) Etzenbach-Effers, K.; Berkessel, A. Top Curr Chem 2010, 291, 1-27. 49 (42) (a) Tillman, A. L.; Dixon, D. J. Org. Biomol. Chem. 2007, 5. (b) Momiyama, N.; Yamamoto, Y.; Yamamoto, H. J. Am. Chem. Soc. 2007, 129, 1190-1195. (c) Matsui, K.; Takizawa, S.; Sasai, H. Synlett 2006, 761-765. (d) Momiyama, N.; Yamamoto, H. J. Am. Chem. Soc. 2005, 127, 1080-1081. (e) Matsui, K.; Takizawa, S.; Sasai, H. J. Am. Chem. Soc. 2005, 127, 3680-3681. (f) Dixon, D. J.; Tillman, A. L. Synlett 2005, 2635-2638. (g) McDougal, N. T.; Schaus, S. E. J. Am. Chem. Soc. 2003, 125, 12094-12095. (h) Dixon, D. J.; Tillman, A. L. Synlett 2005, 2635-2638. (43) (a) Privileged Chiral Ligands and Catalysts; Zhou, Q.-L., Ed.; Wiley-VCH: Weinheim, 2011. (b) Brunel, J. M. Chem. Rev. 2008, 108, 1170-1170. (c) Chen, Y.; Yekta, S.; Yudin, A. K. Chem. Rev. 2003, 103, 3155-3211. (d) Jorgensen, K. A.; Simonsen, K. B.; Gothelf, K. V. J. Org. Chem. 1998, 63, 7536-7538. (44) (a) Heumann, L. V.; Keck, G. E. J. Org. Chem. 2008, 73, 4725-4727. (b) Takasaki, M.; Motoyama, Y.; Yoon, S.-H.; Mochida, I.; Nagashima, H. J. Org. Chem. 2007, 72, 10291-10293. (c) Korostylev, A.; Tararov, V. I.; Fischer, C.; Monsees, A.; Borner, A. J. Org. Chem. 2004, 69, 3220-3221. (d) Au-Yeung, T. T. L.; Chan, S.-S.; Chan, A. S. C. Adv. Synth. Catal. 2003, 345, 537-555 and references therein. (e) Ding, K.; Guo, H. Tetrahedron Lett. 2000, 41, 10061-10064. (45) Ding, Z.; Osminski, W. E. G.; Ren, H.; Wulff, W. D. Org. Process Res. Dev. 2011, 15, 1089-1107 and references therein. (46) (a) Zhou, Q. L.; Xie, J. H. Top. Organomet. Chem. 2011, 36, 1-28. (b) Ding, K. L.; Han, Z. B.; Wang, Z. Chem.–Asian. J. 2009, 4, 32-41 and references therein. (c) Cheng, X.; Hou, G. H.; Xie, J. H.; Zhou, Q. L. Org. Lett. 2004, 6, 2381-2383. (d) Zhu, S. F.; Fu, Y.; Xie, J. H.; Liu, B.; Xing, L.; Zhou, Q. L. Tetrahedron: Asymmetry 2003, 14, 3219-3224. (e) Zhang, J. H.; Liao, J.; Cui, X.; Yu, K. B.; Zhu, J.; Deng, J. G.; Zhu, S. F.; Wang, L. X.; Zhou, Q. L.; Chung, L. W.; Ye, T. Tetrahedron: Asymmetry 2002, 13, 1363-1366. (f) Birman, V. B.; L. Rheingold, A.; Lam, K.C. Tetrahedron: Asymmetry 1999, 10, 125-131. (47) (a) Lam, H. W. Synthesis 2011, 2011-2043. (b) Pellissier, H. Tetrahedron 2008, 64, 1027910317. (c) Seebach, D.; Beck, A. K.; Heckel, A. Angew. Chem., Int. Ed. 2001, 40, 92-138. (48) Zhang, Z.; Jain, P.; Antilla, J. C. Angew. Chem., Int. Ed. 2011, 50, 10961-10964. (49) Martin, N. J. A.; List, B. J. Am. Chem. Soc. 2006, 128, 13368-13369. (50) Hu, G. PhD Thesis, Michigan State University, 2007. 50 (51) Hu, G.; Huang, L.; Gupta, A. K.; Huang, R.; Wulff, W. D., manuscript in preparation. (52) Guan, Y.; Wulff, W. D., Unpublished results. (53) Gupta, A. K.; Wulff, W. D., Unpublished results. (54) Desai, A.; Wulff, W. D., Unpublished results. (55) (a) Huang, L.; Zhang, Y.; Staples, R. J.; Huang, R. H.; Wulff, W. D. Chem.–Eur. J. 2012, 18, 5302-5313. (b) Mukherjee, M. PhD Dissertation, Michigan State University, 2012. (56) Hamilton, G. L.; Kanai, T.; Toste, F. D. J. Am. Chem. Soc. 2008, 130, 14984-14986. (57) Gausepohl, R.; Buskens, P.; Kleinen, J.; Bruckmann, A.; Lehmann, C. W.; Klankermayer, J.; Leitner, W. Angew. Chem., Int. Ed. 2006, 45, 3689-3692. (58) Periasamy, M.; Venkatraman, L.; Sivakumar, S.; Sampathkumar, N.; Ramanathan, C. R. J. Org. Chem. 1999, 64, 7643-7645. (59) Loewer, Y.; Weiss, C.; Biju, A. T.; Fröhlich, R.; Glorius, F. J. Org. Chem. 2011, 76, 23242327. (60) Llewellyn, D. B.; Arndtsen, B. A. Can. J. Chem. 2003, 81, 1280-1284. (61) Huang, X.-R.; Chen, C.; Lee, G.-H.; Peng, S.-M. Adv. Synth. Catal. 2009, 351, 3089-3095. (62) (a) Raskatov, J. A.; Brown, J. M.; Thompson, A. L. Crystengcomm 2011, 13, 2923-2929. (b) Wrackmeyer, B.; Klimkina, E. V.; Milius, W. Eur. J. Inorg. Chem. 2011, 2164-2171. (c) Tu, T.; Maris, T.; Wuest, J. D. Cryst. Growth Des. 2008, 8, 1541-1546. (d) Green, S.; Nelson, A.; Warriner, S.; Whittaker, B. J. Chem. Soc., Perkin Trans. 1 2000, 4403-4408. (63) Danjo, H.; Hirata, K.; Yoshigai, S.; Azumaya, I.; Yamaguchi, K. J. Am. Chem. Soc. 2009, 131, 1638-1639. 51 (64) (a) Baker, S. J.; Tomsho, J. W.; Benkovic, S. J. Chem. Soc. Rev. 2011, 40. (b) Carrano, C.; Schellenberg, S.; Amin, S.; Green, D.; Küpper, F. Mar. Biotechnol. 2009, 11, 431-440. (c) Dembitsky, V. M.; Smoum, R.; Al-Quntar, A. A.; Ali, H. A.; Pergament, I.; Srebnik, M. Plant Science 2002, 163, 931-942. (65) (a) Dunitz, J. D.; Hawley, D. M.; Mikloš, D.; White, D. N. J.; Berlin, Y.; Marušić, R.; Prelog, V. Helv. Chim. Acta 1971, 54, 1709-1713. (b) Hütter, R.; Keller-Schien, W.; Knüsel, F.; Prelog, V.; Rodgers, G. C.; Suter, P.; Vogel, G.; Voser, W.; Zähner, H. Helv. Chim. Acta 1967, 50, 1533-1539. (66) Kohno, J.; Kawahata, T.; Otake, T.; Morimoto, M.; Mori, H.; Ueba, N.; Nishio, M.; Kinumaki, A.; Komatsubara, S.; Kawashima, K. Biosci. Biotechnol., Biochem. 1996, 60, 10361037. (67) White, J. D.; Avery, M. A.; Choudhry, S. C.; Dhingra, O. P.; Gray, B. D.; Kang, M. C.; Kuo, S. C.; Whittle, A. J. J. Am. Chem. Soc. 1989, 111, 790-792. (68) Okami, Y.; Okazaki, T.; KIitahara, T.; Umezawa, H. J. Antibiot. 1976, 29, 1019-1025. (69) (a) Matsuda, F.; Tomiyoshi, N.; Yanagiya, M.; Matsumoto, T. Tetrahedron 1990, 46, 34693488. (b) White, J. D.; Vedananda, T. R.; Kang, M. C.; Choudhry, S. C. J. Am. Chem. Soc. 1986, 108, 8105-8107. (c) Nakata, T.; Saito, K.; Oishi, T. Tetrahedron Lett. 1986, 27, 6345-6348. (d) Corey, E. J.; Pan, B. C.; Hua, D. H.; Deardorff, D. R. J. Am. Chem. Soc. 1982, 104, 6816-6818. (e) Corey, E. J.; Hua, D. H.; Pan, B. C.; Seitz, S. P. J. Am. Chem. Soc. 1982, 104, 6818-6820. (70) Irschik, H.; Schummer, D.; Gerth, K.; Höfle, G.; Reichenbach, H. J. Antibiot. 1977, 48, 2630. (71) (a) Mulzer, J.; Berger, M. J. Org. Chem. 2004, 69, 891-898. (b) Berger, M.; Mulzer, J. J. Am. Chem. Soc. 1999, 121, 8393-8394. (72) Hemscheidt, T.; Puglisi, M. P.; Larsen, L. K.; Patterson, G. M. L.; Moore, R. E.; Rios, J. L.; Clardy, J. J. Org. Chem. 1994, 59, 3467-3471. (73) Chen, T. S. S.; Chang, C.-J.; Floss, H. G. J. Org. Chem. 1981, 46, 2661-2665. 52 (74) (a) Lee, J. J.; Dewick, P. M.; Gorst-Allman, C. P.; Spreafico, F.; Kowal, C.; Chang, C. J.; McInnes, A. G.; Walter, J. A.; Keller, P. J.; Floss, H. G. J. Am. Chem. Soc. 1987, 109, 54265432. (b) Chen, T. S. S.; Chang, C.-J.; Floss, H. G. J. Am. Chem. Soc. 1981, 103, 4565-4568. (75) Schummer, D.; Schomburg, D.; Irschik, H.; Reichenbach, H.; Höfle, G. Liebigs Ann. Chem. 1996, 965-969. (76) Bassler, B. L.; Wright, M.; Showalter, R. E.; Silverman, M. R. Mol. Microbiol. 1993, 9, 773-786. (77) Chen, X.; Schauder, S.; Potier, N.; Van Dorsselaer, A.; Pelczer, I.; Bassler, B. L.; Hughson, F. M. Nature 2002, 415, 545-549. 53 CHAPTER 2   A NEW ARRAY OF BRØNSTED ACID CATALYSTS DERIVED FROM CHIRAL BORATE ANIONS I think you don’t have enough work in the lab. Plus, I think you need another paper. -William D. Wulff As discussed in chapter 1, the field of asymmetric Brønsted acid catalysis has made 1 amazing advances over the last few years. Particularly, there has been an exponential growth in the field of chiral phosphoric 2 acids, 5 3 phosphoramides, 6 bis(sulfuryl)imides, chiral dicarboxylic acids, and chiral disulfonic acids 1a BINOL and H8-BINOL and their derivatives. 8 8-9 derived from VANOL, VAPOL, 10 SPINOL, 4 bis(sufonyl)imides, 7 prepared from More recently, novel chiral phosphoric acids 10f,11 and TADDOL have also been employed. In the case of Brønsted acids derived from chiral borate anions, there is no example reported prior to our work. Although Brønsted acid catalyst derived from spiroborate anions 12 have been reported, they have been proposed to mechanistically function as a Lewis acid until it was found in work for this thesis that they can function as Brønsted acids (Scheme 4.6, Chapter 4). At the present time, there are three different kinds of Brønsted acid catalysts derived from chiral borate anions as shown in Figure 2.1. These are characterized by NMR spectroscopy and are discussed in subsequent sections of this chapter. 54 Figure 2.1 Brønsted acid catalysts derived from chiral borate anions and imines as the base Ph Ph Ar OPh P O B O– N+ B O H O O B R OPh OPh O B O– B O O O B OPh Ar P N+ H R 185 (Ar = H) 104a/105a 186 (Ar ≠ H) B3 (BOROX) B3 (BOROX) P + NH O – B O O R O – O B O O R O + P N H 92 B1 (FSB) 2.1 74 B1 (SB) B3 or BOROX Catalysts Prior to our report, a Brønsted acid derived from a chiral boroxinate anion has never been reported (Scheme 2.1). 13 Since the boroxinate anion can be viewed as a derivative of a boroxine ring, we coined a new term “BOROX catalyst” for this class of catalysts. These novel spiroboroxinate catalysts are formed only upon the addition of a base (usually imines) and thus it belongs to class II type catalysts (Table 1.1, Chapter 1). Initially, only imines were used to generate these catalysts. The aim of this part of the project is two fold: a) refinement of the study 55 towards the discovery of unique chiral boroxinate catalysts generated by imines b) screening other bases and thereby generating an array of novel Brønsted acid catalysts and subsequently their application in asymmetric catalysts. Hence, a number of novel BOROX catalysts were 1 generated using different bases. These catalysts were characterized by H NMR, 11 B NMR spectroscopy and computational chemistry. It must be noted that these catalysts could also be chiral Lewis acids as similar NMR behavior is expected in the case of Lewis acids. However, we were able to obtain X-ray crystals of the BOROX catalysts with bases such as imines 13f and 2,6- lutidine (this work). The screening of different bases is discussed below. 2.1.1 Imines as the base: IMINO-BOROX catalyst Over the past few years, we have developed a universal catalytic asymmetric aziridination reaction of imines utilizing a catalyst derived from either of the vaulted ligands 13 VAPOL 58 or VANOL 59 and commercial B(OPh)3 (Chapter 1, Scheme 1.13). the work reported by Brookhart and Templeton, 14 Inspired by we reported the catalytic asymmetric 15 aziridination of imines 78 to afford cis-aziridines in 1999 and 2000. Meanwhile, a lot of mechanistic studies were carried out in our group regarding the identification of the structure of the active catalyst. Prior to these studies, it was believed that the active catalyst was B1 106/107 (Scheme 2.1) that was generated from VAPOL or VANOL when reacted with triphenyl borate 187a. This proposed structure was based on analogous studies carried out by Yamamoto on 12a,16 BINOL 55, however no spectroscopic evidence was presented by Yamamoto for his proposed structure. Further, Yu Zhang, one of the former group members, found that on the 56 basis of NMR and MS studies there are two boron species identified as B2 108/109 and B1 13a 106/107 (Scheme 2.1). Additionally, it was found that the catalyst enriched with B2 108/109 gives higher asymmetric inductions and higher rates in the aziridination reaction compared with catalyst enriched with B1 106/107. In the continuing effort to probe the mechanistic rationale for the asymmetric inductions observed for catalysts generated from VAPOL and VANOL, a major breakthrough was the identification of the active boroxinate catalyst 188/189 (Scheme 2.1). Surprisingly, the catalyst for the aziridination reaction proved to be a Brønsted acid catalysis in operation contrary to the common belief that a Lewis-acid catalyst was involved. In general, the pKa of protonated imines is approximately 7. 17 This suggests that the pKa value of the protonated boroxinate species should be in the same range i.e. either lower or equal to 7. Scheme 2.1 The Wulff asymmetric cis-aziridination reaction with benzhydryl imines 78 O Ph R N Ph OH OH OEt N2 toluene 25 °C, 24 h 85 78 Ph Ph + IMINO-BOROX catalyst 188 or 189 (5-10 mol %) Ph Ph N R CO2Et 86 B(OPh)3 187a (3 equiv) imine B1 + B2 + 78 Ph other boron Ph toluene, 80 °C, 1 h compounds then 0.5 mmHg pre-catalyst 80 °C. 0.5 h Ph OPh Ph O B O– N+ B O H O O B R OPh 188 (for (S)-VAPOL) 189 (for (S)-VANOL) B3 (IMINO-BOROX) (S)-VAPOL 58 (S)-VANOL 59 57 Scheme 2.1 cont’d O Ph Ph O Ph Ph B OPh 106 (for (S)-VAPOL) 107 (for (S)-VANOL) B1 OPh B O B O OPh O 108 (for (S)-VAPOL) 109 (for (S)-VANOL) B2 This is the first ever example of a chiral boroxinate catalyst reported in the literature. Gang Hu, one of the former group members, was able to characterize the catalyst by obtaining 13f the X-ray crystal structure of the boroxinate catalyst with the MEDAM phenyl imine 111a. The crystal structure of catalyst 190a showed a complex consisting of a protonated imine and a chiral counteranion in the form of a boroxinate anion derived from (S)-VAPOL 58 and commercial B(OPh)3 (Figure 2.2). Apart from the strong hydrogen bond (d1), a number of important non-covalent interactions (d2-d7, CH-π and π-π) were observed as shown in Figure 2.2. The nature of the involvement of the imine suggested that the actual catalyst was formed upon the addition of imine. X-ray structure revealed the presence of a tetra-coordinate boron which was further confirmed by 11 1 B NMR spectroscopy. A H NMR study of the crystals revealed that the bay proton (Hb) of VAPOL shifted up field to δ 10.2-10.4 ppm. Our understanding of the catalyst was greatly enhanced since we were able to obtain crystals and structural information about the actual boroxinate catalyst in the aziridination reaction. However, it is not easy to grow crystals on demand. It was then thought to design an NMR 58 protocol in order to characterize these kinds of catalysts. Gang Hu, a former group member, initiated certain NMR experiments, however, a quantitative assessment of the BOROX catalysts and other VAPOL derivatives was missing. Figure 2.2 (A) Generation of the BOROX catalysts 190a and 191a. (B) Diagrammatic representation of the solid-state structure of the chemzyme-substrate complex 190a. A Ph Ph MeO 1. B(OPh)3 187a (3 equiv) H2O (3 equiv) OH OH OPh O B O– B O O O B OPh Ph Ph Ph THF, 80 °C, 1 h then 0.5 mmHg 80 °C. 0.5 h + N H OMe 2. imine 111a (1 equiv) 190a (for (S)-VAPOL) 191a (for (S)-VANOL) B3 (IMINO-BOROX) (S)-VAPOL 58 (S)-VANOL 59 B d2 d3 d4 B C – O O B O O B O B O O H Me MeO Me d5 d7 d6 d1 IMINO-BOROX 190a 59 CH-π 4.42 Å CH-π 4.14 Å CH-π 3.83 Å d5 + N H d2 π-π 3.44 Å d6 CH-O 2.86 Å d7 H 2.02 Å d4 Me H-Bond d3 Me A d1 OMe CH-π 4.57 Å 2.1.1.1 B(OPh)3 as the boron source A series of NMR experiments were designed to devise the protocol for the characterization of BOROX catalysts generated by vaulted ligands and commercial B(OPh)3. The identification of various species generated in the process is facilitated by the fact that the bay proton (Hb) of VAPOL 58, its derivatives B1 106 and B2 108 along with the IMINO-BOROX catalyst 190a are quite distinct. The chemical shift of the bay protons for VAPOL is at δ = 9.77 ppm (CDCl3). To begin with, we employed the traditional method for catalyst formation which involves heating (S)-VAPOL with 3 equiv of commercial B(OPh)3 at 80 °C. This resulted in the generation of a 53% yield of pyroborate B2 106 (δ = 9.22 ppm, CDCl3) along with a 6% yield of the meso-borate B1 104 (δ = 9.55 ppm, CDCl3) and 20% of unreacted VAPOL (entry 1, Figure 2.3B). Treatment of this mixture with 2 equivalents of the imine 111a at room temperature within a few minutes results in the conversion of the colorless solution of 106 and 108 to a red solution of boroxinate 190a (δ = 10.26 ppm, CDCl3) in 81% yield (entry 2, Figure 2.3B). Another tool that has been used in the characterization of these catalysts is 11 B NMR spectroscopy. Three coordinate aryl borate compounds show very broad absorptions at 16-18 ppm in the 11 B NMR spectrum. However, the increased spherical symmetry of a tetra- coordinate boron leads to a sharpening of the absorption and the negative charge of the borate causes an upfield shift. The IMINO-BOROX catalyst 190a has a sharp absorption at 5.33 ppm (entry 2, Figure 2.3C). The ratio of the tetra-coordinate boron to tri-coordinate boron is found to 60 be 1:2 which furthers supports the structure of the BOROX catalyst. This study was published in a recent publication. 13f Figure 2.3 (A) Imine induced boroxinate catalyst formation using commercial B(OPh)3. (B) 1 a H NMR spectra in CDCl3 with Ph3CH as internal standard with percent yields of 190a given parenthesis. (C) A 11 1 B NMR spectra corresponding to the H NMR spectra in Figure 2.3B MeO Ph Ph 1. B(OPh)3 187a H2O (x equiv) Method A-C OH OH 2. imine 111a (2 equiv) CDCl3, 25 °C 10 min OPh O B O– B O O O B OPh Ph Ph Ph IMINO-BOROX B3 190a (S)-VAPOL 58 B + N H B3 190a (76%) 58 58 B3 190a (83%) B2 108 B1 106 B2 108 B3 190a (88%) 58 58 B1 106 B3 190a (81%) B2 108 B2 108 B2 108 58 B1 106 61 B2 108 OMe Figure 2.3 C cont’d B3 190a B3 190a B3 190a B3 190a a Note for Figure 2.3B: Entry 1: (S)-VAPOL (0.1 mmol) plus 3 equiv commercial B(OPh)3 were heated at 80 °C in toluene for 1 h followed by removal of volatiles under vacuum for 0.5 h (method A). Entry 2: 2.0 equiv of imine 111a added to the solution in entry 1 for 10 min at 25 °C. Entry 3: Same as entry 1 except that 3 equiv of H2O was also added to make the precatalyst in THF (method B). Entry 4: 2.0 equiv of imine 111a added to the solution in entry 3 for 10 min at 25 °C. Entry 5: Same as entry 1 except that 4 equiv of commercial B(OPh)3 and 1 equiv of H2O was used to make the pre-catalyst (method C). Entry 6: 2.0 equiv of imine 111a added to the solution in entry 5 for 10 min at 25 °C. Entry 7: (S)-VAPOL (0.1 mmol) plus 3 62 equiv commercial B(OPh)3 at 25 °C for 10 min. Entry 8: (S)-VAPOL (0.1 mmol) plus 3 equiv commercial B(OPh)3 and 2 equiv imine 111a at 25 °C for 10 min. The formation of the three B-O-B linkages in the boroxine ring in the BOROX catalyst 190a requires 3 equivalents of water along with commercial B(OPh)3. The source of the water in the cases where the water is not added is most probably results from partial hydrolysis of 13f commercial B(OPh)3. Hence, the ratio of 190a, 106, 108, and unreacted 58 may vary significantly depending on the nature and amount of hydrolyzed boron species present in commercially available B(OPh)3. It must be remembered that no boroxinate catalyst was observed when highly purified B(OPh)3 was employed. 13f It was then decided to add the 3 equivalents of water to the mixture of VAPOL and commercial B(OPh)3 in order to compensate for any variation in the quality of commercial B(OPh)3 and to study the subsequent effect in the NMR studies. As shown in the third entry of Figure 2.3B, this method for catalyst formation generated the pyroborate B2 108 and mesoborate B1 106 in 41% yield and 5% yield 1 respectively. The amount of unreacted VAPOL 58 was found to be 45% as monitored by H NMR spectroscopy. After the addition of 2 equivalents of imine 111a, an 88% yield of the boroxinate catalyst 190a was formed (entry 4, Figure 2.3B). Also, the pre-catalyst made from method C (B(OPh)3:H2O = 4:1) gave B2 108 in 90% yield and B1 106 in 5% yield. Subsequent treatment with 2 equiv of imine 111a resulted in 190a in 83% yield (entry 6, Figure 2.3B). 63 Interestingly, we found that the formation of the IMINO-BOROX catalyst 190a can be observed simply upon the treatment of VAPOL 58 and 3 equivalents of B(OPh)3 with 2 equivalents of imine 111a at room temperature in 76% yield (entry 8, Figure 2.3B). More interestingly, VAPOL 58 and commercial B(OPh)3 barely react with each other to afford a 3% yield of B2 108 and this does not change after 24 h (entry 7, Figure 2.3B). However, an 18% yield of B2 108 was observed with another sample of commercial B(OPh)3. 2.1.1.2 Other boron sources A special feature of the BOROX catalyst is that a variety of catalysts can be made by utilizing various trialkyl or triaryl borates 187 and different boroxines 191 (Figure 2.5A and 2.5B). However, these approaches are not feasible due to the limited commercial availability of these compounds. This limitation has been solved by employing BH3•Me2S 192a, B(OH)3 193 and BH3•THF 192b in conjunction with different alcohols (Figure 2.5C and 2.5D). A comparison of these boron sources and of B(OPh)3 for catalyst preparation and their impact on the outcome in the aziridination reaction has been presented in Table 2.1. Table 2.1 Asymmetric aziridination with different boron sources and (S)-VAPOL 58 O Ph Ph N 78a Ph + OEt N2 85 Boron source H2O (S)-VAPOL 58 (10 mol%) Method A-F IMINO-BOROX catalyst 188a (10 mol %) Ph N toluene 25 °C, 24 h precatalyst Ph Ph CO2Et 86a Imine 78a 64 IMINO-BOROX catalyst 188a a OPh Ph Ph O B O – N+ B O * H O O B OPh Ph IMINO-BOROX catalyst 188a OH = (S)-VAPOL 58 * OH Table 2.1 cont’d # Boron Source Pre-catalyst b (method) Ratio (‘B’ source: PhOH:H2O) Procedure Yield 86a c (%) ee 86a d (%) 1 B(OPh)3 A 3:0:0 I 83 91 2 B(OPh)3 3:0:0 II 80 92 3 B(OPh)3 – B 3:0:3 III 84 4 B(OPh)3 C 5 B(OPh)3 6 BH3•Me2S – E 7 BH3•Me2S 8 9 a e 4:0:1 IV 4:0:0 V 3:2:3 VI F 3:2:3 VII B(OH)3 G 3:2:0 BH3•THF H 3:2:3 VIII IX f 82 (81) 80 h 85 (81) 89 i 92 g g 94 (96) 92 94 (91) 92 85 g 90 82 g 94 Unless otherwise specified, all reactions were run with 1 mmol of imine 78a in toluene (0.5 M in imine 78a) with 1.2 equiv of 85. b Method A: The pre-catalyst was prepared by heating 1 equiv of (S)-VAPOL with 3 equiv of commercial B(OPh)3 in toluene at 80 °C for 1 h, followed by removing all volatiles under high vacuum (0.1 mm Hg) for 0.5 h at 80 °C. Method B: By heating 1 equiv of (S)-VAPOL, 3 equiv of commercial B(OPh)3 and 3 equiv of H2O in THF at 80 °C for 1 h, followed by removing all volatiles under high vacuum (0.1 mm Hg) for 0.5 h at 80 °C. Method C: Same as Method A except 4 equiv of commercial B(OPh)3 with 1 equiv of H2O was used. Method E: By heating 1 equiv of (S)-VAPOL, 3 equiv of BH3•Me2S, 2 equiv of PhOH and 3 equiv of H2O in toluene at 100 °C for 1 h, followed by removing all volatiles under high vacuum (0.1 mm Hg) for 0.5 h at 100 °C. Method F: Same as Method E except removals of volatiles was excluded. Method G: Same as Method A except 3 equiv of B(OH)3 with 2 equiv of PhOH was used. Method H: By mixing 1 equiv of (S)-VAPOL, 3 equiv of BH3•THF, 2 equiv of PhOH and 3 equiv of H2O in toluene at 25 °C for 15 min followed by removing all volatiles under high vacuum (0.1 mm c d e Hg) for 0.5 h at 25 °C. Isolated yield. Determined by HPLC. In this case, cat 188a is directly generated by mixing 1 equiv of (S)-VAPOL, 3 equiv of B(OPh)3 and 10 equiv of f imine 78a in toluene at 25 °C for 5 min. In this case, cat 188a is directly generated by heating a mixture of 1 equiv of (S)-VAPOL, 4 equiv of B(OPh)3 and 10 equiv of imine 78a in toluene at 80 °C for 0.5 h. g m-xylene used as the solvent for results in parenthesis. i contributed by Wynter Osminski. Data contributed by Li Huang. 65 h Data It was then decided to carry out NMR analyses in order to quantify the amount of boroxinate catalyst formed in each case. The generation of the BOROX catalyst with 2 equiv of imine 111a resulted in 55%, 71% and 26% yields of 190a from triphenoxyboroxine 191a, BH3•Me2S 192a and B(OH)3 193, respectively (entries 2, 4 and 6, Figure 2.4A). Figure 2.4 Imine induced boroxinate catalyst formation using other boron sources. (A) a 1 H NMR spectra in CDCl3 with Ph3CH as internal standard with percent yields of 190a given in parenthesis. (B) 11 1 B NMR spectra corresponding to the H NMR spectra in Figure 2.4A. A 58 B3 190a (26%) 58 B2 108 B3 190a (88%) B2 108 58 B3 190a (55%) B2 108 58 58 B2 108 66 Figure 2.4 cont’d B B3 190a B3 190a B3 190a a Note for Figure 2.4A: Entry 1: (S)-VAPOL (0.1 mmol) plus 1 equiv triphenoxyboroxine 191a at 25 °C for 10 min (method D). Triphenoxyboroxine 191a was prepared when a mixture of 3 equiv BH3•Me2S 192a, 3 equiv PhOH and 3 equiv H2O was heated at 80 °C in toluene for 1 h followed by removal of volatiles under vacuum for 0.5 h (see experimental). Entry 2: 2.0 equiv of imine 111a added to the solution in entry 1 for 10 min at 25 °C. Entry 3: (S)-VAPOL (0.1 mmol) plus 3 equiv BH3•Me2S 192a, 2 equiv PhOH and 3 equiv H2O were heated at 100 °C in toluene for 1 h followed by removal of volatiles under vacuum for 0.5 h (method E). Entry 4: 2.0 equiv of imine 111a added to the solution in entry 3 for 10 min at 25 °C. Entry 5: (S)- 67 VAPOL (0.1 mmol) plus 3 equiv B(OH)3 193 and 2 equiv PhOH were heated at 80 °C in CH3CN for 1 h followed by removal of volatiles under vacuum for 0.5 h (method G). Entry 6: 2.0 equiv of imine 111a added to the solution in entry 5 for 10 min at 25 °C. A detailed summary of the results obtained from the various NMR experiments on mixtures of (S)-VAPOL 58, imine 111a and various boron sources are presented in Table 2.2. Table 2.2 NMR Analysis of mixtures of (S)-VAPOL 58, imine 111a and various boron sources * Boron source imine 111a (x equiv) OH OH 58 + [imine-H] OPh O –O B + B O * O O B 190a OPh Method A-G CDCl3 25 °C, 10 min 0.1 M # B3 Pre-Cat method b B(OPh)3 Before imine After imine 1 A 6 After imine 7 8 * O O B2 Equiv Cat. of (%) imine (x) (S)VAPOL B B OPh + 106 B1 B1 d B2 d B3 d c,d 1 H (δ) e - - 20 6 53 - 2 10 1 0.5 2 3 4 5 B(OPh)3 Before imine OPh + B O B * O OPh 108 O 50 10 100 200 2 <1 6 41 <1 <1 <1 <1 13 6 4 11 81 55 90 g 49 - - 45 5 41 - 2 1 50 100 4 1 <1 <1 4 2 88 90 68 OH * OH 58 (unreacted) 11 B (δ) f 18.29 10.24 10.29 10.23 10.23 15.92, 5.33 16.73, 5.37 15.96, 5.38 18.29, 5.42 18.46 10.23 10.25 a 15.92, 5.36 16.00, 5.35 Table 2.2 cont’d B(OPh)3 Before imine After imine 9 - - B(OPh)3 Before imine After imine Boroxine Before imine After imine BH3•Me2S Before imine After imine B(OH)3 Before imine After imine a 17 18 19 G 20 21 76 41 - <1 5 88 - 50 1 <1 15 83 - 69 4 23 - 50 19 <1 <1 55 - 33 5 53 - 50 100 <1 <1 <1 <1 20 30 71 62 - E <1 <1 - 65 2 9 - 2 1 16 <1 <1 2 1 15 11 11 - D 50 10 2 14 - - 13 3 - C <1 2 12 85 2 10 10 11 - 50 100 39 50 <1 <1 <1 <1 26 23 18.24 10.31 10.41 19.16, 5.51 17.75, 5.52 18.39 10.26 19.33, 5.42 18.39 10.25 19.33, 5.42 18.27 10.26 10.28 16.18, 5.50 16.04, 5.45 18.31 10.16 10.16 19.13, 5.43 19.49, 5.42 Unless otherwise specified, all NMR samples were prepared from (S)-VAPOL (0.1 mmol), boron sources and imine 111a in CDCl3 (1 mL) utilizing methods A-G for pre-catalyst b preparation. See Table 2.1 for various methods. Method D: The pre-catalyst was prepared by simple mixing of 1 equiv of (S)-VAPOL and pre-formed triphenoxyboroxine 191a. Unreacted (S)-VAPOL 58. limiting reagent. NMR spectrum. e f c d NMR yield with Ph3CH as internal standard with ligand as the 1 Chemical Shift of the peaks observed in the bay region of 190a in the H Chemical Shift of the peaks observed in the 11 B NMR spectrum. NMR yield with Ph3CH as internal standard with respect to imine is 89%. 69 g The Finally, we have four different protocols for the generation of the BOROX catalyst as shown in Figure 2.5. Figure 2.5 Generation of a BOROX catalyst from (A) trialkyl/triaryl borates 187 (B) boroxines 191 (C) B(OH)3 193 (D) BH3•Me2S complex 192a VAPOL + 3 B(OR4)3 + 3H2O A Imine VAPOL VAPOL + OR4 B O O B B O R4O OR4 Imine B Imine OR4 H O B O B O O O B OR4 Ph Ph + Imine D 3 BH3•SMe2 + 2 HO-R4 + 3 H2O Imine C VAPOL + 3 B(OH)3 + 2 HO-R4 2.1.1.3 Temperature studies of IMINO-BOROX catalyst 190a 1 A temperature study on the H NMR spectrum of the IMINO-BOROX catalyst 190a 1 provided additional information of the dynamics of this complex. The H NMR spectrum of 190a has only one peak for bay protons (Figure 2.6A, entry 2). This was interpreted to mean that the migration of the protonated imine from top face of the catalyst to the bottom face is fast on the NMR time scale. On decreasing the temperature from 25 ºC to -44 ºC, the two sets of bay 70 protons in the imine-boroxinate complex 190a begin to appear (Figure 2.6A, entry 5). This reflects a decreased rate of migration of the iminium on the NMR time scale at low temperature. Figure 2.6 (A) a1 1 H NMR spectra of the bay region of 190a in CDCl3. (B) H NMR spectra of the methyl and methoxy regions of 190a in CDCl3 corresponding to the entries of Figure 2.6A. A 190a 190a –44 ºC –30 ºC 0 ºC 25 ºC 190a 58 50 ºC 71 108 Figure 2.6 cont’d B MeO Me MeO Me –44 ºC –30 ºC 0 ºC 25 ºC MeO 50 ºC a MeO Me Me Note for Figure 2.6A: Entry 1: (S)-VAPOL (0.1 mmol) plus 3 equiv commercial B(OPh)3 and 3 equiv H2O were heated at 80 °C in THF for 1 h followed by removal of volatiles under vacuum for 0.5 h. Thereafter, 1.0 equiv of imine 111a was added to the pre-catalyst followed by the addition of CDCl3 (1 mL) and the stirred for 10 min at 25 °C. The NMR taken at 50 °C. Entry 2: Same as entry 1 but the NMR taken at 25 °C. Entry 3: Same as entry 1 but the NMR taken at 0 °C. Entry 4: Same as entry 1 but the NMR taken at –30 °C. Entry 5: Same as entry 1 but the NMR taken at –44 °C. 72 Another important observation was made in the methyl and the methoxy region of the boroxinate complex 190a (Figure 2.6B). At ambient temperature (25 ºC), one of the methoxy groups was found to be much broader than the other. This observation indicates that one of the methoxy groups is more restricted than the other one in complex 190a. However, at low temperature (–44 ºC), the equivalent methyl and methoxy groups of the free imine 111a are desymmetrized in the boroxinate 190a (Figure 2.6B, entry 5). This behavior of boroxinate complex at low temperature is ambiguous and not completely understood at present. Both methyl (δ = 1.85 ppm and 1.74 ppm) and methoxy (δ = 3.70 ppm and 3.49 ppm) groups are substantially shielded as compared to the free imine (δ = 3.69 ppm and δ = 2.26 ppm for methyl and methoxy groups in free imine 111a, respectively). 2.1.1.4 Multiplex diversity in the generation of BOROX catalyst As discussed earlier, the diversity of BOROX catalyst is exemplified by the fact that different alcohols, ligands and imines can be employed. These variations can generate a potentially large pool of catalysts and thereby provide new opportunities in asymmetric catalysis. Considerable time was devoted during the course of this doctoral research to the development of these novel catalysts. One of the first variations that were tried was the generation of catalyst 196a with cubenol 194c. No significant change in the yield or enantioselectivity was observed in the aziridination reaction (Table 2.3, entry 3). However, this work was carried out in more detail by another group member namely Wynter Osminski. Cyclohexanol 194b was found to be the optimum alcohol for the Wulff asymmetric aziridination reaction (Table 2.3, entry 2). 73 Table 2.3 Catalytic asymmetric aziridination with different alcohols and (S)-VAPOL a IMINO-BOROX Ph Ph catalyst OR Ph Ph (10 mol %) O B N Ph + O – OEt N+ N B O toluene * Ph H N2 O O B Ph CO2Et 25 °C, 24 h 85 78a 86a OR Ph BH3•Me2S (3 equiv) IMINO-BOROX catalyst ROH (2 equiv) Imine H2O (3 equiv) 78a OH IMINO-BOROX pre(S)-VAPOL = (S)-VAPOL 58 * catalyst tolulene, 100 °C, 1 h catalyst (10 mol%) OH O Ph Yield 86a b (%) ee 86a c (%) 194a 89 92 195a OH 194b 90 95 196a OH 89 92 # Catalyst Alcohol Source 1 188a OH 2 3 194c e d a Unless otherwise specified, all reactions were performed with 1 mmol of imine 78a in toluene (0.5 M in imine 78a) with 1.2 equiv of 85. The pre-catalyst was prepared heating 1 equiv of (S)-VAPOL, 3 equiv of BH3•Me2S, 2 equiv of alcohol or phenol and 3 equiv of H2O in toluene at 100 °C for 1 h, followed by removing all volatiles under high vacuum (0.1 mm b c d Hg) for 0.5 h at 100 °C (method F). Isolated yield. Determined by HPLC. Data contributed by Wynter Osminski. e Generously provided by Victor Prutyanov. A number of comprehensive studies have shown that both VAPOL and VANOL are broadly effective in the asymmetric aziridination reaction. 13 In search of more diversity in the catalyst and in continued improvement in the aziridination with benzhydryl imines 78, we envisioned the possibility of the (S)-ISOVAPOL 197. 18 following the new protocol for the synthesis of VAPOL. 74 The ligand was easily synthesized The results are discussed in detail in chapter 5. Unfortunately, no significant improvement was observed when ISOVAPOL was employed in the aziridination reaction (Table 2.4, entry 3). Recently, another group member namely Yong Guan was able to increase the stereo-induction of the aziridines from benzhydryl imines by synthesizing a derivative of VANOL that has tert-butyl groups in the 7,7ʹ′ positions ((S)-7,7ʹ′-tBu2-VANOL 198, Table 2.4, entry 4). Additionally, another group member, Li Huang found that 3,3ʹ′-Ph2-BINOL 56a gave satisfactory results. Later on, in order to investigate the structure of the catalyst, we screened a number of chiral diols such as BINOL derivatives 56 and TADDOL 61a. The results and NMR analysis are discussed in detail in chapter 5. Table 2.4 Catalytic asymmetric aziridination with different ligands O Ph N Ph Ph + OEt N2 85 78a B(OPh)3 (4 equiv) H2O (1 equiv) IMINO-BOROX catalyst (10 mol %) toluene 25 °C, 24 h preLigand toluene, 80 °C, 1 h catalyst (10 mol%) then 0.5 mm Hg 80 °C, 0.5 h Ph Ph N Ph CO2Et 86a Imine 78a IMINO-BOROX catalyst a OPh Ph Ph O –O B B O * N+ O O B H OPh Ph IMINO-BOROX catalyst OH = Ligand * OH # Catalyst 1 2 3 4 188a 189a 199a 200a (S)-VAPOL (S)-VANOL (S)-ISOVAPOL (S)-7,7ʹ′-tBu2-VANOL 58 59 197 198 Yield 86a b (%) 82 87 82 82 5 201a (R)-3,3ʹ′-Ph2-BINOL 56a 88 6 7 8 9 202a 203a 204a 205a (R)-3,3ʹ′-I2-BINOL (R)-BINOL (R)-3,3ʹ′-TRIP2-BINOL (R, R)-TADDOL 56e 55 56f 61a 80 66 78 73 Ligand 75 ee 86a c (%) 94 93 92 d 98 –76 –51 –13 2 <1 e Table 2.4 cont’d a Unless otherwise specified, all reactions were performed with 1 mmol of imine 78a in toluene (0.5 M in imine 78a) with 1.2 equiv of 85. The pre-catalyst was prepared by heating 1 equiv of (S)-ligand with 4 equiv of commercial B(OPh)3 and 1 equiv of H2O in toluene at 80 °C for 1 h, followed by removing all volatiles under high vacuum (0.1 mm Hg) for 0.5 h at 80 b c d °C (method C). Isolated Yield. Determined by HPLC. Data contributed by Yong Guan. e Data contributed by Li Huang. Lastly, a variation on the protecting group of the imine was examined (Table 2.5). Prior to this doctoral research, benzyhydryl, 13a DAM 19 and BUDAM 13b N-protecting groups were already employed in the search for the optimal substituent. Bh and DAM groups were found to be equally good and the BUDAM group was found to be the best for aryl imines. Although DAM imines 110 were already examined by Zhenjie Lu, a former group member, they were needed to be tested under new reaction conditions (toluene as the solvent instead of CCl4 and a new procedure for catalyst preparation) for the optimization of alkyl imines. We were able to establish a simplified procedure utilizing DAM imines. The results are discussed in detail in chapter 6. Meanwhile, a new protecting group, MEDAM was developed by another group member namely Munmun Mukherjee. This group was found to be the optimal N-substituent for 13c the asymmetric aziridination reactions of both aryl and alkyl imines. In terms of mechanistic findings, a combination of results from benzyl, benzhydryl and homo-benzhydryl (this work) protecting groups revealed the requirement for two aromatic rings separated by a methine group, which is directly attached to the nitrogen of the imine (Table 2.5, entries1-3). 76 Table 2.5 Catalytic asymmetric aziridination with imines from different protecting groups O PG Ph N + OEt IMINO-BOROX catalyst (10 mol %) N2 206a (CH2Ph) 207a (CH2CHPh2) 78a (CHPh2) 110a (DAM) 111a (MEDAM) 112a (BUDAM) cat 1 210a CH2Ph 2 211a CH2CHPh2 3 188a CHPh2 4 212a DAM 5 190a MEDAM Ph 85 CO2Et 208a (CH2Ph) 209a (CH2CHPh2) 86a (CHPh2) 113a (DAM) 114a (MEDAM) 115a (BUDAM) pre(S)-VAPOL (10 mol%) toluene, 80 °C, 1 h catalyst then 0.5 mm Hg 80 °C, 0.5 h # N Solvent 25 °C, 24 h B(OPh)3 (4 equiv) H2O (1 equiv) Protecting Group (PG) PG Imine 78a a OPh Ph Ph O B O – B O * N+ O O B H Ph OPh IMINO-BOROX catalyst * IMINO-BOROX catalyst OH OH OH OH = Ph Ph Solvent C6H5CH3 Yield azi ee azi b c (%) (%) – – CH2Cl2 Yield azi ee azi b c (%) (%) d 32 52 51 35 82 95 e 98 94 92 e 99.8 83 80 e 89 43 39 d CCl4 Yield azi ee azi b c (%) (%) 54 15 89 90 e 97.5 d 84 84 e 81 48 54 d 93 94 e 99 d d d d d d 6 213a BUDAM 96 99 84 99 94 99 a Unless otherwise specified, all reactions were performed with 1 mmol of imine 78a in toluene (0.5 M in imine 78a) with 1.2 equiv of 85. The pre-catalyst was prepared by heating 1 equiv of (S)-VAPOL with 4 equiv of commercial B(OPh)3 and 1 equiv of H2O in toluene at 80 °C for 1 h, followed by removing all volatiles under high vacuum (0.1 mm Hg) for 0.5 h at b 80 °C (method C). The concentration of the reaction was 0.2 M in imine 78a for entry 2. c Isolated Yield. Determined by HPLC. by Munmun Mukherjee. d e Data contributed by Yu Zhang. Data contributed 77 A NMR analysis of various imines was then performed and it is shown in Figure 2.7. All the imines show the formation of the boroxinate catalysts. Figure 2.7 Imine induced boroxinate catalyst formation (See Table 2.5 for structures of different imines used). (A) a1 H NMR spectra in CDCl3 with Ph3CH as internal standard. (B) 1 spectra corresponding to the H NMR spectra in Figure 2.7A. A B3 190a (76%) PhCH=NMEDAM 58 (11%) 58 (31%) B3 188a (55%) PhCH=NBh B2 108 (<1%) B3 211a (41%) 58 (5%) PhCH=NCH2Bh B3 210a (90%) PhCH=NBn 58 (3%) 58 (30%) B3 214a (63%) B2 108 (3%) PhCH=NPh 78 11 B NMR Figure 2.7 cont’d B B3 190a PhCH=NMEDAM B3 188a PhCH=NBh B3 211a PhCH=NCH2Bh B3 210a PhCH=NBn B3 214a PhCH=NPh a Note for Figure 2.7A: Entry 1: (S)-VAPOL (0.1 mmol) plus 3 equiv commercial B(OPh)3 and 2 equiv imine 75a (PhCH=NPh) at 25 °C for 10 min. Entry 2: same as entry 1 with imine 206a (PhCH=NCH2Ph). Entry 3: same as entry 2 with imine 207a (PhCH=NCH2CHPh2). Entry 4: same as entry 2 with imine 78a (PhCH=NCHPh2). Entry 5: same as entry 2 with imine 111a (PhCH=NMEDAM). 2.1.1.5 A comparison of X-ray structure and calculated structure of BOROX catalyst We have previously reported the solid-state structure of the IMINO-BOROX catalyst13f substrate complex 190a. The X-ray analysis revealed the presence of a number of non- 79 covalent interactions between the protonated imine substrate as it is bound in the anionic boroxinate catalyst (Figure 2.2B). In the follow-up work where a lot different bases were examined for BOROX complex, we have used computational chemistry to predict the possible structures of the BOROX catalysts with various bases. As a prelude, computations were first performed on the IMINO-BOROX 190a since the results could be compared with the solid-state structure determined by X-ray analysis. B3LYP/6-31g* level of theory. 20 13f Calculations were preformed using Gaussian ʹ′03 at The results of DFT calculations on 190a are shown in Figure 2.8 and are very similar to the structure determined by X-ray. There are some differences as one might expect for a substrate-catalyst complex in the gas phase versus solid state. The strongest non-covalent interaction would be expected to be the H-bond between the protonated iminium and the boroxinate core. As in the solid state this was found to be with O-2 of the boroxinate core with a calculated distance of 1.73 Å vs. 2.02 Å in the solid state (d1 in Figure 2.8 and Figure 2.2B). Common to both structures is the edge-face interaction (CH-π) between of one of the aryl rings of the MEDAM group with one of the phenyl rings of the VAPOL ligand (d2 in Figure 2.8 and Figure 2.2B). 21 This distance in the calculated structure is 3.92 Å (Figure 2.8) and it is 4.42 Å (Figure 2.2B) in the solid state. It should be noted that the CH-π interaction distances are by convention indicted as the distance between the carbon bearing the hydrogen and the centroid of the benzene ring participating in the interaction. 22 There are also differences in the orientation of the phenyl group of the benzaldehyde imine relative to one of the phenanthrene walls of the VAPOL ligands (d5 in Figure 2.8 and Figure 2.2B). The contact distance is about the same (3.56 vs 3.44 Å) but the angle between the planes containing these two rings increases from 4 to 39° in 80 the calculated structure. This twisting of the phenyl ring in the calculated structure allows for a closer edge-face interaction between one of the phenoxy groups of the boroxinate core and the phenyl group of the benzaldehyde imine (d8, Figure 2.8). This distance is 4.66 Å in the calculated structure and 5.52 Å in the solid state. This phenoxy group of the boroxinate core in the calculated structure also moves about a half an Angstrom closer for a better CH-π interaction with one of the methyl groups on the back-end aryl substituent of the MEDAM group (d9 in Figure 2.8). Also, there is another interaction (CH-O) between the methine CH of the iminium and the O-1 of the boroxinate anion (d6 in Figure 2.8 and Figure 2.2B). Figure 2.8 Calculated structure of IMINO-BOROX catalyst 190a using Gaussian ʹ′03. (A) Calculated B3LYP/6-31g* structure visualized by the Mercury Program (C, gray; O, red; N, blue; B, yellow; H, white). Hydrogen atoms omitted for clarity (except N-H and C-H). Some secondary interactions are highlighted: d1 = 1.73 Å (H-bonding), d2 = 3.92 Å (CH-π), d5 = 3.56 Å (CH-π or π-π stack), d6 = 2.53 Å (CH-Ο), d8 = 4.66 Å (CH-π), d9 = 4.02 Å (CH-π). (B) Space-filling rendition of 190a with the same orientation and showing hydrogens. boroxinate anion is given in green and the iminium cation is in traditional colors. 81 The Figure 2.8 cont’d A B d9 d8 d1 O2 d2 d6 O1 d5 As the complex involves hydrogen bonding, it was also examined with BHandHLYP/631g* level of theory and the results were not significantly different from that with B3LYP/631g* (Table 2.6). Table 2.6 Comparison of distances in computed structure 190a using different levels of theories Methods d1 (Å) d2 (Å) d5 (Å) d6 (Å) d8 (Å) d9 (Å) X-ray crystals B3LYP/3-21g* B3LYP/6-31g* BHandHLYP/6-31g* 2.02 1.53 1.73 1.73 4.42 3.89 3.92 3.84 3.44 3.52 3.56 3.52 2.86 2.21 2.53 2.47 5.52 4.42 4.66 4.55 4.78 4.19 4.02 3.88 82 2.1.2 Amines as the base: AMINO-BOROX catalyst After establishing the catalytic system where imines are the bases that generate the catalysts, we envisioned to screen other bases in order to broaden the diversity of the BOROX catalyst. To begin with, one of the obvious choices for the base is an amine as they are more basic than imines. An ulterior motive to screening amines was to examine the possibility of developing the first example of a catalytic asymmetric multicomponent aziridination (MCAZ). To our delight, all kinds of aliphatic amines (1°, 2°, 3°) generated B3 catalysts in good yields (Table 2.7, entries 1-5 and Figure 2.9, entries 1-5). The pKa of protonated triethylamine is 10.65 (in water). 23 Table 2.7 NMR Analysis of a mixture of (S)-VAPOL, B(OPh)3 and amines 126 as bases B(OPh)3 (3 equiv) + [Base-H] OPh Base 126 (x equiv) OH O –O B + * B O * OH CDCl3 O O B 25 °C, 10 min 58 215 OPh 0.1 M OPh + B O B * O OPh 108 O B3 (S)VAPOL B1 106 B2 108 B3 215 1 a Ph2CHNH2 2 7 <1 2 c MEDAM-NH2 2 3 g iPr2NH 2 h Bn2NH i 6 7 8 9 g 106 Equiv of Base series 4 5 O B OPh + B1 # g O B2 Base b 126 3 * 1 H a OH * OH 58 (unreacted) 11 B d e f <1 66 10.36 17.77, 5.58 <1 <1 50 10.37 18.48, 5.48 <1 <1 <1 74 10.31 16.13, 5.18 2 <1 <1 <1 34 10.45 18.25, 5.56 Et3N 2 8 <1 <1 63 10.25 16.00, 5.37 j 4-MeO-C6H4NH2 2 5 <1 <1 23 10.30 15.85, 5.49 k C6H5NH2 2 24 <1 <1 61 10.29 16.04, 5.56 l – (C6H5)2NH No base 2 0 51 57 <1 5 28 18 <1 <1 – – 16.41 16.00 c ,d 83 d d Table 2.7 cont’d a Unless otherwise specified, all NMR samples were prepared by mixing (S)-VAPOL 58 (0.1 mmol) and commercial B(OPh)3 (0.3 mmol) and base 126 in CDCl3 (1 mL) at 25 °C and stirring 10 min before spectra were taken. c Unreacted (S)-VAPOL 58. limiting reagent. e d b All bases were distilled or sublimed prior to use. NMR yield with Ph3CH as internal standard with ligand as the Chemical Shift for the bay proton in B3-base complex. 11 g f Chemical Shift of the peaks observed in B NMR spectrum. There is an unknown specie at 10.41 ppm (40% yield, determined by the integration of the bay proton of the new species against the internal standard) for entry 4 and at 9.66 ppm (44% yield, determined by the integration of the bay proton of the new species against the internal standard) for entry 6. To our surprise, even an aromatic amine such as aniline 126k (pKa of protonated aniline is 4.62 in water) entry 7). 24 gave BOROX catalyst 215k in 61 % yield (Table 2.7, entry 7 and Figure 2.9 + However, Ph2NH 126l (pKa of Ph2N H2 is 0.78 in water) failed to give any boroxinate. After these results, we moved on to develop a true MCAZ reaction and were able to successfully accomplish that goal and this is discussed in detail in Chapter 7. Figure 2.9 Amine induced boroxinate catalyst formation. (A) Ph3CH as internal standard. (B) 11 a1 H NMR spectra in CDCl3 with 1 B NMR spectra corresponding to the H NMR spectra in Figure 2.9A. 84 Figure 2.9 cont’d A 58 no base 58 (C6H5)2NH B3 58 C6H5NH2 B3 4-MeO-C6H4NH2 B3 Et3NH Bn2NH B3 B3 iPr2NH MEDAMNH2 Ph2CHNH2 B3 B3 58 B B3 B3 B3 B3 B3 B3 B3 85 B2 B2 a Note for Figure 2.9A: Entry 1: (S)-VAPOL (0.1 mmol) plus 3 equiv commercial B(OPh)3 and 2 equiv amine 126a (Ph2CHNH2) at 25 °C for 10 min. Entry 2: same as entry 1 but with amine 126c (MEDAM-NH2). Entry 3: same as entry 2 but with amine 126g (iPr2NH). Entry 4: same as entry 2 but with amine 126h (Bn2NH). Entry 5: same as entry 2 but with amine 126i (Et3N). Entry 6: same as entry 2 but with amine 126j (4-MeO-C6H4NH2). Entry 7: same as entry 2 but with amine 126k (C6H5NH2). Entry 8: same as entry 2 but with amine 126l ((C6H5)2NH). Entry 9: (S)-VAPOL (0.1 mmol) plus 3 equiv commercial B(OPh)3 at 25 °C for 10 min. A lot effort has been given to obtain crystals of AMINO-BOROX catalyst. Unfortunately, no success was achieved. Therefore, computational methods were undertaken to explore the possible structures of the AMINO-BOROX 215c derived from MEDAM amine 126c. Calculations were preformed using Gaussian ʹ′03 at B3LYP/6-31g* level of theory. 20 The protonated amine 126c-H should have a very different binding mode in the boroxinate species 215c due to the absence of the benzylidene group on the nitrogen atom and the presence of an ammonium ion with three hydrogens capable of H-bonding to the anionic boroxinate platform. The calculated structure for the BOROX species 215c is presented in Figure 2.10. The key interactions between the cationic protonated amine and the anionic boroxinate core are the two hydrogen bonds from the ammonium ion to O-1 and O-2 of the boroxinated anion (Figure 2.10). The hydrogen bond to O-2 (d1 = 1.75 Å) is slightly shorter than that to O-1 (d2 = 1.96 Å) consistent with the computational finding that the electron density of the boroxinate core is 86 highest at O-2 (see experimental). There is also a short distance between the ammonium nitrogen and the centroid of the A-ring of one of the phenanthrene units in the VAPOL ligand (d3 = 3.21 Å), which is indicative of an NH-π interaction. The iminium ion in 190a and the ammonium ion in 215c both have the protonated nitrogen H-bonded to O-2 of the boroxinate core, but the head groups of the nitrogen substituent (MEDAM group) are on opposite sides of the boroxinate platform. In 190a the MEDAM group has an edge-face interaction with the phenyl substitutent of VAPOL and in 215c, the MEDAM group has an edge-face interaction with the C-ring of VAPOL (d4 = 4.18 Å). Figure 2.10 Calculated structure of AMINO-BOROX catalyst 215c (derived from MEDAM amine 126c) using Gaussian ʹ′03. (A) Calculated B3LYP/6-31g* structure visualized by the Mercury Program (C, gray; O, red; N, blue; B, yellow; H, white). Hydrogen atoms omitted for clarity (except N-H). Some secondary interactions are highlighted: d1 = 1.75 Å (H-bonding), d2 = 1.96 Å (H-bonding), d3 = 3.21 Å (NH-π or cation-π), d4 = 4.18 Å (CH-π). (B) Space-filling rendition of 215c with the same orientation and showing hydrogens. The boroxinate anion is given in green and the ammonium cation is in traditional colors. 87 Figure 2.10 cont’d A B d1 d3 d2 d4 O2 O1 The boroxinate complex 215c was also examined with BHandHLYP/6-31g* level of theory and the results were not significantly different from that with B3LYP/6-31g* (Table 2.8). In fact, a calculated structure of 215k (not shown here) derived from aniline 126k also revealed the presence of dual hydrogen bonding and an NH-π interaction. Table 2.8 Comparison of distances in computed structure 215c using different levels of theories Methods X-ray crystals B3LYP/3-21g* B3LYP/6-31g* d1 (Å) 1.60 1.75 d2 (Å) 1.86 1.96 d3 (Å) 3.15 3.21 d4 (Å) 4.05 4.18 BHandHLYP/6-31g* 1.74 1.99 3.16 4.13 2.1.3 Pyridines and Quinolines as the base: PYRIDINO- and QUINOLINO-BOROX catalyst It was interesting to find that heterocyclic bases were also able to generate B3 in good yields. Simple mixing of pyridine 216a with VAPOL and commercial B(OPh)3 in CDCl3 gave a 88 white precipitate in the NMR tube (unsuitable for shimming). However, we were able to obtain 1 a good quality H NMR and 11 B NMR spectra (in d8-toluene), when the boroxinate catalyst was made via pre-catalyst (Figure 2.11). The boroxinate 217a was obtained in 85% yield when one equivalent of pyridine was added to the pre-catalyst. The pKa of protonated pyridine is 5.14. 24 1 Figure 2.11 Pyridine induced boroxinate catalyst formation. (A) H NMR spectra of 217a in d8toluene. A mixture of (S)-VAPOL (0.1 mmol), 3 equiv commercial B(OPh)3 was heated at 80 °C in toluene for 1 h followed by removal of volatiles under vacuum for 0.5 h (method A). Thereafter, 1.0 equiv of pyridine 216a was added to the pre-catalyst followed by the addition of d8-toluene (1 mL) and the stirred for 10 min at 25 °C. (B) 11 B NMR spectra corresponding to 1 the H NMR spectra in Figure 2.11A. A Hb Hb Ph Ph OPh Hb O B O– B O O O B Hb OPh 217a 89 + N H Figure 2.11 cont’d 15.73 B 6.26 2.32 1.00 1 The H NMR spectrum of 217a has two peaks (δ = 10.07 ppm and δ = 10.51 ppm) for the bay protons (Figure 2.11A). This was interpreted to mean that the migration of the protonated pyridine from top face of the catalyst to the bottom face is slow on the NMR time scale. Pyridine derivatives such as 2,6-lutidine 216b and DMAP 216c also gave the catalyst in good yields (Table 2.9 and Figure 2.11, entries 1-2). In fact, Gang Hu, a former group member, 13e was able to obtain an X-ray crystal structure of boroxinate 217c. + – H] [B(OPh)4] 218 (δ=2.30 ppm, 11 A small amount of [DMAP- B NMR) was also observed during the NMR study of 217c complex. The structure of 218 was confirmed by X-ray analysis and is discussed in chapter 4. 90 Table 2.9 NMR Analysis of a mixture of (S)-VAPOL, B(OPh)3 and pyridine derivatives, pyrrole, imidazole and quinoline derivatives as bases B(OPh)3 (3 equiv) + [Base-H] OPh Base 216 (x equiv) OH O –O B + * B O * OH CDCl3 O O B 25 °C, 10 min 58 217 OPh 0.1 M a OPh + B O B * O OPh 108 O B3 # O O B OPh + 106 B2 B1 OH * OH 58 (unreacted) (S)VAPOL B1 106 B2 108 B3 217 d e f <1 <1 <1 74 10.13 13.26, 5.30 2 <1 <1 <1 78 10.46 17.58, 5.90 2 65 5 29 <1 – 16.16 2 nd <1 <1 nd nd nd 1 2 nd nd <1 <1 3 3 27 29 10.35 10.35 15.95, 5.38 15.98, 5.44 1 2 2 <1 <1 <1 <1 <1 59 59 10.19 10.21 15.79, 5.66 15.45, 5.56 1 2 b Equiv of Base 2 Base b 216 series 1 * 14 13 <1 <1 <1 <1 65 71 10.19 10.25 15.92, 5.92 15.98, 5.59 0 57 5 18 <1 – 16.00 c ,d d d 1 H 11 B N N 2 c N 3 d N H N 4 e 5 f N H N Ph Ph N 6 g 7 h 8 – 3 2 N No base 91 Table 2.9 cont’d a Unless otherwise specified, all NMR samples were prepared by mixing (S)-VAPOL 58 (0.1 mmol) and commercial B(OPh)3 (0.3 mmol) and base 216 in CDCl3 (1 mL) at 25 °C and stirring 10 min before spectra were taken. Compounds 216f-h were generously provided by b c Amila Dissanayake. All bases were distilled or sublimed prior to use. Unreacted (S)VAPOL 58. reagent. e d NMR yield with Ph3CH as internal standard with ligand as the limiting f Chemical Shift for the bay proton in B3-base complex. Chemical Shift of the peaks observed in 11 B NMR spectrum. In case of pyrrole 216d, there was no sign of catalyst formation (Table 2.9 and Figure 25 2.12, entry 3). This was expected, as the pKa of protonated pyrrole is –3.80. The case of imidazole 216e was a little complex as there was no tri-coordinate boron observed in the 11 B NMR spectrum (Figure 2.11, entry 4). It might be possible that all three boron atoms are coordinated by imidazole. Quinoline derivatives were also screened for the generation of QUINOLINO-BOROX catalyst (Table 2.9 and Figure 2.11, entries 5-7). Direct generation of a boroxinate from quinolines lead us to the discovery of another asymmetric reaction mediated by QUINOLINO-BOROX catalyst i.e. asymmetric reduction of quinolines 26 as discussed in Scheme 1.20 of Chapter 1. The pKa of protonated quinoline and 5,6-benzoquinoline are 4.85 and 5.15 respectively. 24 Figure 2.12 Pyridine and quinoline derivatives in the induction of boroxinate catalyst formation. (A) a 1 H NMR spectra in CDCl3 with Ph3CH as internal standard. (B) 1 corresponding to the H NMR spectra in Figure 2.12A. 92 11 B NMR spectra Figure 2.12 A cont’d 58 no base B3 quinoline 216h B2 58 B3 quinoline 216g B3 58 quinoline 216f imidazole 216e 58 58 pyrrole 216d DMAP 216c 2,6-lutidine 216b B2 B3 B3 B B3 B3 B3 B3 218 B3 93 B2 a Note for Figure 2.12A: Entry 1: (S)-VAPOL (0.1 mmol) plus 3 equiv commercial B(OPh)3 and 2 equiv 216b at 25 °C for 10 min. Entry 2: same as entry 1 with 216c. Entry 3: same as entry 2 with 216d. Entry 4: same as entry 2 with 216e. Entry 5: same as entry 2 with 216f. Entry 6: same as entry 2 with 216g. Entry 7: same as entry 2 with 216h. Entry 8: (S)-VAPOL (0.1 mmol) plus 3 equiv commercial B(OPh)3 at 25 °C for 10 min. While studying the NMR spectra of the complex 217b (base = 2,6 lutidine) derived from (R)-VAPOL, colorless crystals were serendipitously formed in the NMR tube and thus the opportunity to determine the crystal structure of the LUTIDINO-BOROX complex 217b presented itself. Structural parameters for 217b are available free of charge from the Cambridge Cystallographic Data Centre under reference number CCDC. The observed crystal structure is found to be different from crystal structures of all the boroxinates we reported so far. A detailed analysis revealed the presence of two BOROX units (B3a and B3b) in a single array (Figure 2.13). Each unit consists of a protonated lutidinium ion, a molecule of phenol and the boroxinate anion derived from a boroxine ring in which the tetra-coordinate boron is spiro-fused to the VAPOL ligand. There is no direct H-bonding between the protonated lutidinium and the boroxinate anion, but rather the protonated lutidinium is H-bonded to the phenol (Figure 2.13, d1 = 1.91 Å in B3a and d1ʹ′ = 1.87 Å in B3b), which in turn is H-bonded to the boroxinate anion (Figure 2.13, d1 = 1.91 Å in B3a and d1ʹ′ = 1.92 Å in B3b). It must be noted that the pKa of protonated lutidine is 5.77. 24 Yamamoto and coworkers reported a similar kind of hydrogen bonding interaction incorporating a molecule of phenol in the case of the crystal structure of a 94 12a spiroborate anion. An important difference between the two B3 units (B3a and B3b) is that they differ at the point of binding of the phenol to the boroxinate: the phenol is H-bonded to O1 in B3a and to O2 in B3b. It must be remembered that we have always observed the presence of hydrogen bonding to O2 in all boroxinates reported so far. 13e,13f Similar to the case of imines, there are several non-covalent interactions like CH-π and π-π interactions. One of the important CH-π interactions is from the methyl group on lutidine to the middle ring of the phenantherene unit in the VAPOL ligand (Figure 2.13, d3 = 3.77 Å in B3a and d3ʹ′ = 4.17 Å in B3b). a Figure 2.13 (A) Solid state structure of the LUTIDINO-BOROX 217b visualized by the Mercury Program (C, gray; O, red; N, blue; B, yellow; H, white). Hydrogen atoms omitted for clarity (except N-H and O-H). (B) Space-filling rendition of 217b with the same orientation and showing hydrogens. The boroxinate anion is given in green and the lutidinium cation is in traditional colors. (C) Diagrammatic representation of B3a and B3b in 217b A d7 d4 d1 d2 O1 d5 d8 d1ʹ′ d10 d4ʹ′ d3ʹ′ d6 d8ʹ′ d6ʹ′ d2ʹ′ O2 d3 d9 B3a d7ʹ′ B3b 217b 95 d5ʹ′ Figure 2.13 cont’d B C Ph Ph O H H B O O B ON B O X O O H N O2 B O1 O H B O O O B O O O2 Z B3a a Ph Ph Y B3b Note for Figure 2.13A: Some secondary interactions are highlighted: d1 = 1.91 Å (H-bonding), d2 = 1.91 Å (H-bonding), d1ʹ′ = 1.87 Å (H-bonding), d2ʹ′ = 1.92 Å (H-bonding), d3 = 3.77 Å (CHπ), d3ʹ′ = 4.17 Å (CH-π), d4 = 3.54 Å (CH-π or π-π stack), d4ʹ′ = 3.44 Å (CH-π or π-π stack), d5 = 3.70 Å (CH-π), d5ʹ′ = 3.92 Å (CH-π), d6 = 3.94 Å (CH-π), d6ʹ′ = 3.50 Å (CH-π), d7 = 3.54 Å 96 (CH-π), d7ʹ′ = 3.43 Å (CH-π), d8 = 3.40 Å (CH-π or π-π stack), d8ʹ′ = 3.54 Å (CH-π or π-π stack), d9 = 3.62 Å (CH-π), d10 = 4.25 Å (CH-π). There are several other CH-π interactions including the two interactions from the phenyl ring of the phenol component of the boroxinate to the end ring of the phenanthrene unit in the VAPOL ligand (Figure 2.13, d5 = 3.70 and d7 = 3.54 in B3a and d5ʹ′ = 3.92 and d7ʹ′ = 3.43 in B3b). One of the interesting CH-π interactions is from the external phenol to the middle ring (in case of B3a) or X-ring (in case of B3b) of the phenanthrene unit in the VAPOL ligand (Figure 2.13, d6 = 3.94 in B3a and d6ʹ′ = 3.50 in B3b). Another important noncovalent interaction between the catalyst and the base is a π-π stacking interaction between the external phenol molecule and the phenyl ring of the phenol component of the boroxinate anion (Figure 2.13, d8 = 3.40 in B3a and d8ʹ′ = 3.54 in B3b). An additional π-π stacking interaction was located between the aryl ring of lutidine and the end ring of the phenanthrene unit in the VAPOL ligand (Figure 2.13, d4 = 3.54 in B3a and d4ʹ′ = 3.44 in B3b). Finally, there are two CH-π interactions, which are possibly holding the two B3 units together (Figure 2.13, d9 = 3.62 and d10 = 4.25 in B3a and B3b). The crystal structure of 217b has provided many new details about the nature and binding of the boroxinate catalyst. The presence of two B3 units suggests the idea of possible aggregation of the catalyst in the mechanism of aziridination reaction. Also, the steric bulk of two methyl groups on lutidine might have made it necessary for the external phenol to serve the role of the sandwich for the hydrogen bonding. This suggests that the asymmetric reduction of 97 quinoline should be tried with an extra molecule of phenol during the preparation of the catalyst as quinoline and lutidine both have steric bulk at the ortho positions. 2.1.4 Amides as the base: AMIDO-BOROX catalyst The next base examined was amides. The pKa of the protonated N, N dimethyl acetamide 27 219 is –0.39. An 18% yield of the catalyst 220 was formed when 2 equiv of 219 was employed 1 based on the integration of the absorption at δ = 10.16 ppm in H NMR spectrum (Figure 2.14). 1 Figure 2.14 Amide induced boroxinate formation. (A) H NMR spectra in CDCl3 with Ph3CH as internal standard. (S)-VAPOL (0.1 mmol) plus 3 equiv commercial B(OPh)3 and 2 equiv 219 at 25 °C for 10 min. (B) A 58 11 1 B NMR spectra corresponding to the H NMR spectra in Figure 2.14A. B2 B3 Ph Ph B OPh + OH O B O– B O N O O B OPh 15.9 220 5.8 98 2.1.5 Sulfoxides as the base: SULFOX-BOROX catalyst In search of a highly acidic BOROX catalyst, we envisioned to employ very weak bases like sulfoxides. It must be noted that the pKa of a protonated dimethyl sulfoxide is –1.8 (in 28 H2O). To our delight and surprise, when 2 equiv of DMSO 221a was used as the base the SULFOX-BOROX catalyst 222a was formed in 66% yield (Table 2.10, entry 1). In fact, good yields of boroxinate catalysts were obtained irrespective of the sulfoxides being acyclic, cyclic, aliphatic or even aromatic (Table 2.10, entries 1-5). Also, mixed sulfoxides like 221e resulted in 28 46% yield of the catalyst (Table 2.10, entry 6). The pKa of protonated 221e is –2.27. Table 2.10 NMR Analysis of a mixture of (S)-VAPOL, B(OPh)3 and sulfoxides as bases a B(OPh)3 (3 equiv) + [Base-H] OPh Base 221 OPh (x equiv) OH OH O –O B O O + * + * * B B O B B OPh + * O * OH CDCl3 OH O O B O O OPh 25 °C, 10 min 58 108 106 58 222 OPh 0.1 M (unreacted) B3 B2 B1 (S)VAPOL B1 106 B2 108 B3 222 21 11 8 <1 <1 <1 1 2 3 a Me2SO b (CH2)4SO Equiv of Base 1 2 2 4 c Bn2SO 2 22 <1 17 38 10.09 15.96, 7.42 5 6 7 8 d e f f g Ph2SO ±Ph(Me)SO (R)-p-tol-(Me)SO (R)-p-tol-(Me)SO (R)-p-tol-(Me)SO 2 2 1 2 1 45 22 32 09 18 <1 <1 <1 <1 <1 21 17 15 17 08 25 46 47 74 64 10.01 9.94 9.81 9.87 10.01 16.01, 8.57 15.96, 7.11 15.95, 7.92 15.97, 6.73 15.94, 7.66 g (R)-p-tol-(Me)SO 2 06 <1 13 70 10.08 15.93, 6.43 h Me2SO2 2 69 07 11 <1 – 15.99 i (CH2)4SO2 2 58 <1 22 <1 – 15.98 series # 9 10 11 12 g g Base b 221 c ,d 99 d 1 H 11 B d e f 15 10 3 53 66 73 9.98 10.02 10.08 16.03, 6.98 15.95, 6.24 15.78, 5.70 d Table 2.10 cont’d 13 a – No base 0 57 5 18 <1 – 16.00 Unless otherwise specified, all NMR samples were prepared by mixing (S)-VAPOL 58 (0.1 mmol) and commercial B(OPh)3 (0.3 mmol) and base 221 in CDCl3 (1 mL) at 25 °C and stirring for 10 min before spectra were taken. use. c Unreacted (S)-VAPOL 58. as the limiting reagent. e b d All bases were distilled or sublimed prior to NMR yield with Ph3CH as internal standard with ligand f Chemical Shift for the bay proton in B3-base complex. Chemical Shift of the peaks observed in the 11 B NMR spectrum. g (R)-VAPOL used for analysis. Chiral sulfoxide 221f was employed with both enantiomers of the ligand. Similar yields were observed in both the cases suggesting the absence of any kind of matched/mismatched case although the bay proton is 0.2 ppm different between the diastereometric SULFOX-BOROX species. Interestingly, sulfones 221h and 221i gave no sign of BOROX catalyst. This was 29 expected, as the pKa of the protonated dimethylsulfone 221h is –12 (in H2O). Figure 2.15 Sulfoxide induced boroxinate catalyst formation. (A) a1 H NMR spectra in CDCl3 1 with Ph3CH as internal standard. (B) The alkyl region corresponding to the H NMR spectra in Figure 2.15A. (C) 11 1 B NMR spectra corresponding to the H NMR spectra in Figure 2.15A. b (D) The shift in the methyl region of the dimethylsulfoxide after the formation of 222a. 1 1 1 H NMR spectra in CDCl3. (E) The bay region of the H NMR spectra corresponding to the H NMR spectra in Figure 2.15D. 100 Figure 2.15 A cont’d no base (CH2)4SO2 Me2SO2 B3 (R)-4-Me-C6H4 (Me)SO B3 (R)-4-Me-C6H4 (Me)SO rac-Ph(Me)SO B3 B3 Ph2SO Bn2SO (CH2)4SO Me2SO B3 B3 B3 B 101 58 B2 Figure 2.15 C cont’d B3 B3 B3 B3 B3 B3 B3 D (R)-VAPOL + B(OPh)3 + (R)-4-Me-C6H4(Me)SO (1:3:2) (S)-VAPOL + B(OPh)3 + (R)-4-Me-C6H4(Me)SO (1:3:2) (R)-4-Me-C6H4(Me)SO (S)-VAPOL + B(OPh)3 + Me2SO (1:3:5) (S)-VAPOL + B(OPh)3 + Me2SO (1:3:4) (S)-VAPOL + B(OPh)3 + Me2SO (1:3:3) (S)-VAPOL + B(OPh)3 + Me2SO (1:3:2) (S)-VAPOL + B(OPh)3 + Me2SO (1:3:1) (S)-VAPOL + B(OPh)3 (1:3) B(OPh)3 + Me2SO (1:2) (S)-VAPOL + Me2SO (1:2) Me2SO 102 Figure 2.15 cont’d E a Note for Figure 2.15A: Entry 1: (S)-VAPOL (0.1 mmol) plus 3 equiv commercial B(OPh)3 and 2 equiv Me2SO 221a at 25 °C for 10 min. Entries 2-6: same as entry 1 with 2 equiv (CH2)4SO 221b, Bn2SO 221c, Ph2SO 221d, rac-Ph(Me)SO 221e and (R)-4-Me-C6H4(Me)SO 221f respectively. Entry 7: (R)-VAPOL (0.1 mmol) plus 3 equiv commercial B(OPh)3 and 2 equiv (R)-4-Me-C6H4(Me)SO 221f at 25 °C for 10 min. Entries 8-9: same as entry 1 with 2 equiv Me2SO2 221h and (CH2)4SO2 221i, respectively. Entry 10: (S)-VAPOL (0.1 mmol) plus 3 equiv commercial B(OPh)3 at 25 °C for 10 min. 103 b Note for Figure 2.15D: Entry 1: neat DMSO. Entry 2: (S)-VAPOL (0.1 mmol) plus 2 equiv Me2SO 221a at 25 °C for 10 min. Entry 3: commercial B(OPh)3 (0.1 mmol) plus 2 equiv Me2SO 221a at 25 °C for 10 min. Entry 4: (S)-VAPOL (0.1 mmol) plus 3 equiv commercial B(OPh)3 at 25 °C for 10 min. Entry 5: (S)VAPOL (0.1 mmol) plus 3 equiv commercial B(OPh)3 and 1 equiv Me2SO 221a at 25 °C for 10 min. Entry 6: same as entry 5 except 2 equiv Me2SO 221a used. Entry 7: same as entry 5 except 3 equiv Me2SO 221a used. Entry 8: same as entry 5 except 4 equiv Me2SO 221a used. Entry 9: same as entry 5 except 5 equiv Me2SO 221a used. Entry 10: neat (R)-4-MeC6H4(Me)SO 221f. Entry 11: (S)-VAPOL (0.1 mmol) plus 3 equiv commercial B(OPh)3 and 2 equiv (R)-4-Me-C6H4(Me)SO 221f at 25 °C for 10 min. Entry 12: (R)-VAPOL (0.1 mmol) plus 3 equiv commercial B(OPh)3 and 2 equiv (R)-4-Me-C6H4(Me)SO 221f at 25 °C for 10 min. With the realization of the SULFOX-BOROX catalyst, we decided to computationally explore the complexes of 222a and 222b in order to gain some insight into their possible structures. Calculations were preformed using Gaussian 03 at B3LYP/6-31g* level of theory. 20 The resulting structures are presented in Figure 2.16. There is hydrogen bond between the protonated DMSO and the boroxinate core (Figure 2.16A, d1 = 1.44 Å). One of the intriguing features in the calculated structure was the possible CH-π interaction between the methyl groups of DMSO and the phenanthrene ring of the ligand (Figure 2.16A, d2 = 3.56 Å and d3 = 3.80 Å). 1 A careful analysis of the H NMR of the SULFOX-BOROX species 222a (Figure 2.15D, entry 1 104 vs. 5) revealed an upfield shift of 0.3 ppm when one equiv of DMSO was used to generate 222a. Although the methyl peak for free DMSO was missing when excess DMSO (up to 5 equivalents) was employed, the difference in chemical shift decreased from 0.3 ppm to 0.15 ppm (Figure 2.15D, entry 1 vs. 5-9). This suggests that there is an exchange between bound DMSO and free DMSO. An up field shift for the methyl protons was also observed in the case of the chiral sulfoxide 221f (Figure 2.15D, entry 10 vs. 11-12). Similar observations (experimental and theoretical) were made for the methylene units in the case of 222b derived from (CH2)4SO 221b (Figure 2.16C and 2.16D). The structure for 222h was also computed and is discussed in Section 2.2. Also, the rationale of the lack of a match/mismatch relationship in catalyst formation, was also found as the sulfoxide 221f shifts in such a way that it has the maximum CH-π interaction (not shown here). The SULFOX-BOROX catalyst 222a was successfully employed for the catalytic asymmetric epoxidation of aldehydes. The details are discussed in Chapter 8. Figure 2.16 Calculated structure of SULFOX-BOROX catalysts 222a and 222b using Gaussian ʹ′03. They are visualized by the Mercury Program (C, gray; O, red; S, orange; B, yellow; H, white). Hydrogen atoms omitted for clarity (except protonated DMSO and TMSO). (A) Calculated B3LYP/6-31g* structure of 222a. Some secondary interactions are highlighted: d1 = 1.44 Å (H-bonding), d2 = 3.56 Å (CH-π), d3 = 3.80 Å (CH-π). (B) Space-filling rendition of 222a with the same orientation and showing hydrogens. The boroxinate anion is given in green and the protonated sulfoxide is in traditional colors. (C) Calculated B3LYP/6-31g* structure of 222b. Some secondary interactions are highlighted: d1 = 1.44 Å (H-bonding), d2 = 3.67 Å (CHπ), d3 = 3.54 Å (CH-π), d4 = 3.39 Å (CH-Ο). (D) Space-filling rendition of 222b with the same 105 Figure 2.16 cont’d orientation and showing hydrogens. The boroxinate anion is given in green and the protonated sulfoxide is in traditional colors. A B d1 d3 d2 C D d4 d1 d3 2.1.6 d2 Phosphine-oxides as the base: PHOSPHINOX-BOROX catalyst Another class of bases examined is phosphine-oxides 223. As expected, aliphatic phosphine-oxides afforded excellent yields of the boroxinate catalysts 224 (Table 2.11, entries 34). 27 The pKa’s of protonated Ph2P(Me)O and Bu2P(Me)O are –3.2 106 30 and –1.51±0.29 respectively. This suggested that there is lower probability that Ph3PO might induce the catalyst formation. In fact, although boroxinate formation did occur with Ph3PO, the catalyst was generated in lower yields than with Bu3PO. (Table 2.11, entries 1-2). Additionally, secondary phosphine oxide m-Xyl2P(H)O 223d was also able to generate the BOROX catalyst as well (Table 2.12, entries 7-8). However, tributyl phosphate 223c and phosphonate 223e were found not to be basic enough to give the catalyst (Table 2.11, entries 5-6 and 9-10). Table 2.11 NMR Analysis of a mixture of (S)-VAPOL, B(OPh)3 and phosphine-oxides as bases a B(OPh)3 (3 equiv) + [Base-H] OPh Base 223 (x equiv) OPh OH OH O –O B O O + * + * * B B O B B OPh + * O * OH CDCl3 OH O O B O O OPh 25 °C, 10 min 58 108 106 58 224 OPh 0.1 M (unreacted) B3 B2 B1 Equiv of Base (S)VAPOL B1 106 B2 108 B3 224 d e f 1 2 29 15 <1 <1 11 11 37 41 9.91 9.96 15.94, 7.16 15.96, 6.59 10 <1 30 12 11 05 60 44 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 43 30 7 <1 10 20 67 94 <1 <1 66 78 <1 <1 10.25 10.28 – – 9.98 10.01 – – 15.94, 5.13 14.76, 5.06 18.23 17.57 15.96, 7.11 15.95, 7.92 16.00 15.97 57 5 18 <1 – 16.00 # series Base b 223 1 2 a Ph3PO b Bu3PO c (BuO)3PO d m-Xyl2P(H)O e (EtO)2P(H)O 1 2 1 2 1 2 1 2 – No base 0 3 4 5 6 7 8 9 10 11 a c ,d d d 1 H 11 B Unless otherwise specified, all NMR samples were prepared by mixing (S)-VAPOL 58 (0.1 mmol) and commercial B(OPh)3 (0.3 mmol) and base 223 in CDCl3 (1 mL) at 25 °C and 107 Table 2.11 cont’d stirring for 10 min before spectra were taken. use. c Unreacted (S)-VAPOL 58. as the limiting reagent. e d b All bases were distilled or sublimed prior to NMR yield with Ph3CH as internal standard with ligand Chemical Shift for the bay proton in B3-base complex. Shift of the peaks observed in the 11 f Chemical B NMR spectrum. 1 The NMR analysis is given in Figure 2.17. Characteristic peaks were observed in the H NMR and 11 B NMR spectra in the cases where it formed the boroxinate catalyst. Although, the 1 bay region of the H NMR spectra do show some new peaks (Figure 2.17A, entries 7 and 12), no significant change in the alkyl region indicated the absence of any boroxinate species when large excesses of tributyl phosphate 223c and phosphonate 223e are used. Figure 2.17 Phosphine-oxide induced boroxinate catalyst formation. (A) CDCl3 with Ph3CH as internal standard. (B) 11 a 1 H NMR spectra in 1 B NMR spectra corresponding to the H NMR 1 spectra in Figure 2.17A. (C) The alkyl region corresponding to the H NMR spectra in Figure 2.17A. (D) 31 P NMR spectra in CDCl3. The chemical shifts in 31 P NMR are referenced with respect to a standard sample of H3PO4. Entry 1: pure m-Xyl2P(H)O 223d. Entry 2: pure mXyl2P(H)O 223d (decoupled). Entry 3: (S)-VAPOL (0.1 mmol) plus 3 equiv commercial B(OPh)3 and 2 equiv m-Xyl2P(H)O 223d at 25 °C for 10 min. Entry 4: same as entry 3 with decoupling. 108 Figure 2.17 A cont’d no base (EtO)2P(H)O (15 equiv) (EtO)2P(H)O (2 equiv) (EtO)2P(H)O (1 equiv) B3 m-Xyl2P(H)O (2 equiv) B3 m-Xyl2P(H)O (1 equiv) (BuO)3PO (2 equiv) (BuO)3PO (2 equiv) Bu3PO (2 equiv) Bu3PO (1 equiv) Ph3PO (2 equiv) Ph3PO (1 equiv) B3 B3 B3 B3 58 B2 B B3 B3 B3 B3 B3 B3 109 Figure 2.17 C cont’d D m-Xyl2P(H)O-B3 224d (decoupled) m-Xyl2P(H)O-B3 224d m-Xyl2P(H)O 223d (decoupled) m-Xyl2P(H)O 223d 110 a Note for Figure 2.17A: Entry 1: (S)-VAPOL (0.1 mmol) plus 3 equiv commercial B(OPh)3 and 1 equiv Ph3PO 223a at 25 °C for 10 min. Entry 2: same as entry 1 with 2 equiv Ph3PO 223a. Entry 3 and 4: same as entry 1 with 1 and 2 equiv Bu3PO 223b respectively. Entry 5 and 6: same as entry 1 with 1 and 2 equiv (BuO)3PO 223c respectively. Entry 7 and 8: same as entry 1 with 1 and 2 equiv m-Xyl2P(H)O 223d respectively. Entry 9, 10 and 11: same as entry 1 with 1, 2 and 15 equiv (EtO)2P(H)O 223e respectively. Entry 12: (S)-VAPOL (0.1 mmol) plus 3 equiv commercial B(OPh)3 at 25 °C for 10 min. Also, the BOROX catalyst 224d was characterized by The 31 31 P NMR analysis (Figure 2.17D). P NMR spectrum of pure m-Xyl2P(H)O 223d exhibits one single peak at δ = 23.29 ppm when the spectrum is proton decoupled. A new broad peak at δ = 29.25 ppm was observed in case of boroxinate 224d. The chemical shifts in the 31 P NMR spectrum are referenced with respect to a standard sample of H3PO4. The computed structure of 224b reveals the presence of possible CH-π interactions between the alkyl groups of the phosphine oxide and the phenanthrene ring of the ligand (calculated structure not shown). 2.1.7 Amine-oxides as the base: AMINOX-BOROX catalyst Given the ability of phosphine-oxides to generate boroxinate species, it was natural to consider that amine-oxides could also generate boroxinates, further broadening the scope of 111 boroxinate catalysts. As documented in the literature, the pKa of protonated Me3NO is 4.6 (in 31 H2O) 32 whereas the pKa of protonated pyridine-N-oxide is 0.79 (in H2O). From NMR studies, it seems that boroxinates 226 are generated when 1 equiv of amine oxides are utilized (Table 2.12, entries 1,5-6 and Figure 2.18D, entries 3,7-8). However, they are not generated in a clean fashion in the cases of Me3NO 225a and N-methyl morpholine oxide 225b as some additional unknown peaks were observed (Figure 2.18A, entries 3 and 6). Table 2.12 NMR Analysis of a mixture of (S)-VAPOL, B(OPh)3 and amine-oxides as bases a B(OPh)3 (3 equiv) + [Base-H] OPh Base 225 (x equiv) OPh OH OH O –O B O O + * + * * B B O B B OPh + * O * OH CDCl3 OH O O B O O OPh 25 °C, 10 min 58 108 106 58 226 OPh 0.1 M (unreacted) B3 B2 B1 + [Base-H] OPh Base O –O B + B O * O O B 226' OPh # series Base b 225 Equiv of Base + [Base-H] OPh Base O –O B B O * O O B Base OPh 226'' (S)VAPOL B3 226 1 d e f f 7 <1 <1 <1 nd nd nd nd nd nd nd nd 15.70, 5.48 17.08, 5.30 17.95, 5.31,2.51 17.63, 5.31,2.48 1.8:1.0 0.2:1.0 0.8:1.0:1.0 0.7:1.0:1.1 c ,d H 11 B 11 B 1 2 3 4 a Me3NO 1 2 3 3 5 b NMO 1 15 nd nd 15.56, 5.50 1.7:1.0 6 c Pyridine-Noxide 1 9 68 9.98 15.66, 6.42 2.2:1.0 7 – No base 0 57 <1 – 16.00 112 – Table 2.12 cont’d a Unless otherwise specified, all NMR samples were prepared by mixing (S)-VAPOL 58 (0.1 mmol) and commercial B(OPh)3 (0.3 mmol) and base 225 in CDCl3 (1 mL) at 25 °C and stirring for 10 min before spectra were taken. All but entry 7 have both B1 106 and B2 108 b <1. Entry 7 has 5% and 18% of 106 and 108 respectively. All bases were distilled or sublimed prior to use. c Unreacted (S)-VAPOL 58. standard with ligand as the limiting reagent. complex. f e d Chemical Shift for the bay proton in B3-base Chemical Shift of the peaks observed in the peaks observed in the 11 NMR yield with Ph3CH as internal 11 B NMR spectrum. g The ratio of B NMR spectrum. With excess amine oxides (Table 2.12, entries 2-4 and Figure 2.18, entries 4-6), extra coordination of amine oxide to boron seems to be operating giving rise possibly to 226ʹ′ or 226ʹ′ʹ′(Table 2.12). These structures are suggested by the integration of the peaks in the 11 B 1 NMR (Table 2.12). A clean generation of B3 (δ = 9.82 ppm in H NMR, 68% yield) was observed when one equiv of pyridine-N-oxide 225c was used (Table 2.12, entry 6 and Figure 2.18, entry 8). Figure 2.18 Amine-oxide induced boroxinate catalyst formation. (A) a 1 H NMR spectra in CDCl3 with Ph3CH as internal standard. (B) same as in Figure 2.18A with a stacked angle of 1 15º. (C) The alkyl region corresponding to the H NMR spectra in Figure 2.18A. (D) 1 spectra corresponding to the H NMR spectra in Figure 2.18A. 113 11 B NMR A no base Figure 2.18 cont’d Pyridine-N-Oxide (1 equiv) 58 B2 B3 58 58 NMO (1 equiv) Me3NO (3 equiv) Me3NO (3 equiv) Me3NO (2 equiv) 58 Me3NO (1 equiv) Me3NO (1 equiv) + B(OPh)3 only B 58 no base B3 Pyridine-N-Oxide (1 equiv) 58 58 NMO (1 equiv) Me3NO (3 equiv) Me3NO (3 equiv) Me3NO (2 equiv) Me3NO (1 equiv) 58 Me3NO (1 equiv) + B(OPh)3 only 114 B2 Figure 2.18 C cont’d D B3 B3 B3 115 a Note for Figure 2.18A: Entry 1: Me3NO 225a plus 1 equiv commercial B(OPh)3 at 25 °C for 10 min. Entry 2: (S)-VAPOL (0.1 mmol) plus 3 equiv commercial B(OPh)3 and 1 equiv Me3NO 225a at 25 °C for 10 min. Entry 3: same as entry 2 with 2 equiv Me3NO 225a. Entry 4: same as entry 2 with 3 equiv Me3NO 225a. Entry 5: 3 equiv Me3NO 225a is added to a preformed mixture of (S)-VAPOL (0.1 mmol) and 3 equiv commercial B(OPh)3 in CDCl3. Entry 6: same as entry 2 with 1 equiv NMO (N-methyl morpholine oxide) 225b. Entry 7: same as entry 2 with 1 equiv pyridine-N-Oxide 225c. Entry 8: (S)-VAPOL (0.1 mmol) plus 3 equiv commercial B(OPh)3 at 25 °C for 10 min. In some cases, with excess amine oxides, an appreciable amount of an absorption at δ = 2.7 ppm is observed in the [B(OPh)4] – 11 + B NMR spectrum which is tentatively assigned as [Me3NO-H] 227 or [Me3NO→B(OPh)3] 227ʹ′ from the NMR study of 226a complex (Figure 2.18, entries 1,4-5). The computed structures of 226a and 226b reveal the presence of the possible CH-π and π-π interactions between the alkyl or aryl groups of the oxide and the phenanthrene ring of the ligand (calculated structure not shown). It would be interesting to examine nitrones as the base (not done). 2.1.8 Aldehydes as the base: ALDO-BOROX catalyst As expected, no sign of any boroxinate was observed when aldehydes 127 were utilized as the bases (Figure 2.19). This is probably due to the high acidity (pKa = –7) of the protonated aldehydes. However, aldehydes with other basic sites do form BOROX catalyst. This is probably due the protonation of the nitrogens attached to these aldehydes (Figure 2.19, entries 5- 116 7). Surprisingly, 2-methyloxazole-4-carbaldehyde 127n failed to give any boroxinate even though it has a free basic nitrogen (Figure 2.19, entry 4). In almost all cases, pyroborate B2 108 was observed. Figure 2.19 (A) Aldehyde induced boroxinate catalyst formation. (B) CDCl3 with Ph3CH as internal standard. (C) 11 a 1 H NMR spectra in 1 B NMR spectra corresponding to the H NMR spectra in Figure 2.19B. A B(OPh)3 (3 equiv) + [Base-H] OPh Base 127 (x equiv) OH O –O B + * B O * OH CDCl3 O O B 25 °C, 10 min 58 228 OPh 0.1 M B3 * OPh + B O B O OPh 108 O * O B OPh + O 106 B2 * B 58 4-(dimethylamino)benzaldehyde B3 B2 B2 58 nicotinaldehyde B3 58 B3 picolinaldehyde 127n 2-methyloxazole-4-carbaldehyde pyrrole-2-carbaldehyde 58 B2 127m B2 58 127a benzaldehyde 58 B2 127w pivalaldehyde 58 117 B2 OH 58 (unreacted) B1 no base OH Figure 2.19 cont’d C B3 B3 B3 a Note for Figure 2.19B: Entry 1: (S)-VAPOL (0.1 mmol) plus 3 equiv commercial B(OPh)3 and 2 equiv pivalaldehyde 127w at 25 °C for 10 min. Entry 2: same as entry 1 with 2 equiv benzaldehyde 127a. Entry 3: same as entry 1 with 2 equiv pyrrole-2-carbaldehyde 127m. Entry 4: same as entry 1 with 2 equiv of 2-methyloxazole-4-carbaldehyde 127n. Entry 5: same as entry 1 with 2 equiv picolinaldehyde 127i. Entry 6: same as entry 1 with 2 equiv nicotinaldehyde 127j. Entry 7: same as entry 1 with 2 equiv 4-(dimethylamino)benzaldehyde 127h. Entry 8: (S)-VAPOL (0.1 mmol) plus 3 equiv commercial B(OPh)3 at 25 °C for 10 min. 2.1.9 Diazo as the base: DIAZO-BOROX catalyst Ethyl diazoacetate 85 was found to be reacting with the VAPOL to afford 230 in 80% yield when tested under conditions optimal for boroxinate generation (Figure 2.20). The mono- 118 alkylated adduct 230 is often observed at the end of the Wulff catalytic asymmetric aziridination reaction. 13a There was no sign of any boroxinate 229a. In a separate experiment, a peak at δ = 5.74 ppm (in 11 B NMR) was observed when N-benzyl diazoacetamide 128b was employed as the base (Figure 2.20). However, there is no conclusive evidence for the formation of the boroxinate 229b. The calculated structure of 229b supports the presence of the boroxinate (not shown here). Also, there was no sign of adduct 231 under these conditions. It must be remembered that most diazo compounds are more basic at the carbon bearing the leaving group. Figure 2.20 (A) Diazo induced boroxinate catalyst formation. (B) with Ph3CH as internal standard. (C) 11 a1 H NMR spectra in CDCl3 1 B NMR spectra corresponding to the H NMR spectra in Figure 2.20B. A N2 O * OH OH 58 B(OPh)3 (3 equiv) EDA 85 (2 equiv) CDCl3 25 °C, 10 min 0.1 M + OH OPh O B O – + B O * O O B 229a OPh N2 * OH OH 58 B(OPh)3 (3 equiv) Diazo 128b (2 equiv) CDCl3 25 °C, 10 min 0.1 M H N O * O 230 Ph + OH OPh O –O B + B O * O O B 229b OPh 119 O OH O * O OH N H 231 Ph Figure 2.20 B cont’d 58 229b ? N-benzyl diazoacetamide 128b 230 230 Ethyl diazoacetate 85 C 229b ? (5.74 ppm) N-benzyl diazoacetamide 128b Ethyl diazoacetate 85 120 a Note for Figure 2.20B: Entry 1: (S)-VAPOL (0.1 mmol) plus 3 equiv commercial B(OPh)3 and 2 equiv EDA 85 at 25 °C for 10 min. Entry 2: same as entry 1 with 2 equiv N-benzyl diazoacetamide 128b. (C) 11 1 B NMR spectra corresponding to the H NMR spectra in. 2.1.10 Miscellaneous bases: Bases such as methyl carbamate 232a and THF 232b failed to give any boroxinate 233 (Figure 2.21). The pKa of protonated THF is –2.02, which is quite similar to DMSO. Hence it is quite interesting to observe the BOROX catalyst with DMSO and not with THF. Figure 2.21 Miscellaneous bases induced boroxinate catalyst formation. (A) in CDCl3 with Ph3CH as internal standard. (B) 11 a1 H NMR spectra 1 B NMR spectra corresponding to the H NMR spectra in Figure 2.21A. 58 (57%) A B2 (18%) no base 58 (59%) B2 (8%) THF 58 (41%) B2 (33%) methylcarbamate 121 Figure 2.21 B cont’d no base THF methylcarbamate a Note for Figure 2.21A: Entry 1: (S)-VAPOL (0.1 mmol) plus 3 equiv commercial B(OPh)3 and 2 equiv methyl carbamate 232a at 25 °C for 10 min. Entry 2: same as entry 1 with 2 equiv THF 232b. Entry 3: (S)-VAPOL (0.1 mmol) plus 3 equiv commercial B(OPh)3 at 25 °C for 10 min. 2.2 Prediction of BOROX catalysts via computational chemistry During the calculations of the possible BOROX complexes, an interesting observation was made. In all the cases, where no boroxinates were observed, it was found that proton is completely transferred to the O2 and the boroxinate ring is also collapsed (Figure 2.21). Specifically, the bond between O2 and tetra-coordinate boron is broken. This is found in the 122 cases of bases like PhCHO 127a, pyrrole 216d, Me2SO2 221h, (CH2)4SO2 221i, BuO3PO 223c, THF 232b etc. A few of calculated structures are presented in Figure 2.21. Hence, we can probably make a guess about the generation of the boroxinate complex even without the NMR study. It must be noted that these calculations are not representative of the actual structures and it should be used as tool to predict the possibility of boroxinate formation. In all cases, the distance (B-O2) between the O-2 and former tetra-coordinate boron was found to more than 1.6 Å. Additionally, the former tetra-coordinate boron is found to be out of the plane by ~ 13º–14º. In the case of the boroxinate anion, the ∠oop and B-O2 was found to be 20.2º and 1.43 Å respectively (not shown here). Figure 2.22 Calculated structures of boroxinates (A) 228b (base = PhCHO 127a), (B) 217d (base = pyrrole 216d), (C) 222h (base = Me2SO2 221h), (D) 222i (base = (CH2)4SO2 221i), (E) 224c (base = (BuO)3PO 223c) and (F) 233b (base = THF 232b) using Gaussian ʹ′03. Calculated B3LYP/6-31g* structure visualized by the Mercury Program (C, gray; O, red; N, blue; B, pink, S, orange; H, white). Hydrogen atoms omitted for clarity (except O-H). ∠oop = angle out of plane for the former tetra-coordinate boron, B-O2 = the distance between O-2 and the former tetra-coordinate boron. A B O2 O2 B B 123 Figure 2.22 cont’d 217d (∠oop = 13.2º, B-O2 = 1.69 Å) 228a (∠oop = 13.1º, B-O2 = 1.71 Å) D C O2 O2 B B 222i (∠oop = 13.7º, B-O2 = 1.66 Å) 222h (∠oop = 13.7º, B-O2 = 1.67 Å) E F O2 O2 B B 222i (∠oop = 14.6º, B-O2 = 1.64 Å) 224c (∠oop = 14.3º, B-O2 = 1.65 Å) 2.3 Possibility of Bench-Top Stable BOROX catalyst The real application of any catalyst lies in its broad applicability in catalytic asymmetric reactions. This, in turn, requires the catalyst to be easily available specifically on a commercial 124 scale. There has been a long lasting dream of the feasibility of the commercial BOROX catalyst. There are two problems regarding this possibility. They are discussed below with their probable solutions. 2.3.1 Substrate induced formation of the catalyst The first problem with our catalyst is its unique characteristic, which is substrate-induced formation of the catalyst. This is a big problem as the commercially available catalyst should ideally be independent of the substrate used. A potential solution of the problem could be that a particular base should be employed to generate the catalyst, which is easily replaced by the substrate without disrupting the catalyst structure. The realization of the SULFOX-BOROX catalyst could be the first step in this direction. In terms of basicity, DMSO should be easily replaced by an imine. In fact, the same was observed when the aziridination reaction was carried out with the pre-formed SULFOX-BOROX catalyst 222a (Scheme 2.2). The aziridination reaction gave comparable results to the reaction carried out by substrate-induced IMINOBOROX catalyst 188a. Later, other boroxinates derived from bases such as aniline and benzhydryl amine were also tried and the results are described in Chapter 7 in detail. Scheme 2.2 The Wulff asymmetric cis-aziridination reaction with benzhydryl imines 78 O Ph Ph N 78a Ph + OEt N2 85 catalyst (10 mol %) CHCl3 25 °C, 24 h Ph Ph N Ph CO2Et 86a IMINO-BOROX catalyst 188a: yield = 82%, ee = 90% SULFOX-BOROX catalyst 222a: yield = 86%, ee = 90% 125 2.3.2 Stability of the BOROX catalyst The second problem is a typical one for any catalyst i.e. stability of the catalyst. One of the complexities of the BOROX catalyst is that its assembly is dependent on a number of variables. One of the ways to increase the stability is to decrease the number of these variables. This can be done by utilizing one of the components in which there is a pre-installed base. Among all the variables, the two obvious choices are the alcohol component and the borane component. These two modifications were tested and are discussed below. 2.3.2.1 Base incorporated in alcohol The major advantage of boroxinate catalysts as revealed by the work in this thesis is that now there are many bases from which to choose to generate the boroxinate catalyst. Since sulfoxides can be easily be replaced by imines, it was thought to utilize the alcohol 234a which has a sulfoxide in the tether. Thereafter, it was utilized and afforded the BOROX catalyst 235a 1 in 40% NMR yield (δ = 11.06 ppm and 10.44 ppm in H NMR and δ = 5.30 in 11 B NMR, Figure 2.23B, entry 1). As the structure of this species is not known, the presented structure is an assumption only. Later, two other alcohols 234b and 234c were also employed. However, the results were not that conclusive from the 11 B NMR spectrum (Figure 2.23, entries 2-3). Figure 2.23 (A) Bases (with pre-installed alcohols) induced boroxinate catalyst formation. (B) 1 H NMR spectra in CDCl3 with Ph3CH as internal standard. (C) 1 11 a B NMR spectra corresponding to the H NMR spectra in Figure 2.23B with the highlighted chemical shifts of the various boron species. 126 Figure 2.23 cont’d A * BH3•Me2S (3 equiv) 234 (2 equiv) H2O (3 equiv) OH OH CH3CN, 100 °C, 1 h then 0.5 mmHg 100 °C. 0.5 h 58 + [H-Base] O O –O B B O * O O B O 235 B NH2 Ph OH 234c OH N 234b Ph O S OH B3 B3 234a 127 Base HO Base = 234 Figure 2.23 cont’d C 9.08 5.36 10.63 8.33 5.30 17.61 a Note for Figure 2.23B: Entry 1: (S)-VAPOL (0.1 mmol) plus 3 equiv BH3•Me2S 192a, 2 equiv ROH 234a and 3 equiv H2O were heated at 100 °C in CH3CN for 1 h followed by removal of volatiles under vacuum for 0.5 h. Entry 2: same as entry 1 with 2 equiv ROH 234b. Entry 3: same as entry 1 with 2 equiv ROH 234c. 128 One of the other ways is to utilize a base, which could simply function as the alcohol component. Hence we tried to generate the boroxinate 236 by employing 1 equiv of (S)VAPOL, 3 equiv of BH3•Me2S, 3 equiv H2O and 3 equiv aniline 126k. The result is presented in Figure 2.24. To our delight, boroxinate complex 236 was observed. However, the structure of 236 is not confirmed and must remain a tentative assignment. Peaks at δ = 10.06 ppm and δ = 1 10.30 ppm (in the H NMR spectrum) and δ = 4.35 ppm (in the 11 B NMR spectrum) supports the formation of the catalyst 236. 1 Figure 2.24 (A) Aniline induced boroxinate catalyst formation. (B) H NMR spectra in CDCl3. (S)-VAPOL (0.1 mmol) plus 3 equiv BH3•Me2S 192a, 3 equiv aniline 126k and 3 equiv H2O were heated at 100 °C in CH3CN for 1 h followed by removal of volatiles under vacuum for 0.5 h. Thereafter, the catalyst was dissolved in CDCl3 and subjected to NMR analysis. (C) 1 NMR spectra corresponding to the H NMR spectra in Figure 2.24B. A * OH OH 58 BH3•Me2S (3 equiv) PhNH2 (3 equiv) H2O (3 equiv) toluene, 100 °C, 1 h then 0.5 mmHg 100 °C. 0.5 h 129 + PhNH3 NHPh O –O B B O * O O B NHPh 236 11 B Figure 2.24 cont’d B C 2.3.2.2 Base incorporated in the boron source Another way is the usage of the borane that has the base installed in it. The base attached to borane should be a weak so that it can be easily be replaced by the substrate i.e. imine. Hence we decided to examine borane like BH3•PPh3 192c and BH3•Et2NPh 192d. While BH3•PPh3 192c failed to give any catalyst, boroxinate 237 was obtained when BH3•Et2NPh 192d was 1 employed (Scheme 2.3, NMR not shown). A peak at δ = 10.73 ppm (in H NMR) and δ = 5.88 ppm (in 11 B NMR) supports the formation of the catalyst 237. It must be noted that structure of 237 is a tentative assignment. 130 Scheme 2.3 Boroxinate formation using BH3•Et2NPh 192d * OH OH 58 2.4 + PhNHEt2 BH3•Et2NPh (3 equiv) PhOH (2 equiv) H2O (3 equiv) OPh O –O B B O * O O B OPh 237 d8-toluene 100 °C, 1 h B1 catalysts So far we have been focused on the BOROX catalyst, which has three boron atoms involved. Another class of the catalyst could be one, which involves only boron atom in a spiroborate such as 74 and 92 (Figure 2.1). The catalysts 74 and 92 will be discussed in detail in Chapter 4 and 5. Given the existence of 74, it was wondered that whether a similar catalyst could be made from our VANOL ligand. Although, the structure of 238 is not confirmed, a characteristic peak at δ = 9.55 ppm was observed when VANOL 59 was subjected to conditions suitable for spiroborate formation (Figure 2.25). 1 Figure 2.25 (A) Attempt to generate dimer catalyst 238. (B) H NMR spectra in CDCl3. (S)VANOL (0.1 mmol) plus 0.5 equiv BH3•Me2S 192a was heated at 100 °C in toluene for 1 h followed by removal of volatiles under vacuum for 0.5 h. Thereafter, 0.5 equiv of imine 111a was added. (C) 11 1 B NMR spectra corresponding to the H NMR spectra in Figure 2.25B. A * OH OH 59 BH3•Me2S (0.5 equiv) toluene, 100 °C, 1 h then 0.5 mmHg 100 °C. 0.5 h Ph N MEDAM (0.5 equiv) CDCl3 25 °C, 10 min O – O B * O * O H + MEDAM N Ph 238 131 Figure 2.25 cont’d B 2.5 C 9.55 Conclusions This chapter describes the generation of novel boroxinate catalysts employing various 1 bases. These catalysts are characterized by H NMR and 11 B NMR spectroscopy, computational chemistry and X-ray analysis. Some of these catalysts have already been utilized for various catalytic asymmetric reactions such as asymmetric aziridination of imines, multicomponent aziridination of aldehydes, [3+2] cycloaddition of imines and aldehydes, asymmetric reduction of quinolines and asymmetric epoxidation of aldehydes. Hopefully, a variety of new asymmetric reactions will be accomplished utilizing these novel catalysts in the near future. 132 APPENDIX 133 2.6 Experimental 2.6.1  General information ........................................................................................................... 135   2.6.2  Synthesis of imines 75a, 78a, 110a-112a, 206a, 207a, boroxine 191a and diazo 128b ... 137   2.6.3  Aziridination with different boron sources and pre-catalyst methods A-H (Table 2.1) .... 143   2.6.4  Aziridination using different alcohols (Table 2.3)/ligands (Table 2.4)/imines (Table 2.5)151   2.6.5  NMR analysis of a mixture of VAPOL, various boron sources, and imine 111a at various conditions (Figure 2.3, 2.4 and Table 2.2) ................................................................................. 154   2.6.6  NMR analysis of a mixture of VAPOL, B(OPh)3 and bases 75a, 78a, 85, 111a, 126, 127, 128b, 206a, 207a, 216, 219, 221, 223, 225, 232 (Figures 2.7, 2.9, 2.11, 2.12, 2.14, 2.15, 2.172.21 and Tables 2.7, 2.9-2.12) .................................................................................................... 158   2.6.7  Aziridination in the presence of SULFOX-BOROX catalyst 222a ................................... 159   2.6.8  NMR analysis of a mixture of VAPOL, B(OPh)3 and the bases 234 and 126k (Figure 2.232.24) ...................................................................................................................................... 160   2.6.9  NMR analysis of a mixture of VAPOL, PhOH, H2O and borane 192d (Scheme 2.3) ...... 161   2.6.10   NMR analysis of a mixture of VAPOL, BH3•Me2S (0.5 equiv) and imine 111a (0.5 equiv) (Figure 2.25) .................................................................................................................... 162   2.6.11  DFT Calculations of 190a, 215c, 222a, 222b, 217d, 222h, 222i, 228a and 233b (Figure 2.8, 2.10, 2.16, 2.22) ................................................................................................................... 163 2.6.12  Crystallographic structure determination of BOROX complex 217b (Figure 2.13) ....... 163 134 2.6.1 General information All reactions were carried out in flame-dried glassware under an atmosphere of argon unless otherwise indicated. Unless otherwise specified, all solvents were strictly dried before use: dichloromethane and acetonitrile were distilled over calcium hydride under nitrogen; tetrahydrofuran, and ether were distilled from sodium and benzophenone; toluene was distilled from sodium under nitrogen. Hexanes and ethyl acetate were ACS grade and used as purchased. Melting points were recorded on a Thomas Hoover capillary melting point apparatus and are uncorrected. IR spectra were recorded in KBr matrix (for solids) and on NaCl disc (for liquids) on a Nicolet IR/42 spectrometer. CDCl3 (with TMS) was dried over activated 4Å overnight and distilled. Purified CDCl3 was stored and handled in a glove box. Commercial CDCl3 in ampoule (CIL®, 100%, 0.75 mL) can be directly used in a glove box without further purification. 1 H NMR and 13 C NMR were recorded on a Varian Inova 300 MHz or Varian Unity Plus 500 MHz or Varian Inova 600 MHz spectrometer using CDCl3 as solvent (unless otherwise noted). The residual peak of CDCl3 or TMS was used as the internal standard for both 1 H NMR (δ = 7.24 ppm for CDCl3 or δ = 0 ppm for TMS) and 13 C NMR (δ = 77.0 ppm). 11 B NMR spectra were recorded on a Varian 500 MHz instrument or Varian Inova 600 MHz spectrometer in CDCl3 unless otherwise noted. 11 B NMR was done in a Norell® quartz NMR tube and referenced to external standard BF3•Et2O (δ = 0 ppm). Chemical shifts were reported in parts per million (ppm). Low-resolution Mass Spectrometry and High Resolution Mass Spectrometry were performed in the Department of Chemistry at Michigan State University 135 Mass Facility. Analytical thin-layer chromatography (TLC) was performed on Silicycle silica gel plates with F-254 indicator. Visualization was by short wave (254 nm) and long wave (365 nm) ultraviolet light, or by staining with phosphomolybdic acid in ethanol or with potassium permanganate. Column chromatography was performed with silica gel 60 (230 – 450 mesh). HPLC analyses were peformed using a Varian Prostar 210 Solvent Delivery Module with a Prostar 330 PDA Detector and a Prostar Workstation. Chiral HPLC data for the aziridines and epoxides were obtained using a CHIRALCEL OD-H column and PIRKLE COVALENT (R, R) WHELK-O 1 column. Optical rotations were obtained on a Perkin-Elmer 341 polarimeter at a wavelength of 589 nm (sodium D line) using a 1.0 decimeter cell with a total volume of 1.0 mL. Specific rotations are reported in degrees per decimeter at 20 °C and the concentrations are given in gram per 100 mL in ethyl acetate unless otherwise noted. All reagents were purified by simple distillation or crystallization with simple solvents unless otherwise indicated. Ethyl diazoacetate 85 and B(OPh)3 (stored in dessicators) are obtained from Aldrich Chemical Co., Inc. and used as received. Amines such as aniline 126k, benzyl amine 126e, homo-benzhydrylamine 126f and benzhydrylamine 126a (distilled prior to use) are also obtained from Aldrich Chemical Co., Inc. and used as received. (S)-VAPOL 58 or (S)-VANOL 59 (>99% ee) were made according to published procedure 18 and were dried over P2O5 overnight under reduced pressure (0.1 mm Hg) with refluxing hexane in a Abderhalden drying apparatus. These ligands are also commercially available from Aldrich Chemical Co., Inc 19 and Strem Chemicals. bis(4-methoxyphenyl)methanamine (DAM amine) 126b, 136 bis-(3,5-di- 13c methyl-4- methoxyphenyl)methanamine (MEDAM amine) 126c, 13b methoxyphenyl)methanamine (BUDAM amine) 126d, 34 234a bis-(3,5-di-tert-butyl-4- m-Xyl2P(H)O 223d 33 and sulfoxide were made according to the published procedure. Unless otherwise noted, all NMR analysis has been carried out using Ph3CH as the internal standard. Home-made Schlenk flask: Figure 2.26 The Schlenk flask was prepared from a single-necked 25 mL pear-shaped flask that had its 14/20 glass joint replaced with a high vacuum threaded Teflon valve. 2.6.2 Synthesis of imines 75a, 78a, 110a, 111a, 112a, 206a, 207a, boroxine 191a and diazo 128b General Procedure for the synthesis of aldimines – Illustrated for the synthesis of Nphenylmethylidene-bis(4-methoxy-3,5-dimethylphenyl)methylamine 111a. Benzaldehyde was distilled before use and all imines were could be purified by crystallization. 137 OMe MeO O MgSO4 + OMe H2N 127a N CH2Cl2 25 °C, 24 h OMe 111a 126c N-phenylmethylidene-bis(4-methoxy-3,5-dimethylphenyl)methylamine 111a: To a 50 mL flame-dried round bottom flask filled with argon was added bis(2,6-di-methyl-4methoxyphenyl)methylamine 126c (1.49 g, 5.00 mmol), MgSO4 (1.0 g, 8.4 mmol, freshly flame-dried) and dry CH2Cl2 (15 mL). After stirring for 10 min, benzaldehyde 127a (0.54 g, 5.05 mmol, 1.01 equiv) was added. The reaction mixture was stirred at room temperature for 24 h. The reaction mixture was filtered through Celite and the Celite bed was washed with CH2Cl2 (10 mL × 3) and then the filtrate was concentrated by rotary evaporation to give the crude imine as an off-white solid. Crystallization (1:9 CH2Cl2/hexanes) and collection of the first crop afforded 111a as a white solid (mp 144-146 °C) in 90% isolated yield (1.74 g, 4.5 mmol). 1 Spectral data for 111a: H NMR (CDCl3, 500 MHz) δ 2.24 (s, 12H), 3.66 (s, 6H), 5.35 (s, 1H), 6.99 (s, 4H), 7.39-7.41 (m, 3H), 7.80–7.82 (m, 2H), 8.35 (s, 1H); 13 C (CDCl3, 125 MHz) δ 16.22, 59.59, 77.41, 127.86, 128.46, 128.49, 130.61, 130.63, 136.45, 139.22, 155.84, 160.28; IR -1 (thin film) 2944w, 1643vs, 1483vs cm ; Mass spectrum: m/z (% rel intensity) 387 M+ (3), 283 (100), 40 (17); Anal calcd for C26H29NO2: C, 80.59; H, 7.54; N, 3.61. Found: C, 80.42; H, 7.24; 138 13c N, 3.55. These spectral data match those previously reported for this compound. N-benzylidene-1,1-diphenylmethanamine 78a: Imine 78a was prepared according to the procedure described above for imine 111a. N Crystallization (1:5 ethyl acetate/hexanes) and collection of the first crop afforded 78a as white solid crystals (mp. 99-101 °C) in 80% 78a isolated yield (1.09 g, 4 mmol). 1 Spectral data for 78a: H NMR (CDCl3, 300 MHz) δ 5.64 (s, 1H), 7.20-7.90 (m, 15H), 8.46 (s, 1H); 13 C NMR (CDCl3, 75 Hz) δ 77.62, 126.69, 127.40, 128.15, 128.19, 128.24, 130.47, 136.07, 143.64, 160.48. These spectral data match those previously reported for this 13a compound. N-benzylidene-bis(4-methoxyphenyl)methylamine OMe 110a: Imine 110a was prepared according to the procedure described above for imine 111a. Crystallization (1:25 CH2Cl2 / hexanes) N OMe 110a and collection of the first crop afforded 110a as white solid crystals (mp 60-61 ºC) in 91% isolated yield (1.51 g, 4.55 mmol). 1 Spectral data for 110a: H NMR (CDCl3, 300 MHz) δ 3.76 (s, 6H), 5.51(s, 1H), 6.84 (d, 4H, J = 8.8 Hz), 7.25-7.27 (m, 4H), 7.37-7.40 (m, 3H), 7.79–7.82 (m, 2H), 8.37 (s, 1H); 139 13 C (CDCl3, 75 MHz) δ 55.17, 76.55, 113.71, 128.35, 128.43, 128.61, 128.70, 130.60, 136.28, 158.43, 160.24. These spectral data match those previously reported for this compound. N-benzylidene-1,1- bis(3,5-di-tert-butyl-4-methoxyphenyl) OMe tBu tBu methanamine 112a: Imine 112a was prepared according to tBu N the procedure described above for imine 111a. Crystallization (1:100 EtOAc/hexanes) and collection of the first crop afforded OMe 112a 19 tBu 112a as white solid crystals (mp. 127-129 °C) in 90% isolated yield (2.5 g, 4.5 mmol). 1 Spectral data for 112a: H NMR (CDCl3, 500 MHz) δ 1.429 (s, 18H), 1.433 (s, 18H), 3.70 (s, 3H), 3.70 (s, 3H), 5.51 (s, 1H), 7.27 (s, 4H), 7.42–7.44 (m, 3H), 7.86–7.89 (m, 2H), 8.52 (s, 1H); 13 C (CDCl3, 75 MHz) δ 32.08, 35.77, 64.13, 78.20, 126.02, 128.40, 128.47, 130.50, 136.55, 137.42, 143.10, 158.29, 160.23. These spectral data match those previously reported for this compound. 13b N-benzylideneaniline 75a: Imine 75a was prepared according to the N 75a procedure described above for imine 111a. Crystallization (1:5 EtOAc/hexanes) and collection of the first crop afforded 75a as white solid crystals (mp. 48-50 °C) in 80% isolated yield (0.72 g, 4.0 mmol). 140 1 Spectral data for 75a: H NMR (CDCl3, 500 MHz) δ 7.19-7.23 (m, 3H), 7.39 (t, 2H, J = 8 Hz), 7.46-7.48 (m, 3H), 7.88-7.91 (m, 2H), 8.45 (s, 1H); 13 C (CDCl3, 125 MHz) δ 120.85, 125.91, 128.76, 128.80, 129.13, 131.36, 136.22, 152.09, 160.38. previously reported for this compound. These spectral data match those 35 N-benzylidene-1-phenylmethanamine 206a: N Imine 206a was prepared according to the procedure described above for imine 111a. 206a Distillation afforded 206a as colorless oil (bp 119-120 °C at 0.1 mm Hg) in 85% isolated yield (0.83 g, 4.25 mmol). 1 Spectral data for 206a: H NMR (CDCl3, 300 MHz) δ 4.79 (s, 2H), 7.20-7.40 (m, 8H), 7.75- 7.78 (m, 2H), 8.35 (s, 1H); 13 C (CDCl3, 75 MHz) δ 64.94, 126.89, 127.88, 128.18, 128.40, 128.50, 130.67, 136.05, 139.20, 161.88. These spectral data match those previously reported for 36 this compound. N-benzylidene-1-phenylmethanamine 207a: Imine 207a was prepared according to the procedure described above for imine 111a. Crystallization (1:9 EtOAc/hexanes) and collection of the first crop N afforded 207a as white solid crystals (mp. 92-94 °C) in 70% isolated 207a yield (1.0 g, 3.5 mmol). 1 Spectral data for 207a: H NMR (CDCl3, 600 MHz) δ 4.26 (dd, J = 7.2, 1.4 Hz, 2H), 4.46 (t, J = 7.2 Hz, 1H), 7.15 – 7.20 (m, 2H), 7.25 – 7.30 (m, 8H), 7.33 – 7.39 (m, 3H), 7.57 – 7.64 (m, 2H), 141 8.07 (t, J = 1.4 Hz, 1H); 13 C (CDCl3, 150 MHz) δ 52.01, 66.29, 126.28, 128.00, 128.32, 128.42, 128.43, 130.47, 136.19, 143.08, 161.92; IR (thin film) 3061 m, 3026 m, 2841 m, 1645 s, 1493 s, + 1451 s, 1309 m cm-1; HRMS (ESI-TOF) m/z 286.1594 [(M+H ); calcd. for C21H20N: 286.1596]. Synthesis of triphenoxyboroxine 191a: OH BH3•Me2S (3 equiv) H2O (3 equiv) 3 194a toluene, 80 °C, 1 h then 0.5 mmHg 80 °C. 0.5 h OPh B O O B B PhO O OPh 191a 2,4,6-triphenoxy-1,3,5,2,4,6-trioxatriborinane 191a: To a 25 mL flame-dried home-made Schlenk flask (see Figure 2.26) equipped with a stir bar and flushed with argon was added phenol 194a (28.2 mg, 0.3 mmol), BH3•Me2S (150 µL, 0.3 mmol, 2.0 M in toluene) and H2O (5.4 µL, 0.3 mmol). Under an argon flow through the side-arm of the Schlenk flask, dry toluene (2 mL) was added. The flask was sealed by closing the Teflon valve, and then placed in an oil bath (80 ºC) for 1 h. After 1 h, a vacuum (0.5 mm Hg) was carefully applied by slightly opening the Teflon valve to remove the volatiles. After the volatiles are removed completely, a full vacuum is applied and is maintained for a period of 30 min at a temperature of 80 ºC (oil bath). The flask was then allowed to cool to room temperature yielding the boroxine 191a as white solid. The boroxine prepared in this manner typically afforded boroxine 191a: B(OPh)3 187a = 12:1 as indicated by 13 C NMR. 142 1 Spectral data for boroxine 191a: H NMR (CDCl3, 500 MHz) δ 7.07 (d, 6H, J = 7.5 Hz), 7.12 (t, 3H, J = 7.0 Hz), 7.30 (t, 6H, J = 7.5 Hz); 13 C NMR (CDCl3, 125 MHz) δ 119.95, 123.95, 129.36, 152.00. These spectral data match those previously reported for this compound. 37 Synthesis of Diazoacetamide 128b: See Chapter 8 2.6.3 Aziridination with different boron sources and pre-catalyst methods A-H (Table 2.1) Pre-catalyst Method A: B(OPh)3 (3 equiv) (S)-VAPOL (10 mol%) tolulene, 80 °C, 1 h then 0.5 mm Hg 80 °C, 0.5 h pre- catalyst (Method A) To a 25 mL flame-dried home-made Schlenk flask (see Figure 2.26) equipped with a stir bar and flushed with argon was added (S)-VAPOL (54 mg, 0.1 mmol) and commercial B(OPh)3 (87 mg, 0.3 mmol). Under an argon flow through the side-arm of the Schlenk flask, dry toluene (2 mL) was added through the top of the Teflon valve to effect dissolution. The flask was sealed by closing the Teflon valve, and then placed in an 80 ºC oil bath for 1 h. After 1 h, a vacuum (0.5 mm Hg) was carefully applied by slightly opening the Teflon valve to remove the volatiles. After the volatiles were removed completely, a full vacuum was applied and maintained for a period of 30 min at a temperature of 80 ºC (oil bath). The flask was then allowed to cool to room temperature and opened to argon through the side-arm of the Schlenk flask. 143 Pre-catalyst Method B: (S)-VAPOL (10 mol%) B(OPh)3 (3 equiv) H2O (3 equiv) THF, 80 °C, 1 h then 0.5 mm Hg 80 °C, 0.5 h pre- catalyst (Method B) To a 25 mL flame-dried home-made Schlenk flask (see Figure 2.26) equipped with a stir bar and flushed with argon was added (S)-VAPOL (54 mg, 0.1 mmol) and commercial B(OPh)3 (87 mg, 0.3 mmol) and water (5.4 µL, 0.3 mmol). Under an argon flow through the side-arm of the Schlenk flask, dry THF (2 mL) was added through the top of the Teflon valve to effect dissolution. The flask was sealed by closing the Teflon valve, and then placed in an 80 ºC oil bath for 1 h. After 1 h, a vacuum (0.5 mm Hg) was carefully applied by slightly opening the Teflon valve to remove the volatiles. After the volatiles were removed completely, a full vacuum was applied and maintained for a period of 30 min at a temperature of 80 ºC (oil bath). The flask was then allowed to cool to room temperature and opened to argon through the sidearm of the Schlenk flask. Pre-catalyst Method C: B(OPh)3 (4 equiv) H2O (1 equiv) (S)-VAPOL (10 mol%) tolulene, 80 °C, 1 h then 0.5 mm Hg 80 °C, 0.5 h pre- catalyst (Method C) This method is similar to method A except that a combination of (S)-VAPOL (54 mg, 0.1 mmol) and commercial B(OPh)3 (116 mg, 0.4 mmol) and water (1.8 µL, 0.1 mmol) was employed. 144 Pre-catalyst Method D: (S)-VAPOL (10 mol%) boroxine 191a (1 equiv) tolulene 25 °C, 5 min pre- catalyst (Method D) To a 25 mL flame-dried home-made Schlenk flask (see Figure 2.26) equipped with a stir bar and pre-made triphenoxyboroxine 191a (0.1 mmol) was added (S)-VAPOL (54 mg, 0.1 mmol). Pre-catalyst Method E: BH3•Me2S (3 equiv) ROH (2 equiv) H2O (3 equiv) (S)-VAPOL (10 mol%) tolulene, 100 °C, 1 h then 0.5 mm Hg 100 °C, 0.5 h pre- catalyst (Method E) To a 25 mL flame-dried home-made Schlenk flask (see Figure 2.26) equipped with a stir bar and flushed with argon was added (S)-VAPOL (54 mg, 0.1 mmol) and BH3•Me2S (150 µL, 0.3 mmol, 2.0 M in toluene), PhOH (18.8, 0.2 mmol) and H2O (5.4 µL, 0.3 mmol). Under an argon flow through the side-arm of the Schlenk flask, dry toluene (2 mL) was added through the top of the Teflon valve to effect dissolution. The flask was sealed by closing the Teflon valve, and then placed in an 100 ºC oil bath for 1 h. After 1 h, a vacuum (0.5 mm Hg) was carefully applied by slightly opening the Teflon valve to remove the volatiles. After the volatiles were removed completely, a full vacuum was applied and maintained for a period of 30 min at a temperature of 100 ºC (oil bath). The flask was then allowed to cool to room temperature and opened to argon through the side-arm of the Schlenk flask. 145 Pre-catalyst Method F: BH3•Me2S (3 equiv) ROH (2 equiv) H2O (3 equiv) (S)-VAPOL (10 mol%) tolulene, 100 °C, 1 h pre- catalyst (Method F) This method is similar to method E except that the removal of volatiles and a full vacuum for 30 min was excluded. Pre-catalyst Method G: B(OH)3 (3 equiv) PhOH (2 equiv) (S)-VAPOL (10 mol%) tolulene, 80 °C, 1 h then 0.5 mm Hg 80 °C, 0.5 h pre- catalyst (Method G) This method is similar to method A except that a combination of (S)-VAPOL (54 mg, 0.1 mmol) and B(OH)3 (18.6 mg, 0.3 mmol) and PhOH (18.8, 0.2 mmol) was employed. Pre-catalyst Method H: BH3•THF (3 equiv) ROH (2 equiv) H2O (3 equiv) (S)-VAPOL (10 mol%) tolulene, 25 °C, 10 min then 0.5 mm Hg 25 °C, 0.5 h pre- catalyst (Method H) To a 25 mL flame-dried home-made Schlenk flask (see Figure 2.26) equipped with a stir bar and flushed with argon was added (S)-VAPOL (54 mg, 0.1 mmol) and BH3•THF (300 µL, 0.3 mmol, 1.0 M in THF), PhOH (18.8, 0.2 mmol) and H2O (5.4 µL, 0.3 mmol). Under an argon 146 flow through the side-arm of the Schlenk flask, dry toluene (2 mL) was added through the top of the Teflon valve to effect dissolution. The flask was sealed by closing the Teflon valve, and then stirred at 25 ºC for 10 min. After 10 min, a vacuum (0.5 mm Hg) was carefully applied by slightly opening the Teflon valve to remove the volatiles. After the volatiles were removed completely, a full vacuum was applied and maintained for a period of 30 min at 25 ºC. The flask was then opened to argon through the side-arm of the Schlenk flask. *Aziridination with procedures I (pre-catalyst method A), III (pre-catalyst method B), IV (pre-catalyst method C), VI (pre-catalyst method E), VII (pre-catalyst method F), VIII (precatalyst method G) and IX (pre-catalyst method H): General Procedure for performing aziridination – Illustrated for the synthesis of (2R,3R)ethyl 1-benzhydryl-3-phenylaziridine-2-carboxylate 86a using pre-catalyst method A. O IMINO-BOROX catalyst 188a (10 mol %) Ph Ph OPh Ph Ph O B O – N Ph + OEt B O * N+ N toluene Ph H N2 O O B Ph CO2Et 25 °C, 24 h OPh Ph 85 78a 86a Imine IMINO-BOROX B(OPh)3 (3 equiv) 78a IMINO-BOROX catalyst 188a pre(S)-VAPOL catalyst catalyst (10 mol%) toluene, 80 °C, 1 h OH 188a = (S)-VAPOL then 0.5 mm Hg (Method A) * OH 80 °C, 0.5 h Ph (2R,3R)- ethyl 1-benzhydryl-3-phenylaziridine-2-carboxylate 86a: The pre-catalyst was made using method A employing 10 mol% of (S)-VAPOL. To the flask containing the pre- 147 catalyst (made from method A) was first added the aldimine 78a (271 mg, 1 mmol) and then dry toluene (2 mL) under an argon flow through side-arm of the Schlenk flask. The reaction mixture was stirred for 5 min to give a light orange solution. To this solution was rapidly added ethyl diazoacetate (EDA) 85 (124 µL, 1.2 mmol) followed by closing the Teflon valve. The resulting mixture was stirred for 24 h at room temperature. Immediately upon addition of ethyl diazoacetate the reaction mixture became an intense yellow, which changed to light yellow towards the end of the reaction. The reaction was dilluted by addition of hexane (6 mL). The reaction mixture was then transferred to a 100 mL round bottom flask. The reaction flask was rinsed with dichloromethane (5 mL × 2) and the rinse was added to the 100 mL round bottom flask. The resulting solution was then concentrated in vacuo followed by exposure to high vacuum (0.05 mm Hg) for 1 h to afford the crude aziridine as an off-white solid. A measure of the extent to which the reaction went to completion was estimated from the 1 H NMR spectrum of the crude reaction mixture by integration of the aziridine ring methine protons relative to either the imine methine proton or the proton on the imine carbon. The 1 cis/trans ratio was determined by comparing the H NMR integration of the ring methine protons for each aziridine in the crude reaction mixture. The cis (J = 7-8 Hz) and the trans (J = 2-3 Hz) coupling constants were used to differentiate the two isomers. The yields of the acyclic enamine 1 side products 87a and 88a were determined by H NMR analysis of the crude reaction mixture by integration of the N-H proton relative to the that of the cis-aziridine methine protons with the aid of the isolated yield of the cis-aziridine. Purification of the crude aziridine by silica gel chromatography (35 mm × 400 mm column, 19:1 hexanes/EtOAc as eluent, under gravity) afforded pure cis-aziridine 86a as a white solid (mp. 127.5-128.5 °C on 92% ee material) in 83 148 % isolated yield (297 mg, 0.83 mmol); cis/trans: >50:1. Enamine side products: 8 % yield of 87a and 4% yield of 88a. The optical purity of 86a was determined to be 91% ee by HPLC analysis ((CHIRALCEL OD-H column, 90:10 hexanes/iPrOH at 222 nm, flow-rate: 0.7 mL/min): retention times; Rt = 9.01 min (major enantiomer, 86a) and Rt = 4.67 min (minor enantiomer, ent-86a). 1 Spectral data for 86a: Rf = 0.3 (1:9 EtOAc/hexanes); H NMR (CDCl3, 500 MHz) δ 0.95 (t, 3H, J = 7.3 Hz), 2.64 (d, J = 6.8 Hz, 1H), 3.19 (d, J = 6.8 Hz, 1H), 3.91 (q, J = 7.1 Hz, 2H), 3.93 (s, 1H), 7.16-7.38 (m, 11H), 7.47 (d, J = 7.1 Hz, 2H), 7.58 (d, J = 7.6 Hz, 2H); 13 C NMR (CDCl3, 75 Hz) δ 13.93, 46.36, 48.01, 60.57, 77.68, 127.18, 127.31, 127.39, 127.52, 127.76, 127.78, 128.48, 135.00, 142.37, 142.49, 167.75; [α ]20 = + 33.4 (c 1.0, CH2Cl2) on 91.0% ee material D (HPLC). These spectral data match those previously reported for this compound. 13a Aziridination with procedure II O OEt Ph Ph N 78a (S)-VAPOL (10 mol%) Ph B(OPh)3 (30 mol%) toluene, 25 °C, 5 min N2 Ph 85 toluene 25 °C, 24 h Ph N Ph CO2Et 86a (2R,3R)- ethyl 1-benzhydryl-3-phenylaziridine-2-carboxylate 86a: To a 25 mL flame-dried round bottom flask filled with argon was added (S)-VAPOL (54 mg, 0.1 mmol), commercial 149 B(OPh)3 (87 mg, 0.3 mmol) and aldimine 78a (271 mg, 1.00 mmol). The mixture was dissolved in toluene (1 mL) at room temperature. The reaction mixture was stirred for 5 min to give a light orange solution. To this solution was rapidly added EDA 85 (124 µL, 1.20 mmol) and the resulting mixture was stirred for 24 h at room temperature. The reaction was diluted by the addition of 6 mL hexane. The reaction mixture was then transferred to a 100 mL round bottom flask. The reaction flask was rinsed with dichloromethane (5 mL × 2) and the rinse was added to the 100 mL round bottom flask. The resulting solution was then concentrated in vacuo followed by exposure to high vacuum (0.05 mm Hg) for 1 h to afford the crude aziridine as an off-white solid. Purification of the crude aziridine by silica gel chromatography (as discussed above) afforded pure aziridine 86a as a white solid in 80 % yield and 92 % ee. Aziridination with procedures V O OEt Ph Ph N 78a (S)-VAPOL (10 mol%) Ph B(OPh)3 (40 mol%) toluene, 80 °C, 1 h N2 Ph 85 toluene 25 °C, 24 h Ph N Ph CO2Et 86a (2R,3R)- ethyl 1-benzhydryl-3-phenylaziridine-2-carboxylate 86a: To a 25 mL flame-dried home-made Schlenk flask (see Figure 1) equipped with a stir bar and flushed with argon was added (S)-VAPOL (54 mg, 0.1 mmol) and commercial B(OPh)3 (116 mg, 0.4 mmol) and aldimine 78a (271 mg, 1 mmol). Under an argon flow through the side-arm of the Schlenk flask, dry toluene (2 mL) was added to dissolve the reagents. The flask was sealed by closing the Teflon valve, and then placed in an 80 ºC (oil bath) for 1 h. The catalyst mixture was then 150 allowed to cool to room temperature and open to argon through the side-arm of the Schlenk flask. To this solution was rapidly added ethyl diazoacetate (EDA) 85 (124 µL, 1.2 mmol) followed by closing the Teflon valve. The resulting mixture was stirred for 24 h at room temperature. Immediately upon addition of ethyl diazoacetate the reaction mixture became an intense yellow, which changed to light yellow towards the completion of the reaction. The reaction was diluted by addition of hexane (6 mL). The reaction mixture was then transferred to a 100 mL round bottom flask. The reaction flask was rinsed with dichloromethane (5 mL × 2) and the rinse was added to the 100 mL round bottom flask. The resulting solution was then concentrated in vacuo followed by exposure to high vacuum (0.05 mm Hg) for 1 h to afford the crude aziridine as an off-white solid. Purification of the crude aziridine by silica gel chromatography (as discussed above) afforded pure aziridine 86a as a white solid in 80 % yield and 92 % ee. 2.6.4 Aziridination using different alcohols (Table 2.3) or ligands (Table 2.4) or imines (Table 2.5) A) With different alcohols (Table 2.3): Aziridination was performed with procedure VII (precatalyst method F) described above using alcohols 194. B) With different ligands (Table 2.4): Aziridination was performed with procedure IV (precatalyst method C) described above using different ligands. See more details in Chapter 5. C) With different imines (Table 2.5): Aziridination was performed with procedure IV (precatalyst method C) described above using different imines. 151 Synthesis of aziridine 113a using imine 110a: O IMINO-BOROX catalyst 212a (10 mol %) DAM OPh DAM O B DAM + O – N OEt B O * N+ N toluene Ph H N2 O O B Ph CO2Et 25 °C, 24 h OPh Ph 85 110a 113a IMINO-BOROX B(OPh)3 (4 equiv) Imine catalyst 212a H2O (1 equiv) pre- 110a IMINO-BOROX (S)-VAPOL OH catalyst (10 mol%) toluene, 80 °C, 1 h catalyst = (S)-VAPOL * 212a (Method C) then 0.5 mm Hg OH 80 °C, 0.5 h (2R,3R)-ethyl-1-(bis(4-methoxyphenyl)methyl)-3-phenylaziridine-2-carboxylate 113a: Imine 110a (332 mg, 1 mmol) was reacted according to the general procedure IV (pre-catalyst method C) described above with (S)-VAPOL (10 mol%) as the ligand. Purification of the crude aziridine by silica gel chromatography (35 mm × 400 mm column, 9:1 hexanes/EtOAc as eluent, after elution of the first fraction, which contains EDA and / or enamine side products 116a and 117a, the eluent was changed to 5:1 hexanes / EtOAc) afforded pure cis-aziridine 113a as a white solid (mp 89-90 ºC on 94% ee material) in 95 % isolated yield (396 mg, 0.95 mmol); cis/trans: 50:1. Enamine side products: 1% yield of 116a and 1% yield of 117a. The optical purity of 113a was determined to be 92% ee by HPLC analysis (CHIRALPAK AD column, 90:10 hexane/2-propanol at 226nm, flow-rate: 1.0 mL/min): retention times; Rt = 8.80 min (major enantiomer, 113a) and Rt = 15.70 min (minor enantiomer, ent-113a) 1 Spectral data for 113a: Rf = 0.28 (1:5 EtOAc/hexanes). H NMR (CDCl3, 500 MHz) δ 0.93 (t, 3H, J = 7.1 Hz), 2.59 (d, 1H, J = 6.8 Hz), 3.13 (d, 1H, J = 6.8 Hz), 3.67 (s, 3H), 3.75 (s, 3H), 152 3.81 (s, 1H), 3.91-3.98 (m, 2H), 6.74 (d, 2H, J = 8.8 Hz), 6.82 (d, 2H, J = 8.8 Hz), 7.14-7.24 (m, 3H), 7.31-7.35 (m, 4H), 7.43 (d, 2H, J = 8.8 Hz); 13 C (CDCl3, 75 MHz) δ 13.94, 46.39, 48.02, 55.15, 55.22, 60.54, 76.44, 113.80, 127.27, 127.75, 127.79, 128.16, 128.49, 134.93, 135.13, 2 135.16, 158.61, 158.71, 167.83 (one sp carbon not located); [α ]20 +36.5 (c 1.0, EtOAc) on D 94% ee material (HPLC). compound. These spectral data match those previously reported for this 19 Synthesis of aziridine 209a using imine 207a: IMINO-BOROX catalyst 211a (10 mol %) Ph OPh CH2Bh O B O – N + OEt B O * N+ N Ph toluene H O O B N2 Ph CO2Et Ph 25 °C, 24 h OPh Ph 85 207a 209a IMINO-BOROX B(OPh)3 (4 equiv) catalyst 211a Imine H2O (1 equiv) pre- 207a IMINO-BOROX (S)-VAPOL OH catalyst catalyst (10 mol%) toluene, 80 °C, 1 h = (S)-VAPOL * 211a (Method C) then 0.5 mm Hg OH 80 °C, 0.5 h Ph O Ph (2R,3R)-ethyl-1-(2,2-diphenylethyl)-3-phenylaziridine-2-carboxylate 209a: Imine 207a (285 mg, 1 mmol) was reacted according to the general procedure IV (pre-catalyst method C) described above with (S)-VAPOL (10 mol%) as ligand except that the concentration of the reaction is 0.2 M i.e. 6 mL of toluene was used. A clear solution was obtained upon the addition imine and toluene. After 2-3 min, the clear solution turned to a yellow gel. A similar observation was made when CCl4 was used as the solvent. However, no gel was observed in the case of CH2Cl2. Purification of the crude aziridine by silica gel chromatography (35 mm × 400 153 mm column, 15:1 hexanes/EtOAc as eluent, gravity) afforded pure cis-aziridine 209a as a white solid (mp 99-101 ºC on 43% ee material) in 32 % isolated yield (119 mg, 0.32 mmol); cis/trans: >50:1. Enamine side products: <1% yield. The optical purity of 209a was determined to be 52% ee by HPLC analysis (CHIRALCEL OD-H column, 99:1 hexane/2-propanol at 226nm, flowrate: 0.7 mL/min): retention times; Rt = 74.06 min (major enantiomer, 209a) and Rt = 21.4 min (minor enantiomer, ent-209a) 1 Spectral data for 209a: Rf = 0.32 (1:9 EtOAc/hexanes). H NMR (CDCl3, 300 MHz) 0.98 (t, J = 7.1 Hz, 3H), 2.30 (d, J = 6.8 Hz, 1H), 2.79 (d, J = 6.8 Hz, 1H), 3.22 (dd, J = 11.6, 6.8 Hz, 1H), 3.33 (dd, J = 11.6, 7.6 Hz, 1H), 3.91 (qq, J = 10.8, 7.1 Hz, 2H), 4.47 (t, J = 7.1 Hz, 1H), 7.10 – 7.44 (m, 15H); 13 C (CDCl3, 125 MHz) δ 13.90, 46.42, 47.82, 51.32, 60.45, 65.45, 126.41, 126.46, 127.17, 127.53, 127.78, 128.15, 128.27, 128.33, 128.40, 135.08, 142.82, 142.97, 167.95; IR (thin film, cm-1) 3061 m, 3028 m, 2930 m, 1747 s, 1495 s, 1450 s, 1196 s; HRMS (ESI-TOF) + m/z 372.1964 [(M+H ); calcd. for C25H26NO2 : 372.1964]; [α ]20 +4.1 (c 1.0, CH2Cl2) on 43% D ee material (HPLC). 2.6.5 NMR analysis of a mixture of VAPOL, various boron sources, and imine 111a at various conditions (Figure 2.3, 2.4 and Table 2.2) As shown in Fig. 2.3, 2.4 and Table 2.2 of this chapter, a mixture of (S)-VAPOL 58 and B(OPh)3 187a or triphenoxyboroxine 191a or BH3•Me2S 192a or B(OH)3 193 gives different yields of unreacted VAPOL 58, mesoborate B1 106 and pyroborate B2 108 employing different 154 reaction conditions (pre-catalyst methods). The yields do not show any significant change after 1 24 h. Also, it was evident from the H NMR and 11 B NMR that no boroxinate B3 190a was formed unless imine 111a was added (characteristic peaks i.e. δ 10.2-10.4 and δ 5.5-5.7 were 1 missing in H NMR and 11 B NMR respectively). The amount of B3 190a differs with respect to different catalyst loading and different methods of preparation of the pre-catalyst. Unless otherwise noted, commercial B(OPh)3 is used in all the experiments. Also, Ph3CH is used as the internal standard. Experimental: * OH OH 58 Boron source imine 111a (2 equiv) Method A-G CDCl3 25 °C, 10 min 0.1 M + [imine-H] OPh O –O B + B O * O O B 190a OPh OPh + B O B * O OPh 108 O B3 * O O B2 B OPh + 106 B1 * OH OH 58 (unreacted) Entry 1, Figure 2.3 and Entry 1, Table 2.2: The pre-catalyst was made using method A employing (S)-VAPOL (54 mg, 0.1 mmol) and commercial B(OPh)3 (87 mg, 0.3 mmol). To the flask containing the pre-catalyst was first added the Ph3CH (12.22 mg, 0.05 mmol) and then CDCl3 (1 mL) under an argon flow through side-arm of the Schlenk flask. The reaction mixture was then stirred for 10 min. The off-white colored solution was then directly transferred to a 1 quartz NMR tube and was subjected to H NMR and Entry 2, Figure 2.3 and Entry 2, Table 2.2: 155 11 B NMR analysis. The pre-catalyst was made using method A employing (S)-VAPOL (54 mg, 0.1 mmol) and commercial B(OPh)3 (87 mg, 0.3 mmol). To the flask containing the pre-catalyst was first added the imine 111a (78 mg, 0.2 mmol), Ph3CH (12.22 mg, 0.05 mmol) and then CDCl3 (1 mL) under an argon flow through side-arm of the Schlenk flask. The reaction mixture was then stirred for 10 min. The red colored solution was then directly transferred to a quartz NMR tube and was 1 subjected to H NMR and 11 B NMR analysis. Entry 3, Figure 2.3 and Entry 6, Table 2.2: Same as entry 1 except that the pre-catalyst was made using method B. Entry 4, Figure 2.3 and Entry 7, Table 2.2: Same as entry 2 except that the pre-catalyst was made using method B. Entry 5, Figure 2.3 and Entry 9, Table 2.2: Same as entry 1 except that the pre-catalyst was made using method C. Entry 6, Figure 2.3 and Entry 10, Table 2.2: Same as entry 2 except that the pre-catalyst was made using method C. Entry 7, Figure 2.3 and Entry 11, Table 2.2: To a 10 mL flame-dried round bottom flask, equipped with a stir bar, filled with argon was added (S)-VAPOL 58 (54 mg, 0.1 mmol, 1 equiv), commercial B(OPh)3 (87 mg, 0.3 mmol, 3 equiv), Ph3CH (12.22 mg, 0.05 mmol) and CDCl3(1 mL). The resultant mixture was stirred for 10 min at room temperature. The off-white colored 1 solution was then directly transferred to a quartz NMR tube and was subjected to H NMR and 156 11 B NMR analysis. A Teflon tape was wrapped on the cap of the NMR tube while storing the sample for 24h. Entry 8, Figure 2.3 and Entry 12, Table 2.2: To a 10 mL flame-dried round bottom flask, equipped with a stir bar, filled with argon was added (S)-VAPOL 58 (54 mg, 0.1 mmol, 1 equiv), commercial B(OPh)3 (87 mg, 0.3 mmol, 3 equiv), imine 111a (78 mg, 0.2 mmol, 2 equiv), Ph3CH (12.22 mg, 0.05 mmol) and CDCl3(1 mL). The resultant mixture was stirred for 10 min at room temperature. The red colored solution was then directly transferred to a quartz NMR 1 tube and was subjected to H NMR and 11 B NMR analysis. Entry 1, Figure 2.4 and Entry 14, Table 2.2: Same as entry 1 of Figure 2.3 except that the precatalyst was made using method D. Entry 2, Figure 2.4 and Entry 15, Table 2.2: Same as entry 2 of Figure 2.3 except that the precatalyst was made using method D. Entry 3, Figure 2.4 and Entry 16, Table 2.2: Same as entry 1 of Figure 2.3 except that the precatalyst was made using method E. Entry 4, Figure 2.4 and Entry 17, Table 2.2: Same as entry 2 of Figure 2.3 except that the precatalyst was made using method E. Entry 5, Figure 2.4 and Entry 19, Table 2.2: Same as entry 1 of Figure 2.3 except that the precatalyst was made using method G and CH3CN used the solvent for catalyst preparation. 157 Entry 6, Figure 2.4 and Entry 20, Table 2.2: Same as entry 2 of Figure 2.3 except that the precatalyst was made using method G and CH3CN used the solvent for catalyst preparation. Temperature Studies of 190a: The pre-catalyst was made using method B employing (S)-VAPOL (54 mg, 0.1 mmol) and B(OPh)3 (87 mg, 0.3 mmol) and H2O (5.4 µL, 0.3 mmol). To the flask containing the precatalyst was first added the imine 111a (39 mg, 0.1 mmol), Ph3CH (12.22 mg, 0.05 mmol) and then CDCl3 (1 mL) under an argon flow through side-arm of the Schlenk flask. The reaction mixture was then stirred for 10 min. The red colored solution was then directly transferred to a 1 quartz NMR tube and was subjected to H NMR and 2.6.6 11 B NMR analysis at various temperatures. NMR analysis of a mixture of VAPOL, B(OPh)3 and bases 75a, 78a, 85, 111a, 126, 127, 128b, 206a, 207a, 216, 219, 221, 223, 225, 232 (Figures 2.7, 2.9, 2.11, 2.12, 2.14, 2.15, 2.17-2.21 and Tables 2.7, 2.9-2.12) + B(OPh)3 (3 equiv) [Base-H] OPh Base OH (x equiv) O –O B + * B O * OH CDCl3 O O B 25 °C, 10 min OPh 58 0.1 M OPh + B O B * O OPh 108 O B3 B2 * O O B OPh + 106 B1 * OH OH 58 (unreacted) To a 10 mL flame-dried round bottom flask, equipped with a stir bar, filled with argon was added (S)-VAPOL 58 (54 mg, 0.1 mmol, 1 equiv.), B(OPh)3 (87 mg, 0.3 mmol, 3 equiv.), base (x equiv.), Ph3CH (12.22 mg, 0.05 mmol) and CDCl3(1 mL). The resultant mixture was stirred for 158 10 min at room temperature. After 10 min, the mixture was then directly transferred to a quartz 1 NMR tube and was subjected to H NMR and 11 B NMR analysis. In case of pyridine 216a, a procedure same as entry 4 of Figure 2.3 and entry 7 of Table 2.2 with one equiv of the base. 2.6.7 Aziridination in the presence of SULFOX-BOROX catalyst 222a O Ph SULFOX-BOROX catalyst 222a (10 mol %) Ph Ph OPh + H O O –O B OEt N B O CHCl3 * S Ph N2 O O B Ph CO2Et 25 °C, 24 h 85 78a 86a OPh SULFOX-BOROX B(OPh)3 (3 equiv) catalyst 222a DMSO H2O (3 equiv) preSULFOX-BOROX (S)-VAPOL OH catalyst (10 mol%) tolulene, 80 °C, 1 h catalyst = (S)-VAPOL * 222a then 0.5 mm Hg (Method B) OH 80 °C, 0.5 h Ph + N (2R,3R)- ethyl 1-benzhydryl-3-phenylaziridine-2-carboxylate 86a: To The pre-catalyst was made using method B employing (S)-VAPOL (54 mg, 0.1 mmol), B(OPh)3 (87 mg, 0.3 mmol) and H2O (5.4 µL, 0.3 mmol). To the flask containing the pre-catalyst was first added the DMSO (7.1 µL, 0.1 mmol) under an argon flow through side-arm of the Schlenk flask. The reaction mixture was then stirred for 1 h. After 1 h, imine 78a (271 mg, 1 mmol) was added to the flask containing the SULFOX-BOROX catalyst 222a under an argon flow through side-arm of the Schlenk flask. To this solution was rapidly added ethyl diazoacetate (EDA) 85 (124 µL, 1.2 mmol) followed by closing the Teflon valve. The resulting mixture was stirred for 24 h at room temperature. Immediately upon addition of ethyl diazoacetate the reaction mixture became an 159 intense yellow, which changed to light yellow towards the end of the reaction. The reaction was dilluted by addition of hexane (6 mL). The reaction mixture was then transferred to a 100 mL round bottom flask. The reaction flask was rinsed with dichloromethane (5 mL × 2) and the rinse was added to the 100 mL round bottom flask. The resulting solution was then concentrated in vacuo followed by exposure to high vacuum (0.05 mm Hg) for 1 h to afford the crude aziridine as an off-white solid. Purification of the crude aziridine by silica gel chromatography (as discussed above) afforded pure aziridine 86a as a white solid in 86 % yield and 90 % ee. The same reaction afforded aziridine 86a in 80% yield and 90% ee in the absence of catalyst 222a. 2.6.8 NMR analysis of a mixture of VAPOL, B(OPh)3 and base 234 and 126k (Figure 2.23-2.24) A) with base 234: BH3•Me2S (3 equiv) * OH OH 58 234 (2 equiv) H2O (3 equiv) CH3CN, 100 °C, 1 h then 0.5 mmHg 100 °C. 0.5 h + [H-Base] O O –O B B O * O O B O 235 Base HO = 234 Base The catalyst 235 was made using the pre-catalyst method E employing (S)-VAPOL (54 mg, 0.1 mmol) and BH3•Me2S (150 µL, 0.3 mmol, 2.0 M in toluene), ROH 234 (18.8, 0.2 mmol) and H2O (5.4 µL, 0.3 mmol). Acetonitrile was used as the solvent to make the catalyst. To the flask containing the catalyst was added Ph3CH (12.22 mg, 0.05 mmol) and then CDCl3 (1 mL) under an argon flow through side-arm of the Schlenk flask. The reaction mixture was then stirred for 160 10 min. The resulting solution was then directly transferred to a quartz NMR tube and was 1 subjected to H NMR and 11 B NMR analysis. B) with base 126k: * BH3•Me2S (3 equiv) PhNH2 (3 equiv) H2O (3 equiv) OH OH toluene, 100 °C, 1 h then 0.5 mmHg 100 °C. 0.5 h 58 + PhNH3 NHPh O –O B B O * O O B NHPh 236 The catalyst 236 was made using the pre-catalyst method E employing (S)-VAPOL (54 mg, 0.1 mmol) and BH3•Me2S (150 µL, 0.3 mmol, 2.0 M in toluene), PhNH2 126k (27.3 µL, 0.3 mmol) and H2O (5.4 µL, 0.3 mmol). To the flask containing the catalyst was added CDCl3 (1 mL) under an argon flow through side-arm of the Schlenk flask. The reaction mixture was then stirred for 10 min. The resulting solution was then directly transferred to a quartz NMR tube and 1 was subjected to H NMR and 2.6.9 11 B NMR analysis. NMR analysis of a mixture of VAPOL, PhOH, H2O and borane 192d (Scheme 2.3) * OH OH 58 BH3•Et2NPh (3 equiv) PhOH (2 equiv) H2O (3 equiv) d8-toluene 100 °C, 1 h + PhNHEt2 OPh O –O B B O * O O B OPh 237 The catalyst 237 was made using the pre-catalyst method F employing (S)-VAPOL (54 mg, 0.1 mmol) and BH3•Et2NPh 192d (53.3 µL, 0.3 mmol), PhOH (18.8, 0.2 mmol) and H2O (5.4 µL, 161 0.3 mmol) in d8-toluene. The resulting solution was then directly transferred to a quartz NMR 1 tube and was subjected to H NMR and NMR) and δ = 5.88 ppm (in 11 11 1 B NMR analysis. A peak at δ = 10.73 ppm (in H B NMR) supports the formation of the catalyst 237. 2.6.10 NMR analysis of a mixture of VAPOL, BH3•Me2S (0.5 equiv) and imine 111a (0.5 equiv) (Figure 2.25) * OH OH 59 BH3•Me2S (0.5 equiv) toluene, 100 °C, 1 h then 0.5 mmHg 100 °C. 0.5 h Ph N MEDAM (0.5 equiv) CDCl3 25 °C, 10 min O – O B * O * O H + MEDAM N Ph 238 To a 25 mL flame-dried home-made Schlenk flask (see Figure 2.26) equipped with a stir bar and flushed with argon was added (S)-VANOL 59 (44 mg, 0.1 mmol) and BH3•Me2S (25 µL, 0.05 mmol, 2.0 M in toluene). Under an argon flow through the side-arm of the Schlenk flask, dry toluene (2 mL) was added through the top of the Teflon valve to effect dissolution. The flask was sealed by closing the Teflon valve, and then placed in an 100 ºC oil bath for 1 h. After 1 h, a vacuum (0.5 mm Hg) was carefully applied by slightly opening the Teflon valve to remove the volatiles. After the volatiles were removed completely, a full vacuum was applied and maintained for a period of 30 min at a temperature of 100 ºC (oil bath). The flask was then allowed to cool to room temperature and opened to argon through the side-arm of the Schlenk flask. To the flask containing the pre-catalyst was first added the imine 111a (19 mg, 0.05 mmol) and then CDCl3 (1 mL) under an argon flow through side-arm of the Schlenk flask. The 162 reaction mixture was then stirred for 10 min. The resulting solution was then directly transferred 1 to a quartz NMR tube and was subjected to H NMR and 11 B NMR analysis. 2.6.11 DFT Calculations of 190a, 215c, 222a, 222b, 217d, 222h, 222i, 228a and 233b (Figure 2.8, 2.10, 2.16, 2.22) 20 All quantum mechanical calculations were performed using the GAUSSIAN 03. B3LYP 38 and BHandHLYP 39 The density functional were used along with 3-21G* and 6-31G* basis sets. There were no imaginary frequencies found in any calculations. The coordinates were provided to Prof. Wulff as a separate file. NBO analysis on (S)-VAPOL-BOROX anion: NBO analysis was performed at the B3LYP/631G* level of theory as shown in Figure 2.27. Ph Ph 3 2 OPh 1 O B O – 4 B O O O B OPh O1= – 0.689 O2= – 0.938 O3= – 0.706 O4= – 0.921 B3 BOROX anion Figure 2.27 Natural charges on the oxygen atoms of the boroxinate anion 2.6.12 Crystallographic structure determination of BOROX complex 217b (Figure 2.13) The crystallographic data of X-ray diffraction studies in this work were collected using a Bruker CCD (charge coupled device) based diffractometer equipped with an Oxford Cryostream lowtemperature apparatus operating at 173 K. Data were measured using omega and phi scans of 0.5° per frame for 30 s. The total number of images was based on results from the program COSMO where redundancy was expected to be 4.0 and completeness to 0.83 Å to 100%. Cell 163 parameters were retrieved using APEX II software and refined using SAINT on all observed reflections. Data reduction was performed using the SAINT software, which corrects for Lp. Scaling and absorption corrections were applied using SADABS multi-scan technique, supplied by George Sheldrick. The structures are solved by the direct method using the SHELXS-97 program and refined by least squares method on F2, SHELXL- 97, which are incorporated in SHELXTL-PC V 6.10. The structure was solved in the space group P2 (# 4). All non-hydrogen atoms are refined anisotropically. Hydrogens were calculated by geometrical methods and refined as a riding model except for those of the water molecules, which could not be found or refined. The Flack parameter is used to determine chirality of the crystal studied, the value should be near zero, a value of one is the other enantiomer and a value of 0.5 is racemic. The Flack parameter was refined to -0.02(18), confirming the absolute stereochemistry. Determination of absolute structure using Bayesian statistics on Bijvoet differences using the program within Platon report that we may have the correct enantiomer based on this comparison. All the drawings are done at 50% ellipsoids. The crystallographic data including hydrogenbonds are summarized in Tables 2.13 and 2.14. The full structural parameters for 217b have been submitted in Cambridge Crystallographic Data Center (Reference numbers CCDC). Table 2.13 Crystal data and structure refinement for BOROX complex 217b: Empirical formula Formula weight Temperature Wavelength Crystal system Space group Unit cell dimensions C66 H66 B3 Cl3 N O11.25 1191.98 173(2) K 0.71073 Å Monoclinic P 21 a = 9.7855(9) Å α= 90°. b = 46.667(5) Å β= 109.379(2)°. 164 Table 2.13 cont’d c = 13.9815(14) Å 6023.0(10) Å3 4 1.315 Mg/m3 0.215 mm-1 Volume Z Density (calculated) Absorption coefficient Table 2.13 cont’d F(000) Crystal size Theta range for data collection Index ranges Reflections collected Independent reflections Completeness to theta = 25.40° Absorption correction Max. and min. transmission Refinement method Data / restraints / parameters Goodness-of-fit on F2 γ = 90°. 2500 0.23 x 0.14 x 0.11 mm3 1.54 to 25.40°. -9<=h<=11, -50<=k<=56, -16<=l<=16 26222 17859 [R(int) = 0.0788] 99.6 % Semi-empirical from equivalents 0.9776 and 0.9528 Full-matrix least-squares on F2 17859 / 1 / 1489 0.983 R1 = 0.1101, wR2 = 0.2734 R1 = 0.2096, wR2 = 0.3440 -0.02(18) 1.075 and -0.388 e.Å-3 Final R indices [I>2sigma(I)] R indices (all data) Absolute structure parameter Largest diff. peak and hole Table 2.14 Hydrogen bonds [Å and °] D-H...A d(D-H) d(H...A) d(D...A) ∠(DHA) O(1B)-H(1BA)...O(4B) 0.84 1.92 2.751(10) 168.2 N(1A)-H(1AA)...O(1A) 0.88 1.91 2.789(13) 175.6 O(1A)-H(1AB)...O(3A) 0.84 1.90 2.701(11) 157.8 N(1B)-H(1BB)...O(1B) 0.88 1.87 2.748(13) 174.1 165 REFERENCES 166 REFERENCES (1) (a) Rueping, M.; Nachtsheim, B. J.; Ieawsuwan, W.; Atodiresei, I. Angew. Chem., Int. Ed. 2011, 50, 6706-6720. (b) Schenker, S.; Zamfir, A.; Freund, M.; Tsogoeva, S. B. Eur. J. Org. Chem. 2011, 2209-2222. (c) Rueping, M.; Kuenkel, A.; Atodiresei, I. Chem. Soc. Rev. 2011, 40, 4539-4549. (d) List, B.; Kampen, D.; Reisinger, C. M. Top Curr Chem 2010, 291, 395-456. (e) Rueping, M.; Koenigs, R. M.; Atodiresei, I. Chem.–Eur. J. 2010, 16, 9350-9365. (f) Sohtome, Y.; Nagasawa, K. Synlett 2010, 1-22. (g) Yamamoto, H.; Payette, J. N. In Hydrogen Bonding in Organic Synthesis; Wiley-VCH 2009, p 73-140. (h) Yu, X.; Wang, W. Chem.–Asian. J. 2008, 3, 516-532. (i) Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713-5743. (j) Akiyama, T. Chem. Rev. 2007, 107, 5744-5758. (k) Taylor, M. S. J., E. N. Angew. Chem., Int. Ed. 2006, 45, 1520-1543. (l) Akiyama, T.; Itoh, J.; Fuchibe, K. Adv. Synth. Catal. 2006, 348, 999-1010. (2) (a) Terada, M. Synthesis 2010, 1929-1982. (b) Terada, M. Bull. Chem. Soc. Jpn. 2010, 83, 101-119. (c) Zamfir, A.; Schenker, S.; Freund, M.; Tsogoeva, S. B. Org. Biomol. Chem. 2010, 8. (d) Terada, M. Chem. Commun. (Cambridge, U. K.) 2008, 4097-4112. (e) Connon, S. J. Angew. Chem., Int. Ed. 2006, 45, 3909-3912. (3) (a) Rueping, M.; Uria, U.; Lin, M.-Y.; Atodiresei, I. J. Am. Chem. Soc. 2011, 133, 37323735. (b) Hashimoto, T.; Nakatsu, H.; Yamamoto, K.; Maruoka, K. J. Am. Chem. Soc. 2011, 133, 9730-9733. (c) Rueping, M.; Nachtsheim, B. J.; Koenigs, R. M.; Ieawsuwan, W. Chem.– Eur. J. 2010, 16, 13116-13126. (d) Vellalath, S.; Coric, I.; List, B. Angew. Chem., Int. Ed. 2010, 49, 9749-9752. (e) Cheon, C. H.; Yamamoto, H. J. Am. Chem. Soc. 2008, 130, 9246-9247. (f) Rueping, M.; Ieawsuwan, W.; Antonchick, A. P.; Nachtsheim, B. J. Angew. Chem., Int. Ed. 2007, 46, 2097-2100. (g) Nakashima, D.; Yamamoto, H. J. Am. Chem. Soc. 2006, 128, 96269627. (4) (a) Ratjen, L.; Garcìa-Garcìa, P.; Lay, F.; Beck, M. E.; List, B. Angew. Chem., Int. Ed. 2011, 50, 754-758. (b) Chen, L.-Y.; He, H.; Chan, W.-H.; Lee, A. W. M. J. Org. Chem. 2011, 76, 7141-7147. (c) He, H.; Chen, L.-Y.; Wong, W.-Y.; Chan, W.-H.; Lee, A. W. M. Eur. J. Org. Chem. 2010, 4181-4184. (d) Treskow, M.; Neudoerfl, J.; Giernoth, R. Eur. J. Org. Chem. 2009, 3693-3697. (5) Berkessel, A.; Christ, P.; Leconte, N.; Neudörfl, J.-M.; Schäfer, M. Eur. J. Org. Chem. 2010, 5165-5170. (6) (a) Hashimoto, T.; Omote, M.; Maruoka, K. Angew. Chem., Int. Ed. 2011, 50, 3489-3492. (b) Hashimoto, T.; Omote, M.; Maruoka, K. Angew. Chem., Int. Ed. 2011, 50, 8952-8955. (c) Hashimoto, T.; Kimura, H.; Nakatsu, H.; Maruoka, K. J. Org. Chem. 2011, 76, 6030-6037. (d) Hashimoto, T.; Kimura, H.; Maruoka, K. Angew. Chem., Int. Ed. 2010, 49, 6844-6847. (e) 167 Hashimoto, T.; Uchiyama, N.; Maruoka, K. J. Am. Chem. Soc. 2008, 130, 14380-14381. (f) Hashimoto, T.; Maruoka, K. J. Am. Chem. Soc. 2007, 129, 10054-10055. (7) (a) Hatano, M.; Sugiura, Y.; Akakura, M.; Ishihara, K. Synlett 2011, 1247-1250. (b) Hatano, M.; Sugiura, Y.; Ishihara, K. Tetrahedron: Asymmetry 2010, 21, 1311-1314. (c) Hatano, M.; Maki, T.; Moriyama, K.; Arinobe, M.; Ishihara, K. J. Am. Chem. Soc. 2008, 130, 16858-16860. (8) (a) Desai, A. A.; Wulff, W. D. Synthesis 2010, 3670-3680. (b) Rowland, E. B.; Rowland, G. B.; Rivera-Otero, E.; Antilla, J. C. J. Am. Chem. Soc. 2007, 129, 12084-12085. (9) (a) Senatore, M.; Lattanzi, A.; Santoro, S.; Santi, C.; Della, S. G. Org. Biomol. Chem. 2011, 9, 6205-6207. (b) Desai, A. A.; Huang, L.; Wulff, W. D.; Rowland, G. B.; Antilla, J. C. Synthesis 2010, 2106-2109. (c) Larson, S. E.; Baso, J. C.; Li, G.; Antilla, J. C. Org. Lett. 2009, 11, 51865189. (d) Della, S. G.; Lattanzi, A. Org. Lett. 2009, 11, 3330-3333. (e) Rowland, G. B.; Rowland, E. B.; Liang, Y.; Perman, J. A.; Antilla, J. C. Org. Lett. 2007, 9, 2609-2611. (f) Liang, Y.; Rowland, E. B.; Rowland, G. B.; Perman, J. A.; Antilla, J. C. Chem. Commun. 2007, 44774479. (g) Li, G.; Liang, Y.; Antilla, J. C. J. Am. Chem. Soc. 2007, 129, 5830-5831. (h) Rowland, G. B.; Zhang, H.; Rowland, E. B.; Chennamadhavuni, S.; Wang, Y.; Antilla, J. C. J. Am. Chem. Soc. 2005, 127, 15696-15697. (10) (a) Xu, B.; Zhu, S.-F.; Xie, X.-L.; Shen, J.-J.; Zhou, Q.-L. Angew. Chem., Int. Ed. 2011, 50, 11483-11486. (b) Xing, C.-H.; Liao, Y.-X.; Ng, J.; Hu, Q.-S. J. Org. Chem. 2011, 76, 41254131. (c) Müller, S.; Webber, M. J.; List, B. J. Am. Chem. Soc. 2011, 133, 18534-18537. (d) Huang, D.; Xu, F.; Lin, X.; Wang, Y. Chiral spirocyclic phosphoric acid, its preparation method and application as catalyst CN102030780A Apr 27, 2011. (e) Xu, F.; Huang, D.; Han, C.; Shen, W.; Lin, X.; Wang, Y. J. Org. Chem. 2010, 75, 8677-8680. (f) Coric, I.; Mueller, S.; List, B. J. Am. Chem. Soc. 2010, 132, 17370-17373. (11) (a) Akiyama, T. Preparation of cyclic erythritol phosphoric acid derivatives as catalysts for asymmetric synthesis WO2006092884A1 . (b) Voituriez, A.; Charette, A. B. Adv. Synth. Catal. 2006, 348, 2363-2370. (c) Akiyama, T.; Saitoh, Y.; Morita, H.; Fuchibe, K. Adv. Synth. Catal. 2005, 347, 1523-1526. (12) (a) Ishihara, K.; Miyata, M.; Hattori, K.; Tada, T.; Yamamoto, H. J. Am. Chem. Soc. 1994, 116, 10520-10524. (b) Ishihara, K.; Kuroki, Y.; Yamamoto, H. Synlett 1995, 41-42. (c) Kuroki, Y.; Ishihara, K.; Hanaki, N.; Ohara, S.; Yamamoto, H. Bull. Chem. Soc. Jpn. 1998, 71, 12211230. (d) Cros, J. P.; Pérez-Fuertes, Y.; Thatcher, M. J.; Arimori, S.; Bull, S. D.; James, T. D. Tetrahedron: Asymmetry 2003, 14, 1965-1968. (e) Kawate, T.; Yamada, H.; Matsumizu, M.; Nishida, A.; Nakagawa, M. Synlett 1997, 761-762. (f) Yamada, H.; Kawate, T.; Matsumizu, M.; Nishida, A.; Yamaguchi, K.; Nakagawa, M. J. Org. Chem. 1998, 63, 6348-6354. 168 (13) (a) Zhang, Y.; Desai, A.; Lu, A.; Hu, G.; Ding, Z.; Wulff, W. D. Chem. –Eur. J. 2008, 14, 3785-3803. (b) Zhang, Y.; Lu, Z.; Desai, A.; Wulff, W. D. Org. Lett. 2008, 10, 5429-5432. (c) Mukherjee, M.; Gupta, A. K.; Lu, Z.; Zhang, Y.; Wulff, W. D. J. Org. Chem. 2010, 75, 56435660. (d) Ren, H.; Wulff, W. D. Org. Lett. 2010, 12, 4908-4911. (e) Hu, G.; Huang, L.; Huang, R. H.; Wulff, W. D. J. Am. Chem. Soc. 2009, 131, 15615-15617. (f) Hu, G.; Gupta, A. K.; Huang, R. H.; Mukherjee, M.; Wulff, W. D. J. Am. Chem. Soc. 2010, 132, 14669–14675. (g) Gupta, A. K.; Mukherjee, M.; Wulff, W. D. Org. Lett. 2011, 13, 5866-5869. (h) Newman, C. A.; Antilla, J. C.; Chen, P.; Predeus, A. V.; Fielding, L.; Wulff, W. D. J. Am. Chem. Soc. 2007, 129, 7216-7217. (i) Desai, A. A.; Wulff, W. D. J. Am. Chem. Soc. 2010, 132, 13100-13103. (j) Vetticatt, M. J.; Desai, A. A.; Wulff, W. D. J. Am. Chem. Soc. 2010, 132, 13104-13107. (k) Desai, A. A.; Morán-Ramallal, R.; Wulff, W. D. Org. Synth. 2011, 88, 224-237. (l) Ren, H.; Wulff, W. D. J. Am. Chem. Soc. 2011, 133, 5656-5659. (m) Desai, A. A.; Ren, H.; Mukherjee, M.; Wulff, W. D. Org. Process Res. Dev. 2011, 15, 1108-1115. (14) Casarrubios, L.; Perez, J. A.; Brookhart, M.; Templeton, J. L. J. Org. Chem. 1996, 61, 83588359. (15) (a) Antilla, J. C.; Wulff, W. D. J. Am. Chem. Soc. 1999, 121, 5099-5100. (b) Antilla, J. C.; Wulff, W. D. Angew. Chem., Int. Ed. 2000, 39, 4518-4521. (16) Hattori, K.; Yamamoto, H. J. Org. Chem. 1992, 57, 3264-3265. (17) Favrot, J.; Vocelle, D.; Sandorfy, C. Photochem. Photobiol. 1979, 30, 417-421. (18) Ding, Z.; Osminski, W. E. G.; Ren, H.; Wulff, W. D. Org. Process Res. Dev. 2011, 15, 1089-1107 and references therein. (19) Lu, Z.; Zhang, Y.; Wulff, W. D. J. Am. Chem. Soc. 2007, 129, 7185-7194. (20) Gaussian 03, Revision D.01 M. J. Frisch, G. W. T., H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman, J. A. Montgomery, Jr., T. Vreven, K. N. Kudin, J. C. Burant, J. M. Millam, S. S. Iyengar, J. Tomasi, V. Barone, B. Mennucci, M. Cossi, G. Scalmani, N. Rega, G. A. Petersson, H. Nakatsuji, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, M. Klene, X. Li, J. E. Knox, H. P. Hratchian, J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R. E. Stratmann, O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli, J. W. Ochterski, P. Y. Ayala, K. Morokuma, G. A. Voth, P. Salvador, J. J. Dannenberg, V. G. Zakrzewski, S. Dapprich, A. D. Daniels, M. C. Strain, O. Farkas, D. K. Malick, A. D. Rabuck, K. Raghavachari, J. B. Foresman, J. V. Ortiz, Q. Cui, A. G. Baboul, S. Clifford, J. Cioslowski, B. B. Stefanov, G. Liu, A. Liashenko, P. Piskorz, I. Komaromi, R. L. Martin, D. J. Fox, T. Keith, M. A. Al-Laham, C. Y. Peng, A. Nanayakkara, M. 169 Challacombe, P. M. W. Gill, B. Johnson, W. Chen, M. W. Wong, C. Gonzalez, and J. A. Pople, Gaussian, Inc., Wallingford CT, 2004 (21) (a) Nishio, M. Tetrahedron 2005, 61, 6923-6950. (b) Nishio, M. H., M.; Umezawa, Y. The CH/π Interaction: Evidence, Nature, and Consequences; Wiley-VCH, 1998. (22) Plevin, M. J.; Bryce, D. L.; Boisbouvier, J. Nat Chem 2010, 2, 466-471. (23) Hall, H. K. J. Am. Chem. Soc. 1957, 79, 5441-5444. (24) Braude, E. A.; Nachod, F. C.; Phillips, W. D.; Zuckerman, J. J. Determination of Organic Structures by Physical Methods; Academic Press: New York, 1955. (25) Chiang, Y.; Whipple, E. B. J. Am. Chem. Soc. 1963, 85, 2763-2767. (26) Desai, A.; Wulff, W. D., Unpublished results. (27) Haake, P.; Cook, R. D.; Hurst, G. H. J. Am. Chem. Soc. 1967, 89, 2650-2654. (28) Landini, D.; Modena, G.; Scorrano, G.; Taddei, F. J. Am. Chem. Soc. 1969, 91, 6703-6707. (29) Hall, S. K.; Robinson, E. A. Can. J. Chem. 1964, 42, 1113-1122. (30) Cook, A. G.; Mason, G. W. J. Org. Chem. 1972, 37, 3342-3345. (31) Bell, R. P.; Higginson, W. C. E. Proc. R. Soc. Lond. A 1949, 197, 141-159. (32) Jaffé, H. H.; Doak, G. O. J. Am. Chem. Soc. 1955, 77, 4441-4444. (33) Kanbayashi, N.; Onitsuka, K. Angew. Chem., Int. Ed. 2011, 50, 5197-5199. (34) Ghorbani-Choghamarani, A.; Sardari, S. Chinese Journal of Catalysis 2010, 31, 1347-1350. 170 (35) Luca, O. R.; Wang, T.; Konezny, S. J.; Batista, V. S.; Crabtree, R. H. New J. Chem. 2011, 35, 998-999. (36) Hu, Z.; Kerton, F. M. Org. Biomol. Chem. 2012, 10, 1618-1624. (37) Cole, T. E.; Quintanilla, R.; Rodewald, S. Synth. React. Inorg. Met.-Org. Chem. 1990, 20, 55-63. (38) (a) Becke, A. D. Phys. Rev. A 1988, 38, 3098. (b) Lee, C. Y., W.; Parr, R. G. Phys. Rev. B 1988, 37, 785. (39) (a) Becke, A. D. J. Chem. Phys. 1993, 98, 1372-1377. (b) Zhao, Y.; Truhlar, D. G. J. Chem. Theory Comput. 2005, 1, 415-432. (c) Yu, W.; Liang, L.; Lin, Z.; Ling, S.; Haranczyk, M.; Gutowski, M. J. Comput. Chem. 2009, 30, 589-600. 171 CHAPTER 3   MECHANISTIC STUDY OF THE CATALYTIC CYCLE OF A BRØNSTED ACID CATALYZED REACTION UTILIZING AZIRIDINATION AS THE TEMPLATE I think you do not have enough work these days. -William D. Wulff 3.1 Introduction Generally, in a Brønsted acid catalyzed reaction (Scheme 3.1), substrate (S) binds to the catalyst (BA) giving S-BA complex that further reacts with nucleophile (Nu) resulting in a complex where product is bound to the catalyst (P-BA). This complex collapses to release the product (P) and the catalyst (BA). There is another associative pathway (Path II) where substrate directly replaces product from P-BA complex to give S-BA complex. To best of our knowledge, there is no example in literature, which provides evidence for the existence of such proposed complexes, especially the product bound to the catalyst in the case of the aziridination reaction. The aim of this work is to characterize and otherwise gain evidence for the existence of such complexes and other intermediates of the catalytic cycle. Another goal of this work is to explore the possibility of observing the depletion of P-BA complex in the presence of the substrate (S). The catalytic cycle of other systems have been studied using NMR spectroscopy, 2 spectrometry and theoretical calculations. 3 172 1 mass Scheme 3.1 Catalytic cycle of a Brønsted acid catalyzed reaction S-BA S Nu P + Nu BA P BA = Brønsted Acid S = Substrate P = Product Nu = Nucleophile Path II BA S S P-BA P 3.2 Path I Characterization of the various stages of the catalytic cycle of a Brønsted Acid catalyzed aziridination reaction In the field of organic synthesis, importance has always been given to efforts to provide tangible evidence to support the proposed mechanisms or reaction pathways. Most of the time, this helps to gain insight which can be the spark leading to new discoveries. With the aim of understanding the mechanistic aspect of our aziridination reaction, we decided to characterize the various proposed complexes and intermediates of the catalytic cycle. This, in turn, might support the existence of the proposed complexes in a general catalytic cycle of any Brønsted acid catalyzed reaction. Hence, our aziridination reaction might serve as the template for the catalytic cycle of a Brønsted acid catalyzed reaction. There is no such study reported in case of a 4 Brønsted acid catalyzed reaction. Over the last several years we have developed a general catalytic asymmetric aziridination that is based on the reaction of diazo compounds with imines mediated by asymmetric catalysts generated from the VANOL or VAPOL ligands and various boron compounds (Scheme 3.2). 5 As discussed in Chapter 2, the protocol for catalyst formation involves 3 equivalents of commercial B(OPh)3 and 1 equivalent of ligand giving the mixture of 173 B1 106/107 and B2 108/109 (Scheme 3.2). Thereafter, the actual IMINO-BOROX catalyst is formed only upon the addition of the substrate i.e. imine. As mentioned earlier, the IMINOBOROX catalyst 190 is comprised of a chiral borate anion containing a spiro-boroxinate ring and 5f a protonated iminium ion (Scheme 3.2). Scheme 3.2 Brønsted acid catalyzed aziridination reaction trans-Aziridination cis-Aziridination O Ar NHPh Ar N2 N R O CONHPh OEt Ar 123a catalyst 190 125 R N N2 Ar 111 Ar = 3,5-Me2-4-OMe-C6H2 Ar 85 catalyst 190 Ar N R CO2Et 114 R = aryl and alkyl 111a (R = Ph) 111o (R = nPr) Ph Ph OH OH B(OPh)3 187a (3 equiv) toluene, 80 °C, 1 h then 0.5 mmHg 80 °C. 0.5 h imine 111 B1 + B2 + other boron compounds 25 °C 5 min pre-catalyst Ph Ph Ar OPh Ar O B O– N+ B O H O O B R OPh 190 (for (S)-VAPOL) 191 (for (S)-VANOL) B3 (IMINO-BOROX) (S)-VAPOL 58 (S)-VANOL 59 174 Scheme 3.2 cont’d Ph Ph O O Ph Ph B OPh 106 (for (S)-VAPOL) 107 (for (S)-VANOL) B1 OPh B O B O OPh O 108 (for (S)-VAPOL) 109 (for (S)-VANOL) B2 The catalytic cycle pertaining to the catalytic asymmetric aziridination reaction is shown in Scheme 3.3. As said earlier, addition of imine 111 to the pre-catalyst and other borates sources including commercial B(OPh)3 and triphenoxyboroxine 191a generates IMINO-BOROX catalyst 190. Subsequent attack of diazoester 85 should form the proposed boroxinate-aziridine complex 239 (AZIRIDINO-BOROX) where aziridine is bound to the catalyst. Turnover then would lead to the loss of aziridine and then incorporation of another molecule of the imine 111 regenerating the IMINO-BOROX 190. While we have not been able to obtain any direct evidence for the presence of the protonated boroxinate species 23-H (Free BOROX), it is not clear if the overall conversion of the AZIRIDINO-BOROX 239 to the IMINO-BOROX 190 involves loss of aziridine to give the Brønsted acid 23-H which then protonates the imine to give 190, or if there is an associative reaction between 239 and the imine 111 which directly leads to the aziridine 114 and the IMINO-BOROX 190. The fact that this reaction turns over is consistent with the assumption that aziridine is, most likely, significantly slower in inducing boroxinate formation than the imine. 175 Scheme 3.3 Catalytic cycle of a Brønsted acid catalyzed aziridination reaction OPh OH OH * + VAPOL * PhO OH 3 B(OPh)3 + OH 3 H2O B O O B B O OPh 191a B1 imine 111 (S) B2 OH OH + * VAPOL VAPOL imine 111 (S) imine 111 (S) IMINO-BOROX (S-BA) imine 111 (S) * H-imine OPh O B O B O 190 O O B OPh O OEt N2 85 (Nu) 23-H aziridine 114 H OPh O B O O * O B O B OPh "Free" BOROX (BA) Path II imine 111 Path I aziridine 114 (P) 3.2.1 * H-aziridine OPh O B O B O 239 O O B OPh AZIRIDINO-BOROX (P-BA) Evidence for IMINO-BOROX complex In terms of the characterization of various stages of the catalytic cycle, we have already presented evidence for the structure and involvement of an IMINO-BOROX species as the 176 catalyst with the help of NMR spectroscopy and X-ray analysis. 5f The identification of this species is facilitated by the fact that the bay protons (Hb) of VAPOL and its derivatives, which include IMINO-BOROX catalyst, are quite distinct (Figure 3.1). For VAPOL this doublet is at δ = 9.77 ppm (CDCl3). The formation of the three B-O-B linkages in the boroxine ring in the BOROX catalyst 190 requires 3 equiv of water and the source of this most certainly results from partial hydrolysis of commercial B(OPh)3. This is supported by the fact that no boroxinate 5f occurs with extremely pure B(OPh)3. Hence, we decided to study the effect of the addition of water on the generation of the IMINO-BOROX catalyst 190. Figure 3.1 Chemical shift of the bay proton of (S)-VAPOL 58 and its different derivatives [H-Imine] Ph Ph Hb OH OH Ph Ph Hb Hb OPh O Ph B O B O OPh Ph O Ph B OPh Ph O (S)-VAPOL 58 mesoborate B1 106 pyroborate B2 108 δ = 9.77 ppm (CDCl3) δ = 9.91 ppm (d8-toluene) δ = 9.55 ppm (CDCl3) δ = 9.77 ppm (d8-toluene) δ = 9.22 ppm (CDCl3) δ = 9.55 ppm (d8-toluene) Hb OPh O OB B O O O B OPh IMINO-BOROX B3 190 (imine = 111) δ ~ 10.3-10.4 ppm (CDCl3) δ ~ 10.5-10.6 ppm (d8-toluene) As shown in Figure 3.2B, the traditional method for catalyst formation involves heating (S)-VAPOL with 3 equiv of commercial B(OPh)3 at 80 °C generating the pre-catalyst (method A, Figure 3.2B, entry 1). Another procedure was also employed where 3 equiv of H2O was 177 added to the mixture of ligand and commercial B(OPh)3 (method B, Figure 3.2B, entry 3). With method A, the pyroborate 108 is formed in 53% yield (41% with H2O, method B) along with a 6% yield (5% with H2O, method B) of the mesoborate 106 and 20% (45% with H2O, method B) 1 of unreacted VAPOL 58 (Figure 3.2B, entries 1 and 3) as monitored by H NMR spectroscopy. Treatment of either of these mixtures with 1 equiv of the imine 111a (R = Ph) at room temperature resulted within a few minutes in the conversion of the colorless solution of 106 and 108 to a red solution of IMINO-BOROX catalyst 190a in 90% yield (also 90% with H2O, method B). There is not much change in terms of the yield of 190a with respect to either method, however the amount of B2 108 is higher in case of method A (entry 1 verses 3). The presence of the BOROX catalyst 190a was indicated by the broadened doublet at δ =10.23 ppm (Figure 3.2B, entries 2 and 4). In order to confirm that other imines could induce catalyst formation, we utilized alkyl imines 111o (R = n-propyl) and 112oʹ′ (R = ethyl) to form the catalyst. Indeed, both imines generated the boroxinate catalysts 190o and 213oʹ′ in 49% yield (Figure 3.2B, entry 5) and 60% yield (Figure 3.2B, entry 6) respectively. Another tool utilized in this analysis is the 11 B NMR spectrum. Most, three coordinate aryl borate compounds have very broad absorptions at 16-18 ppm in the 11 B NMR spectrum. However, the increased spherical symmetry of four coordinate boron leads to sharp lines in the spectrum and the negative charge of the borate causes an up field shift. The IMINO-BOROX catalysts 190a, 190o and 213oʹ′ have sharp absorptions at 5.38, 5.35 and 5.48 ppm respectively (Figure 3.2C, entries 2, 5 and 6). The X-ray structure of 190a has been reported previously. 178 5f Figure 3.2 (A) Imine induced boroxinate catalyst formation. (B) a 1 H NMR spectra in CDCl3 with Ph3CH as internal standard with yields of boroxinate catalysts in parenthesis. (C) 11 B 1 NMR spectra corresponding to the H NMR spectra in Figure 3.2B. A Ph Ph OH OH 3. imine 111 or 112 (1equiv) CDCl3 (S)-VAPOL 58 25 °C, 10 min B B3 213o' (60%) OMe [H-imine] 1. B(OPh)3 (3 equiv) H2O (3 equiv) THF, 80 °C, 1 h Ph Ph 2. 0.1 mm Hg 80 °C, 0.5 h OPh A O B O B O O O B OPh A A N R IMINO-BOROX B3 190a (imine = 111a) 190o (imine = 111o) 213o' (imine = 112o') OMe imine A R A 111a 111o 112o' Ph n-Pr Et Me Me tBu B2 108 58 B3 190o (49%) B2 108 58 B3 190a (90%) B2 108 58 B2 108 B1 106 B3 190a (90%) 58 58 179 B2 108 B2 108 B1 106 Figure 3.2 cont’d C B3 213o' B3 190o B3 190a B3 190a a Note for Figure 3.2B: Entry 1: (S)-VAPOL (0.1 mmol) plus 3 equiv of commercial B(OPh)3 were heated at 80 °C in THF for 1 h followed by removal of volatiles under vacuum for 0.5 h (method A). Entry 2: 1.0 equiv of imine 111a added to the solution in entry 1 for 10 min at 25 °C. Entry 3: Same as entry 1 except that 3 equiv of H2O was also added to make the precatalyst (method B). Entry 4: 1.0 equiv of imine 111a added to the solution in entry 3 for 10 min at 25 °C. Entry 5: 1.0 equiv of imine 111o added to the solution in entry 3 for 10 min at 25 °C. Entry 6: 1.0 equiv of imine 112oʹ′ added to the solution in entry 3 for 10 min at 25 °C. 180 3.2.2 Evidence for an AZIRIDINO-BOROX complex Next, we moved on with the attempts to find evidence for the AZIRIDINO-BOROX specie 239. In the past, there have been a lot of unsuccessful attempts in our group. 1 3.2.2.1 Monitoring the reaction by H NMR Spectroscopy One of the ways of observing AZIRIDINO-BOROX 239 is to follow the aziridination 1 reaction by H NMR spectroscopy. Presumably, that imine has higher binding affinity compared to the aziridine, which results in turnover. However, it was thought that the presence of 239 could perhaps be observable towards the end of the reaction when the amount of aziridine is much larger than the amount imine and this might help shift the equilibrium towards 239. Hence 1 we decided to follow the reaction using H NMR spectroscopy. We employed three different procedures as shown in Scheme 3.4. The formation of aziridine and the alkylated VAPOL derivative 230 was observed in each case. The results are summarized in Table 3.1. A detailed discussion on the formation of 230 is given in section 3.2.4. Scheme 3.4 Different procedures used to perform and monitor the aziridination reaction Procedure i OH 1. Toluene, 80 °C, 1 h 2. 80 °C, 0.5 h 0.1 mmHg B(OPh)3 * (0.3 mmol) 3. imine 111a OH (0.2 or 1 mmol) (S)-VAPOL 58 4. CDCl3, stir, 10 min (0.1 mmol) 5. EDA 85 (0.24 or 1.2 mmol) + O MEDAM N Ph + * CO2Et 114a O OEt 1H NMR Analysis OH 230 Procedure ii O MEDAM 1. imine 111a O 1 (0.2 mmol) OH OEt H NMR N + * + Boroxine * Analysis (0.1 mmol) 2. CDCl3, stir, 10 min OH OH Ph CO2Et 3. EDA 85 (0.24 mmol) (S)-VAPOL 58 230 114a (0.1 mmol) 181 Scheme 3.4 cont’d Procedure iii OH B(OPh)3 * (0.3 mmol) 2. CDCl3, stir, 10 min OH 3. EDA 85 (1.2 mmol) (S)-VAPOL 58 (0.1 mmol) + O MEDAM 1. imine 111a (1 mmol) N Ph + * CO2Et # B(OPh)3 Before imine b 230 B1 d 106 B2 d 108 a B3 B3 e d e 114a 190a 190a 3 i 10 20 3 3 - 6 53 3 3 3 3 After imine (10 equiv) X2 i 10 <1 - <1 6 55 6 - After EDA (12 equiv) X3 X4 X5 X6 i i i i 10 30 80 95 <1 14 18 15 <1 38 37 32 <1 8 <1 <1 <1 20 27 25 62 20 8 <1 6 2 1 <1 31 96 97 99 3 3 i 10 20 3 3 - 6 53 3 3 3 3 After imine (2 equiv) Y2 i 10 2 - <1 13 81 41 - After EDA (2.4 equiv) Boroxine Before imine Y3 Y4 i i 10 15 2 <1 <1 26 3 7 10 27 82 23 41 11 11 90 Y5 ii - 69 - 4 23 - - - After imine (2 equiv) Y6 ii 10 19 - <1 <1 55 28 - After EDA (2.4 equiv) Y7 Y8 Y9 ii ii ii 10 15 25 24 12 7 9 38 45 <1 <1 <1 1 4 4 66 46 38 33 23 19 65 73 78 B(OPh)3 Before imine Y1 3 182 3 Analysis 3 X1 3 (S)VAPOL c,d 58 1H NMR 230 1 Time (min) OEt OH 114a Table 3.1 Monitoring aziridination reaction by H NMR spectroscopy Proc O 3 - - - - - - Table 3.1 cont’d Y10 B(OPh)3 Before imine ii 3 3 75 4 3 3 52 3 3 4 3 33 17 79 3 - <1 3 3- 3 - 11 - <1 <1 41 4 - 10 10 11 11 12 13 14 20 26 27 <1 <1 <1 <1 <1 <1 <1 <1 9 11 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 <1 31 31 34 34 34 34 34 47 45 30 3 3 3 3 3 3 3 5 5 3 15 17 21 22 35 65 69 82 86 88 Z1 iii 10 85 After imine (10 equiv) Z2 iii 10 After EDA (12 equiv) Z3 Z4 Z5 Z6 Z7 Z8 Z9 Z10 Z11 Z12 iii iii iii iii iii iii iii iii iii iii 15 20 25 30 60 75 90 120 160 170 a <1 Unless otherwise specified, all NMR samples were prepared with (S)-VAPOL 58 (0.1 mmol), commercial B(OPh)3 (0.3 mmol) or boroxine 191a (0.1 mmol) and imine 111a in CDCl3 (1 mL) utilizing method i-iii. (S)-VAPOL 58. limiting reagent. limiting reagent. d e b For different methods; see scheme 3.4. c Unreacted NMR yield with Ph3CH as internal standard with (S)-VAPOL 58 as the NMR yield with Ph3CH as internal standard with imine 111a as the Irrespective of various methods, there is no sign of AZIRIDINO-BOROX complex at any time interval. This was most evident in Figure 3.3A as there was no new significant peak in the 1 bay region of the H NMR spectrum of the ligand nor in the 11 B NMR spectrum. 1 Figure 3.3 (A) A-01: H NMR spectra in CDCl3 with Ph3CH as internal standard (procedure i). Entry 1: (S)-VAPOL (0.1 mmol) plus 3 equiv commercial B(OPh)3 were heated at 80 °C in toluene for 1 h followed by removal of volatiles under vacuum for 0.5 h. Entry 2: 10 equiv of imine 111a added to the solution in entry 1 for 10 min at 25 °C. Entry 3: 12 equiv of EDA 85 added to the solution in entry 2 for 10 min at 25 °C. Entry 4: Same as entry 3 after 30 min. 183 Figure 3.3 cont’d 1 Entry 5: Same as entry 3 after 80 min. Entry 6: Same as entry 3 after 95 min. A-02: H NMR spectra of the methoxy and methyl regions corresponding to the entries in Figure 3.3A-01. A-03: 11 1 B NMR spectra corresponding to the H NMR spectra (entries 1, 2, 5 and 6) in Figure 3.3A1 01. (B) H NMR spectra in CDCl3 with Ph3CH as internal standard. The reaction is performed using procedures i and ii using 2 equiv of imine 111a and 2.4 equiv of EDA 85; see scheme 3.4 1 for procedures i and ii. (C) H NMR spectra in CDCl3 with Ph3CH as internal standard. The reaction is performed using method iii using 10 equiv of imine 111a and 12 equiv of EDA 85; see scheme 3.4 for procedure iii. A A-01 230 58 230 230 58 230 E-3 (95 min) E-3 (80 min) 230 E-3 (30 min) E-2 + 12 equiv EDA 85 (10 min) E-1 + 10 equiv imine 111a (10 min) 190a 58 230 190a 190a 108 58 E-1 (Pre-catalyst, procedure i) 184 106 A-02 Figure 3.3 cont’d E-3 (95 min) 114a (99%) E-3 (80 min) 114a (97%) E-3 (30 min) 114a (96%) E-2 + 12 equiv EDA 85 (10 min) 114a (31%) 190a 190a E-1 + 10 equiv imine 111a (10 min) E-1 (Pre-catalyst, procedure i) A-03 E-3 (95 min) 190a E-2 + 12 equiv EDA 85 (10 min) 190a E-1 + 10 equiv imine 111a (10 min) E-1 (Pre-catalyst, procedure i) 185 B E-7 (75 min) Figure 3.3 cont’d E-7 (25 min) E-7 (15 min) E-6 + 2.4 equiv EDA 85 (10 min) E-5 + 2 equiv imine 111a (10 min) E-5 (Pre-catalyst, procedure ii) E-3 (30 min) E-2 + 2.4 equiv EDA 85 (10 min) E-1 + 2 equiv imine 111a (10 min) E-1 (Pre-catalyst, procedure i) C E-3 (170 min) E-3 (160 min) E-3 (120 min) E-3 (90 min) E-3 (75 min) E-3 (60 min) E-3 (30 min) E-3 (25 min) E-3 (20 min) E-2 + 12 equiv EDA 85 (10 min) E-1 + 10 equiv imine 111a (10 min) E-1 (Pre-catalyst, procedure iii) 186 One of the interesting aspects of our catalytic aziridination reaction is that it is a substrate-induced catalytic system. Since imines are generally more basic than aziridines it should not be surprising that all of the NMR studies in Figure 3.3 and Table 3.1 failed to turn up any evidence for an aziridine-catalyst complex. However, this suggests that the second line of thought should be to employ aziridine 114 as a base to generate a boroxinate in the absence of an imine to avoid any competition for the catalyst. Presumably, the behavior of the species 239 should be similar to IMINO-BOROX catalyst 190. 3.2.2.2 Initial attempts towards the generation of AZIRIDINO-BOROX complex using aziridine 114a Initial attempts towards the generation of aziridine-boroxinate complex 239a (with phenyl aziridine 114a) by following the reaction were not that conclusive. We used aziridine 114a to affect the desired result. At first instant, it seemed that the desired complex was formed. 1 This inference was suggested by the H NMR spectrum of the bay region and by the spectrum. A very small peak at 5.95 ppm was seen in the 11 11 B NMR B NMR spectrum. With the help of NOESY1D and COSY, we were able to identify the peaks for the bay region protons at δ = 10.59 and δ = 11.12 ppm in d8-toluene (δ = 10.5 and δ = 10.8 ppm in CDCl3) at room temperature. Also, the proton attached to the N of aziridinium was found to be at δ = 10.89 ppm in d8-toluene (δ = 10.32 ppm in CDCl3). A simple temperature study (–20 ºC to 80 ºC) revealed that aziridinium cation exchanges with increased rate on NMR time scale at higher temperature as both the bay protons come closer (Figure 3.4B). However, this complex was found to unstable at room temperature over a period of time. The evidence for the existence of complex 239a was only indicative and not conclusive. 187 a1 Figure 3.4 (A) Aziridine 114a induced boroxinate catalyst formation. (B) H NMR spectra of the bay region in d8-toluene. A Ph Ph OH OH [Ha-aziridine] 1 B(OPh)3 (3 equiv) H2O (3 equiv) THF, 80 °C, 1 h Ph Ph 2 0.1 mm Hg 80 °C, 0.5 h 3 aziridine 114a (1equiv) d8-toluene (S)-VAPOL 58 25 °C, 10 min OPh MeO Hb B O O B O O O Hb B OPh OMe N Ph AZIRIDINO-BOROX B3 239a CO2Et aziridine 114a B d8-toluene Hb Hb 80 ºC Hb 50 ºC 25 ºC Hb Hb Ha Ha Hb Hb Hb – 20 ºC a Note for Figure 3.4B: Entry 1: (S)-VAPOL (0.1 mmol) plus 3 equiv commercial B(OPh)3 and 3 equiv H2O were heated at 80 °C in THF for 1 h followed by removal of volatiles under 188 vacuum for 0.5 h. Thereafter, 1.0 equiv of aziridine 114a added to the pre-catalyst in d8-toluene (1 mL) for 10 min at 25 °C. The NMR was taken at –20 °C. Entry 2: Same as entry 1 but the NMR was taken at 25 °C. Entry 3: Same as entry 1 but the NMR was taken at 50 °C. Entry 4: Same as entry 1 but the NMR was taken at 80 °C. 3.2.2.3 First glimpse of an AZIRIDINO-BOROX complex using aziridine 114o Next, we examined aziridine 114o as the substrate for the generation of a boroxinateaziridine complex 239o. To our delight, this provided the first conclusive evidence of an AZIRIDINO-BOROX 239o. A characteristic peak at δ 5.36 ppm was observed in the 11 B NMR 1 spectrum (Figure 3.5H). In fact, few peaks were observed at bay region of the ligand in H NMR spectrum that is expected for a boroxinate species (Figure 3.5D and 3.5G). A bit of a more careful look revealed the presence of two bay protons of the ligand at δ = 10.2 ppm and δ = 10.6 ppm in CDCl3 (Figure 3.5D). The presence of two bay protons peak is probably due the slow exchange of the aziridinium cation with the top and bottom face of the catalyst on the NMR time scale. The same peaks were observed at δ = 10.6 ppm and δ = 11.0 ppm in d8-toluene (Figure 3.5D). With the help of COSY and HMBC, we were able to identify the changes in the chemical shifts of key protons of aziridine 114o. These observations are discussed below. Figure 3.5 (A) Aziridine 114o induced boroxinate catalyst formation. (B) a1 H NMR spectra in 1 CDCl3. (C) Expanded view of H NMR spectrum of neat aziridine 114o (entry 2 in Figure 1 3.5B); (D) Expanded view of H NMR spectrum of B3 239o (entry 1 in Figure 3.5B). (E) 1 Expanded view of the superimposed H NMR spectra of B3 239o and 114o for the region 189 Figure 3.5 cont’d 1 between δ = 3 ppm to δ = 5.5 ppm. (F) Expanded view of the superimposed H NMR spectra of B3 239o and 114o for the region between δ = 0.1 ppm to δ = 2.5 ppm. (G) Same as entry 1 in 1 Figure 3.5B except that the H NMR spectrum was taken in d8-toluene. (H) 11 B NMR spectrum 1 corresponding to the H NMR spectrum of entry 1 in Figure 3.5B. A Ph Ph OH OH 3 aziridine 114o (1equiv) NMR solvent (S)-VAPOL 58 25 °C, 10 min B MeO [Ha'-aziridine] 1 B(OPh)3 (3 equiv) H2O (3 equiv) THF, 80 °C, 1 h Ph Ph 2 0.1 mm Hg 80 °C, 0.5 h OMe OPh MeO Hb' OB O B O O O B Hb' OPh AZIRIDINO-BOROX B3 239o CDCl3 CO2Et [Ha'-aziridine] Ph Ph N CO2Et N 114o OMe OPh Hb' OB O B O O O B Hb' OPh B3 239o 190 aziridine 114o Figure 3.5 cont’d Me Me X 2 C MeO Me MeO MeO OMe Hi Me H Me e eH N O CHh3 CHf3 c d Hj Hj H H O Hg Hg 114o h H f H i d H g H H c H j j H H e e H H D Me 58 OMe OPh Hb' i' H O OB Me Me B O O O B He' N Ha' He' Hb' O CHh'3 OPh CHf'3 c' d' Hj' j' H H O Hg' Hg' H B3 239o Hb' Hb' Ha' Me MeO 108 Ph Ph AZIRIDINO-BOROX B3 239o MeO Me MeO Me h' H i' H THF THF g' H c' H CDCl3 191 j' j' H H d' H e' e' H H f' H E Figure 3.5 cont’d MeO MeO B3 239o MeO MeO 114o THF i' g H H F Me i H h Me Me X 2 g' H B3 239o H 114o f H h' H THF d H c H c' H j' H j' j j d' H H H e H H 192 e' e H e' H H f' H G Figure 3.5 cont’d 58 B3 239o Hb' Hb' Ha' 108 Me MeO Me MeO d8-tol THF i' H g' H c' H d8-toluene H 5.36 B3 239o 18.26 2.35 193 1 h' H f' H a Note for Figure 3.5B: Entry 1: (S)-VAPOL (0.1 mmol) plus 3 equiv commercial B(OPh)3 and 3 equiv H2O were heated at 80 °C in THF for 1 h followed by removal of volatiles under vacuum for 0.5 h. Thereafter, 1.0 equiv of aziridine 114o was added to the pre-catalyst as a 1 solution in CDCl3 (1 mL) for 10 min at 25 °C. H NMR spectrum was taken at 25 °C. Entry 2: 1 H NMR spectrum of the pure aziridine 114o. The chemzyme-product complex 239o derived from the aziridine 114o could not be induced to form crystals suitable for an X-ray diffraction study. It was then decided to explore 1 the structure of 239o by computational chemistry in order to compliment our observations by H NMR spectroscopy. The possible AZIRIDNINO-BOROX complex 239o was then computed by 6 DFT calculations using Gaussian ʹ′03 at B3LYP/6-31g* level of theory. The calculated structure of 239o not only supports the boroxinate ion pair motif, but also gives some insight as to how the aziridine might be docking with the boroxinate. The structural analysis further confirms the presence of an ion pair consisting of a protonated aziridinium ion and the boroxinate anion derived from a boroxine ring in which the tetra-coordinate boron is spiro-fused to the VAPOL ligand. This structure is consistent with the many non-covalent interactions 1 observed between the boroxinate anion and the aziridinium observed by H NMR spectroscopy. 5f These interactions are summarized in Figure 3.6. As was seen in the case of iminiums, there is a hydrogen bond from the protonated aziridinium to the oxygen in the boroxinate ring that is attached to the four coordinate boron (O2). The H-O distance of 1.75 Å (Figure 3.6, d1) suggests a strong to moderate hydrogen bond 4o and the chemical shift of this proton is δ = 9.8 ppm in 194 CDCl3 (δ = 10.3 ppm in d8-toluene) which is quite different from the proton associated with the 5f nitrogen of the protonated imine in the IMINO-BOROX catalyst 190 (δ = 13-14 ppm). Figure 3.6 Calculated structure of AZIRIDINO-BOROX complex 239o using Gaussian ʹ′03. (A) Calculated B3LYP/6-31g* structure visualized by the Mercury program (C, gray; O, red; N, blue; B, yellow; H, white). Hydrogen atoms are omitted from ligand for clarity (except that of aziridine and O2-H). Some secondary interactions are highlighted: d1 = 1.75 Å (H-bonding), d2 = 3.95 Å (CH-π), d3 = 4.57 Å (CH-π), d4 = 4.30 Å (CH-π), d5 = 4.35 Å (CH-π), d6 = 4.00 Å (CH-π) and d7 = 2.71 Å (CH-O). (B) Space-filling rendition of 239o with the same orientation and showing hydrogens. The boroxinate anion is given in green and the aziridinium is in traditional colors. A d3 d2 d7 O2 d1 O1 d 6 195 d4 d5 Figure 3.6 cont’d B The calculated structure of 239o provides insight to the up field shift observed for the key protons of the aziridine 114o upon formation of the aziridine-boroxinate complex 239o. There 7 are several CH-π interactions. One of the interesting interactions is between one of the MEDAM methoxy groups and the phenyl ring of the phenol component (Figure 3.6, d2 = 3.95 Å). There are other CH-π interactions including one from a MEDAM methyl to the phenyl ring of the phenol component (Figure 3.6, d3 = 4.57 Å). The observed dissymmetry (Figure 3.5E and 3.5F) in the case of methyl and methoxy groups of the MEDAM rings is consistent with these CH-π interactions. In fact, these interactions which place these methyl and methoxy groups in 196 1 the shielding region of various arene rings furthers confirms the observation in the H NMR spectrum of complex 239o (Figure 3.5E and 3.5F). The methoxy groups are observed as two singlets (δ = 3.42 ppm and δ = 3.31 ppm, 6H), which are shielded relative to the free aziridine 114o (δ = 3.67 ppm and δ = 3.65 ppm, 6H) by 0.25 ppm and 0.34 ppm (Figure 3.5E). Similarly, the methyl groups are also observed as two singlets (δ = 2.23 ppm and δ = 1.68 ppm, 12H), which are shielded relative to the free aziridine 114o (δ = 2.22 ppm, 12H) by 0.54 ppm (Figure 3.5F). A similar upfield shift also occurs for the methyl groups in the propyl group and in the ester group of the aziridine 114o. Both triplets were found to be shifted upfield by 0.53 and 0.65 f h fʹ′ hʹ′ ppm respectively (Figure 3.5F, H and H vs. H and H ). This upfield shift can be explained by the CH-π interactions between these groups and the phenyl ring of the phenol component (Figure 3.6, d5 = 4.35 Å) and also with the arene rings of the phenanthrene ring of the VAPOL (Figure 3.6, d4 = 4.30 Å). Similar upfield shifts and CH-π interactions were observed regarding the CH2 units of propyl and ester groups of the aziridine 114o (Figure 3.5F and Figure 3.6, H g gʹ′ vs. H , d6 = 4.00 Å). One of the interesting observations was the downfield shift of the methine i iʹ′ proton (Figure 3.5E, H vs. H ) by 1.87 ppm. The factors contributing to this high shift could be a) the adjacent protonated nitrogen behaves as an electron withdrawing group, b) the CH-O iʹ′ interaction between H and O1 (Figure 3.6, d7 = 2.71 Å). A similar downfield shift (~1.37 ppm) was observed for the BOROX catalyst 190a where the CH-O interaction (2.86 Å) was found to be present between the methine proton of imine and the O1 of the boroxinate anion (Chapter 2, 197 5f Figure 2.2B). To summarize, the first evidence for product binding to the catalyst in a 1 Brønsted acid catalyzed aziridination reaction has been established by H NMR spectroscopy, 8 and which is well supported by theoretical calculations. 3.2.2.4 Temperature studies of 239o and recovery of aziridine 114o We then decided to carry out some additional experiments in order to confirm the 1 presence of 239o. The H NMR spectrum of 239o has two different bay proton absorptions (Figure 3.5D and 3.5G) and this was interpreted to mean that migration of the protonated aziridine from the top face of the catalyst to the bottom face is slow on the NMR time scale. To 1 gain evidence for this interpretation a temperature study on the H NMR spectrum of the complex 239o was performed. On elevating the temperature from 25 ºC to 80 ºC, the two sets of bay protons (Hb') in the aziridine-boroxinate complex 239o begin to coalesce to give one single doublet (entry 3, Figure 3.7A). This reflects an increased exchange rate on NMR time scale at higher temperature. However, this complex seems to be unstable at higher temperature (80 ºC) 1 as new peaks are observed in the H NMR spectrum when the sample is brought back to room temperature (Figure 3.7A, entry 4). In order to study their exchange processes, NOE experiments were carried out at 50 ºC. Upon irradiation of one of the bay proton (δ = 11.06 ppm), the other bay proton appeared with the same sign (δ = 10.67 ppm). This observation further confirms that the aziridinium cation exchanges with the faces of the catalyst slowly on the NMR time scale. 198 1 Figure 3.7 (A) H NMR spectra of the bay region of boroxinate 239o in d8-toluene. Entry 1: (S)-VAPOL (0.1 mmol) plus 3 equiv commercial B(OPh)3 and 3 equiv H2O were heated at 80 °C in THF for 1 h followed by removal of volatiles under vacuum for 0.5 h. Thereafter, 1.0 equiv of aziridine 114o was added to the pre-catalyst as a solution in d8-toluene (1 mL) for 10 min at 25 °C. The NMR was taken at 25 °C. Entry 2: Same as entry 1 but the NMR was taken at 50 °C. Entry 3: Same as entry 1 but the NMR was taken at 80 °C. Entry 4: entry 3 is cooled to 25 °C. (B) NOE (at 50 ºC) performed by irradiating one of the bay protons (δ = 11.06 ppm) in entry 2 of Figure 3.7A. A Hb' Hb' Ha' cooled to 25 ºC Hb' Hb' 80 ºC Hb' Ha' Hb' 50 ºC Hb' 25 ºC 199 Hb' Ha' 10.67 11.06 Figure 3.7 cont’d B Additionally, it was thought that if the observed NMR behavior is due to the formation of AZIRIDINO-BOROX complex then it should be possible to recover aziridine upon the addition of water. In fact, aziridine release was observed when water was added in portions as shown in Figure 3.8. In fact, disappearance of the aziridine-boroxinate complex occurs concomitant with appearance of the free aziridine 114o (Figure 3.8). The description of the protons labeled in Figure 3.8C has been given in the Figure 3.5. The aziridine 114o was obtained with 85% 1 recovery. The difference in amount of aziridine 114o observed in the H NMR spectrum (entry 4, after the addition of 0.4 mmol H2O) and % recovery (70% vs. 85%) can be attributed to the 200 possibility that the aziridine 114o can form complexes with other boron sources such as B(OPh)3 or hydrolyzed derivatives. 1 Figure 3.8 (A) Treatment of 239o with water. (B) H NMR spectra of the bay region in CDCl3 with Ph3CH as internal standard. Entry 1: (S)-VAPOL (0.1 mmol) plus 3 equiv commercial B(OPh)3 and 3 equiv H2O were heated at 80 °C in THF for 1 h followed by removal of volatiles under vacuum for 0.5 h. Thereafter, 1.0 equiv of aziridine 114o was added to the pre-catalyst as a solution in CDCl3 (1 mL) for 10 min at 25 °C. The NMR was taken at 25 °C. Entry 2: 1 equiv H2O added to entry 1. Entry 3: 2 equiv H2O added to entry 1. Entry 4: 4 equiv H2O added to 1 entry 1. Entry 5: 10 equiv H2O added to entry 1. (C) H NMR spectra corresponding to the entries 1–4 in Figure 3.8B highlighting the methyl and methoxy regions. The description of the protons labeled in Figure 3.8C has been given in the Figure 3.5. Entry 5: aziridine 114o isolated (purified by silica gel chromatography) after the addition of 1.0 mmol H2O to entry 1. (D) 11 B 1 NMR spectra corresponding to the H NMR spectra of entries in Figure 3.8B A [Ha'-aziridine] Ph Ph OPh Hb' O OB B O O O B Hb' OPh H2O MeO Ph Ph OH OH + N 114o + AZIRIDINO-BOROX B3 239o OMe (S)-VAPOL 58 201 CO2Et unidentified boron compounds B Figure 3.8 cont’d 58 E-1 + 10 equiv H2O (70% 114o + <1% 239o) 58 E-1 + 4 equiv H2O (70% 114o + <1% 239o) 58 E-1 + 2 equiv H2O (61% 114o + 9% 239o) E-1 + 1 equiv H2O (48% 114o + 18% 239o) Hb' Ha' Hb' 58 Hb' Ha' Hb' 58 E-1 (23% 114o + 43% 239o) C 114o (recovered) MeO (85% isolated yield) Hb' 108 Ha' Hb' Me MeO i d c H H H h j H e H H f H E-1 + 4 equiv H2O (70% 114o + <1% 239o) E-1 + 2 equiv H2O (61% 114o + 9% 239o) E-1 + 1 equiv H2O (48% 114o + 18% 239o) E-1 (23% 114o + 43% 239o) Me MeO MeO g' H c' H 202 Me j' H h' f' H e' H H Figure 3.8 cont’d D E-1 + 10 equiv H2O (70% 114o + <1% 239o) B(OH)3 E-1 + 4 equiv H2O (70% 114o + <1% 239o) E-1 + 2 equiv H2O (61% 114o + 9% 239o) E-1 + 1 equiv H2O (48% 114o + 18% 239o) B3 239o E-1 (23% 114o + 43% 239o) 3.2.2.5 Dependence of the formation of AZIRIDINO-BOROX 239o on various protocols After the confirmation of the presence of AZIRIDINO-BOROX complex, we became interested to find out whether the generation of the 239o depends on the protocol used for precatalyst generation. As shown in Table 3.2, different yields were obtained for different protocols. Also, we found that this complex decomposes to some extent at elevated temperatures of as 80 °C and 50 °C (Table 3.2, entries 2 and 6). The complex is relatively stable to storage, however it decomposes slowly on being kept for long periods of time (Table 3.2, entry 7). 203 Table 3.2 Generation of AZIRIDINO-BOROX 239o with different boron sources a [H-aziridine] Ph Ph Boron source OH OH aziridine 114o Method B-G precatalyst solvent 25 °C 10 min OPh O B O B O O O B OPh Ph Ph (S)-VAPOL 58 AZIRIDINO-BOROX B3 239o # Pre-catalyst b (method) Solvent c Yield 239o d (%) 1 B(OPh)3 B d8-toluene 47 2 B(OPh)3 B d8-toluene 3 B(OPh)3 B CDCl3 26 43 4 B(OPh)3 C CDCl3 19 5 Boroxine D CDCl3 6 BH3•Me2S E CDCl3 31 7 a Boron Source BH3•Me2S E CDCl3 17 e 30 (26) g f Unless otherwise specified, all NMR samples were prepared with 0.1 mmol of aziridine 114o in solvent (0.1 M in aziridine 114o) with 1.0 equiv of (S)-VAPOL 58. b Method B: The pre-catalyst was prepared by heating 1 equiv of (S)-VAPOL, 3 equiv of commercial B(OPh)3 and 3 equiv of H2O in THF at 80 °C for 1 h, followed by removing all volatiles under high vacuum (0.1 mm Hg) for 0.5 h at 80 °C. Method C: Same as Method B except 4 equiv of commercial B(OPh)3 with 1 equiv of H2O was used. Method D: By mixing 1 equiv of (S)VAPOL and 1 equiv of triphenoxyboroxine 191a. Triphenoxyboroxine 191a was prepared by heating 3 equiv of BH3•Me2S, 2 equiv of PhOH and 3 equiv of H2O in toluene at 100 °C for 1 h, followed by removing all volatiles under high vacuum (0.1 mm Hg) for 0.5 h at 100 °C. Method E: By heating 1 equiv of (S)-VAPOL, 3 equiv of BH3•Me2S, 2 equiv of PhOH and 3 equiv of H2O in toluene at 100 °C for 1 h, followed by removing all volatiles under high c vacuum (0.1 mm Hg) for 0.5 h at 100 °C. NMR Solvent. Ph3CH as an internal standard. e d 1 Determined by H NMR using In this case, the resulting mixture was heated at 80 °C for 0.5 h after the addition of aziridine 114o. f In this case, the resulting mixture was heated at 50 g °C for 1.0 h after the addition of aziridine 114o. Results in parenthesis are from NMR sample that was kept at 25 °C for 24 h prior to analysis. 204 3.2.2.6 Direct generation of AZIRIDINO-BOROX at room temperature Recently, we have shown that IMINO-BOROX 190a can be generated in 76% yield at 5f room temperature by simple mixing the ligand, commercial B(OPh)3 and imine 111a. At this point, it became interesting to find out whether AZIRIDINO-BOROX 239o can be directly generated at room temperature or not. It was delightful to observe 239o in 15% yield when 2 equiv of aziridine 114o was mixed with 1equiv of (S)-VAPOL and 3 equiv of commercial 1 B(OPh)3 (Figure 3.9, entry 5). The yield was determined by H NMR using Ph3CH as the internal standard. The low yield can be attributed to low binding affinity of aziridines to the catalyst as compared to imines. However, it must be noted that the conversion of pre-catalyst to AZIRIDINO-BOROX 239o is higher than direct generation from commercial B(OPh)3 (43% yield vs 15% yield, Table 3.2 vs Figure 3.9). The evidence for AZIRIDINO-BOROX 239a is not observed on the NMR time scale possibly due to fast exchange processes (entry 4, Figure 3.9B). One observation to be noted was the presence of aldehydes due to partial hydrolysis of imines (entries 2 and 3, Figure 3.9B). Figure 3.9 (A) Direct generation of aziridine-boroxinate complex at room temperature. (B) NMR spectra of the bay region in CDCl3 with Ph3CH as internal standard. (C) 1 corresponding to the H NMR spectra in Figure 3.9A 205 11 a1 H B NMR spectra Figure 3.9 cont’d A Ar [H-base] Ph Ph OH OH B(OPh)3 (3 equiv) base (2 equiv) CDCl3 25 ºC, 10 min OPh O B O B O O O B OPh Ph Ph (S)-VAPOL 58 BOROX B3 N B3 CO2Et Base R 190a imine 111a Ph 190o imine 111o n-Pr 239a azi 114a Ph 239o azi 114o n-Pr B3 239o 58 nPrCHO 127o B3 190o PhCHO 127a 58 58 B2 108 206 N Ar2CH = MEDAM 58 B3 190a Ar Ar R R B 58 Ar Figure 3.9 cont’d C B3 239o B3 239a B3 190o B3 190a a Note for Figure 3.9B: Entry 1: (S)-VAPOL (0.1 mmol) plus 3 equiv commercial B(OPh)3 at 25 °C for 10 min. Entry 2: (S)-VAPOL (0.1 mmol) plus 3 equiv commercial B(OPh)3 and 2 equiv imine 111a at 25 °C for 10 min. Entry 3: (S)-VAPOL (0.1 mmol) plus 3 equiv commercial B(OPh)3 and 2 equiv imine 111o at 25 °C for 10 min. Entry 4: (S)-VAPOL (0.1 mmol) plus 3 equiv commercial B(OPh)3 and 2 equiv aziridine 114a at 25 °C for 10 min. Entry 5: (S)-VAPOL (0.1 mmol) plus 3 equiv commercial B(OPh)3 and 2 equiv aziridine 114o at 25 °C for 10 min. 207 3.2.2.7 Generation of AZIRIDINO-BOROX complexes from other alkyl aziridines Although the phenyl substituted aziridine 114a failed to provide any conclusive evidence for an AZIRIDINO-BOROX complex, the n-propyl aziridine 114o was able to assemble the boroxinate 239o in 43% yield. This suggested that aziridines derived from aliphatic aldehydes are more prone to provide convincing evidence for boroxinate complexes formation. Hence, we decided to screen the ethyl, cyclohexyl and tert-butyl substituted aziridines 115oʹ′, 114v and 114w, respectively. Indeed, it was possible to observe the assembly of AZIRIDINO-BOROX 240oʹ′ when aziridine 115oʹ′ (protecting group = BUDAM) was reacted with the pre-catalyst. Interestingly, only one peak for bay protons of the boroxinate complex 240oʹ′ was observed which indicates that the migration of the protonated aziridine from top face of the catalyst to the bottom face is fast on the NMR time scale in this case (Figure 3.10A, entry 1). It must be noted that aziridine 115oʹ′ has the BUDAM group as the protecting group. When aziridine 114v was used, two distinct bay protons were observed (Figure 3.10A, entry 3). In addition to the bay protons, an unknown peak around δ = 10.6 ppm was observed which increased along with the boroxinate species when excess aziridine 114v was added (Figure 3.10A, entry 4). Interestingly, aziridine 114w generated only a small amount of boroxinate 239w as illustrated by the 11 B NMR spectrum (Figure 3.10B, entry 5). Figure 3.10 (A) Examination of alkyl aziridines for boroxinate formation. (B) of the bay region in CDCl3 with Ph3CH as internal stardard. (C) 1 corresponding to the H NMR spectra in Figure 3.10B 208 a1 11 H NMR spectra B NMR spectra Figure 3.10 cont’d A Ph Ph OH OH [H-aziridine] 1. B(OPh)3 (3 equiv) H2O (3 equiv) THF, 80 °C, 1 h Ph Ph 2. 0.1 mm Hg 80 °C, 0.5 h OPh O B O B O O O B OPh 3. aziridine 114 or 115 (1equiv) CDCl3 (S)-VAPOL 58 25 °C, 10 min Ar N R B3 azi 239o 239v 239w 240o' BOROX B3 Ar 114o 114v 114w 115o' CO2Et Ar2CH MEDAM n-Pr MEDAM Cy MEDAM tBu BUDAM Et B 58 108 ? E-5 (B3 239w) 58 E-4 (E-3 + 4 equiv of 114v) Hb' ? Hb' Ha' 58 E-3 (B3 239v) Hb' ? Hb' 108 Ha' 58 E-2 (B3 239o) Hb' Hb' Hb' E-1 (B3 240o') 209 Ha' 108 58 R 108 Figure 3.10 cont’d C E-5 (B3 239w) E-4 (E-3 + 4 equiv of 114v) E-3 (B3 239v) E-2 (B3 239o) E-1 (B3 240o') a Note for Figure 3.10B: Entry 1: (S)-VAPOL (0.1 mmol) plus 3 equiv commercial B(OPh)3 and 3 equiv H2O were heated at 80 °C in THF for 1 h followed by removal of volatiles under vacuum for 0.5 h. Thereafter, 1.0 equiv of aziridine 115oʹ′ was added to the pre-catalyst as a solution in CDCl3 (1 mL) for 10 min at 25 °C. Entry 2: Same as entry 1 except that aziridine 114o was employed. Entry 3: Same as entry 1 except that aziridine 114v was employed. Entry 4: 4 equiv of aziridine 114v added to entry 1. Entry 5: Same as entry 1 except that aziridine 114w was employed. 210 3.2.3 Equilibrium studies After the establishment of conditions for the formation of a product-catalyst complex, it was important to know whether these species exist in equilibrium or not. It is a challenging task since it is not a simple case where the product binds to a pre-existing catalyst. In the present case, the equilibrium is in between the product and the catalyst and between all of the species from which the catalyst is assembled with the aid of substrate. However, we chose to carry out this study using the aziridine-catalyst complex rather than the imine-catalyst complex since the aziridine has a lower binding affinity (basicity) and it should be easier to observe equilibrium effects. We designed two sets of experiments. In the first, we started off with a concentrated mixture containing AZIRIDINO-BOROX complex and then diluted the mixture with the subsequent addition of solvent. As shown in Figure 3.11B, amount of the boroxinate 239o decreases with the decrease in the concentration of the reaction mixture. A corresponding increase in the amount of (S)-VAPOL 58 was also observed. With further dilution, unbounded aziridine 114o was also observed (entry 8, Figure 3.11B). This suggests that there is shift in the equilibrium towards free aziridine and ligand upon dilution. Figure 3.11 (A) Aziridine induced boroxinate formation and its subsequent dilution studies. (B) a 1 H NMR spectra of the reaction mixture in d8-toluene with Ph3CH as internal standard. The numbers given in the spectra shows the NMR yield of respective species (red, 239o; green, 58; blue, 108). The description of the protons labeled in Figure 3.11A has been given in the Figure 3.5. (C) 11 1 B NMR spectra corresponding to the H NMR spectra in Figure 3.11B 211 Figure 3.11 cont’d A Ph Ph OH OH (S)-VAPOL 58 1. B(OPh)3 (3 equiv) H2O (3 equiv) THF, 80 °C, 1 h 2. 0.1 mm Hg 80 °C, 0.5 h 3. aziridine 114o, d8-toluene 25 °C, 10 min [H-aziridine] OPh O B O B O O O B OPh Ph Ph dilution analysis AZIRIDINO-BOROX B3 239o 32% 33% 6% Hh Hh' 28% 0.05 M (E-6 diluted) 36% 7% 0.1 M (E-4 after 24 h) 21% 46% 18% 47% 0.08 M (E-5 diluted) 42% 16% 0.1 M 46% 14% 8% 8% 10% 11% 0.1 M (E-2 diluted) 53% 8% 11% 56% 7% 13% 0.2 M (E-1 after 24 h) 0.2 M 239o 58 108 212 and 11B NMR B 0.04 M (E-7 diluted) 1H NMR Hh' Figure 3.11 cont’d C 0.04 M (E-7 diluted) 0.05 M (E-6 diluted) 0.08 M (E-5 diluted) 0.1 M (E-4 after 24 h) 0.1 M 0.1 M (E-2 diluted) 0.2 M (E-1 after 24 h) 0.2 M a Note for Figure 3.11B: Entry 1: (S)-VAPOL (0.2 mmol) plus 3 equiv commercial B(OPh)3 and 3 equiv H2O were heated at 80 °C in THF for 1 h followed by removal of volatiles under vacuum for 0.5 h. Thereafter, 1.0 equiv of aziridine 114o was added to the pre-catalyst as a solution in d8-toluene (1 mL) for 10 min at 25 °C. Entry 2: Same as entry 1 after 24 h. Entry 3: An additional 1 mL of d8-toluene was added to entry 2 (0.1 M). Entry 4: (S)-VAPOL (0.1 mmol) plus 3 equiv commercial B(OPh)3 and 3 equiv H2O were heated at 80 °C in THF for 1 h followed by removal of volatiles under vacuum for 0.5 h. Thereafter, 1.0 equiv of aziridine 114o was added to the pre-catalyst as a solution in d8-toluene (1 mL) for 10 min at 25 °C. Entry 5: 213 Same as entry 4 after 24 h. Entry 6: An additional 0.25 mL of d8-toluene was added to entry 4 (0.08 M). Entry 7: An additional 0.75 mL of d8-toluene was added to entry 6 (0.05 M). Entry 8: An additional 0.50 mL of d8-toluene was added to entry 7 (0.04 M). The corresponding 11 B NMR spectra also show that there is an increase in the amount of tri- coordinate boron compounds as compared to tetra-coordinated boroxinate upon dilution. Hence these data suggest that these species are in equilibrium. This equilibrium was further confirmed by another experiment where the concentration of aziridine 114o was increased. An increase in AZIRIDINO-BOROX 239o was observed with an increase in aziridine 114o due to the shift in the equilibrium. This is presented in Figure 3.12 1 with the help of H NMR and 11 B NMR spectroscopy. Figure 3.12 (A) Aziridine induced boroxinate formation and its behavior with excess aziridine. (B) a1 H NMR spectra of the reaction mixture in CDCl3 with Ph3CH as internal standard. The numbers given in the spectra shows the NMR yield of respective species. (C) 1 corresponding to the H NMR spectra in Figure 3.12B. 214 11 B NMR spectra Figure 3.12 cont’d A Ph Ph OH OH (S)-VAPOL 58 1. B(OPh)3 (3 equiv) H2O (3 equiv) THF, 80 °C, 1 h 2. 0.1 mm Hg 80 °C, 0.5 h 3. aziridine 114o, CDCl3 25 °C, 10 min [H-aziridine] OPh O B O B O O O B OPh Ph Ph aziridine 114o 1H NMR and 11B NMR analysis AZIRIDINO-BOROX B3 239o B 16% Hh 56% Hh' 0.20 M 01% 57% 14% 0.16 M 03% 50% 13% 08% 0.12 M 46% 16% 18% 0.08 M 22% 25% Hh' 0.04 M 239o 35% 58 108 215 Figure 3.12 cont’d C 0.20 M 0.16 M 0.12 M 0.08 M 0.04 M a Note for Figure 3.12B: Entry 1: (S)-VAPOL (0.4 mmol) plus 3 equiv commercial B(OPh)3 and 3 equiv H2O were heated at 80 °C in THF for 1 h followed by removal of volatiles under vacuum for 0.5 h. Thereafter, 1.0 equiv of aziridine 114o was added to the pre-catalyst as a solution in CDCl3 (10 mL) for 10 min at 25 °C. Further, an aliquot of 1mL of this resulting CDCl3 solution was taken for NMR analysis (0.04 M). Entry 2: An additional 0.36 mmol aziridine 114o was added to the remaining solution (9 mL). Thereafter, an aliquot of 1mL of the resulting CDCl3 solution was taken for NMR analysis (0.08 M). Entry 3: An additional 0.32 216 mmol aziridine 114o was added to the remaining solution (8 mL). Thereafter, an aliquot of 1mL of the resulting CDCl3 solution was taken for NMR analysis (0.12 M). Entry 4: An additional 0.28 mmol aziridine 114o was added to the remaining solution (7 mL). Thereafter, an aliquot of 1mL of the resulting CDCl3 solution was taken for NMR analysis (0.16 M). Entry 5: An additional 0.24 mmol aziridine 114o was added to the remaining solution (6 mL). Thereafter, an aliquot of 1mL of the resulting CDCl3 solution was taken for NMR analysis (0.20 M). The dilution experiments and the increase in concentration experiments provide enough support to conclude that there is an equilibrium operating between these species as the absorptions for the aziridine-catalyst complex increase with increasing concentration as the absorptions for the free ligand and the free aziridine decrease (Figure 3.13A). The reverse is true with decreasing concentration. The 11 B NMR spectrum also reveals an increase in the amount of 3-coordinate borate species as the amount of free ligand and free aziridine increases. The identity of these borate species can’t be determined from these experiments but certainly could include commercial B(OPh)3, B1 106, B2 108 (Scheme 3.2) and triphenoxy boroxine 191a (Scheme 3.3). The data in Figures 3.11 and 3.12 are plotted in Figure 3.13B and 3.13C, respectively. Note that in both experiments the same amount of AZIRIDINO-BOROX 239o is observed at 0.2 M and at 0.04 M. Figure 3.13 (A) Equilibrium between boroxinate 239o, (S)-VAPOL 58, aziridine 114o and various borate species. (B) Plot corresponding to Figure 3.11 (C) Plot corresponding to Figure 3.12 217 Figure 3.13 cont’d A MeO Ph Ph OH OH OMe Ph Ph N + CO2Et 114o + (S)-VAPOL 58 Borate species B [Ha-aziridine] OPh Hb O B O B O O O B Hb OPh AZIRIDINO-BOROX B3 239o C 50   40   40   30   0   30   0.04   0.08   0.12   0.16   0.2   0.2   0.16   0.12   0.08   0.04   Conc (M) 3.2.4 239o 60   50   239o 60   0   Conc (M) Probing path II of the catalytic cycle At this point, it is unclear whether “free” BOROX catalyst 23-H exists or not (path I, Scheme 3.3). Hence, we decided to probe path II of the catalytic cycle. In path II, the real question is whether we can observe the depletion of the aziridine-boroxinate complex in the presence of substrate i.e. imine. As shown in entry 1 of Figure 3.14, AZIRIDINO-BOROX complex 239o is formed in 43% yield. To this mixture was then added one equivalent of imine 111o. The bay region shows the complete replacement of the aziridine-boroxinate complex 239o 218 by imine-boroxinate 190o (Figure 3.14, entry 2). This further support the fact the imine (reactant) has a much higher binding affinity towards the catalyst as compared to the aziridine (product). These boroxinates 239o and 190o can also be easily followed by the methine protons Hazi and Himi of aziridine and imine respectively (Figure 3.14C). The ratio of the 190o:239o was found to be >100:1 for entry 2 based on the integration of the methine protons. The stability of the IMINO-BOROX catalyst 190o was then examined and it was found that it slowly decomposes over a period of three days (Figure 3.14, entry 3). At this juncture, we decided to affect the generation of aziridine by the addition of the ethyl diazoacetate. The interesting part of this experiment is that we were able to observe the co-existence of both the complexes 190o and 239o (Figure 3.14, entry 4). Figure 3.14 (A) Probing Path II of the catalytic cycle (part i). (B) a1 H NMR spectra of the bay and methine region in CDCl3 with Ph3CH as internal standard. (C) The methine region in the 1 1 H NMR spectra of the 239o and 190o corresponding to H NMR spectra in Figure 3.14B A OPh O * O O B B O O B OPh Hazi Ar Ar H N CO2Et imine 111o O * aziridine 114o AZIRIDINO-BOROX B3 239o O OPh O B B O O B OPh Himi Ar Ar N IMINO-BOROX B3 190o 219 H Figure 3.14 cont’d B E-3 + EDA 85 (1.1 equiv) 8% 239o 58 19% 190o 27% 190o 230 58 E-2 (after 3 d) 40% 190o 58 E-1 + imine 111o (1 equiv) 58 43% 239o E-1 (AZIRIDINO-BOROX 239o) C Himi Hazi Himi Himi Hazi PhOH 220 108 a Note for Figure 3.14B: Entry 1: (S)-VAPOL (0.1 mmol) plus 3 equiv commercial B(OPh)3 and 3 equiv H2O were heated at 80 °C in THF for 1 h followed by removal of volatiles under vacuum for 0.5 h. Thereafter, 1.0 equiv of aziridine 114o was added to the pre-catalyst as a solution in CDCl3 (1 mL) for 10 min at 25 °C. Entry 2: 1 equiv of imine 111o was added to entry 1. Entry 3: entry 2 after 3 days. Entry 4: 1.1 equiv EDA 85 was added to entry 3. An experiment was performed by the addition of 0.5 equivalent of imine 111o to the aziridine-catalyst complex 239o in order to observe the co-existence of 190o and 239o in a clean fashion. The results are shown in entry 2 of Figure 3.15. However at this point, it must be remembered that there is still a lot of unreacted VAPOL and some unreacted borate species in the mixture. Hence, after 1 h, the amount of imine-boroxinate increased from 34% to 53% showcasing higher binding affinity of imines (Figure 3.15, entries 2 and 3). Finally, the amount of imine complex 190o started decreasing upon the addition of ethyl diazoacetate, possibly, due to the reaction between the imine 111o and EDA (Figure 3.15, entry 4). Figure 3.15 (A) Probing Path II of the catalytic cycle (part ii). (B) a1 H NMR spectra of the bay and methine region in CDCl3 with Ph3CH as internal standard. (C) The methine region in the 1 1 H NMR spectra of the 239o and 190o corresponding to H NMR spectra in Figure 3.15B A OPh O * O O B B O O B OPh Hazi Ar Ar H N CO2Et OPh imine 111o O * aziridine 114o AZIRIDINO-BOROX B3 239o O O B B O O B OPh Himi Ar Ar N IMINO-BOROX B3 190o 221 H B Figure 3.15 cont’d 49% 190o 27% 239o 230 58 108 E-3 + EDA 85 (0.5 equiv) 53% 190o E-2 (after 1 h) 58 27% 239o 108 34% 190o 58 108 27% 239o E-1 + imine 111o (0.5 equiv) 58 E-1 (AZIRIDINO-BOROX 239o) 43% 239o C Himi Hazi Himi Hazi Hazi Himi Hazi PhOH 222 108 a Note for Figure 3.15B: Entry 1: (S)-VAPOL (0.1 mmol) plus 3 equiv commercial B(OPh)3 and 3 equiv H2O were heated at 80 °C in THF for 1 h followed by removal of volatiles under vacuum for 0.5 h. Thereafter, 1.0 equiv of aziridine 114o was added to the pre-catalyst as a solution in CDCl3 (1 mL) for 10 min at 25 °C. Entry 2: 0.5 equiv of imine 111o was added to entry 1. Entry 3: entry 2 after 1 h. Entry 4: 0.5 equiv EDA 85 was added to entry 3. 3.2.5 Termination of the catalytic cycle of the aziridination reaction When the reaction approaches completion; a mono-alkylated derivative of VAPOL i.e. 5a 230 is often observed (Scheme 3.4 and 3.5). The alkylated VAPOL-derivative 230 has characteristic set of bay proton doublets at δ = 9.55 ppm and δ = 9.83 ppm in CDCl3 (δ = 9.74 ppm and δ = 9.99 ppm in d8-toluene). The various components present in the mixture near the end of the reaction are as follows: AZIRIDINO-BOROX 239, VAPOL 58, aziridine 114, unreacted ethyl diazoacetate 85 and a mixture of boron compounds (Scheme 3.5). There are two possible pathways that might lead to the formation of the VAPOL-derivatve 230. These pathways could also be functioning in tandem. The alkylated ligand 230 is formed from the reaction of the AZIRIDINO-BOROX species 239o with EDA perhaps mediated by an unspecified borate species. The second path Y involves the direct reaction between the free VAPOL ligand and EDA mediated by some borate species. Both pathways were considered and examined and are discussed below. 223 Scheme 3.5 Termination of the catalytic cycle and the aziridination reaction OPh Ar Ar Ar Ar O O B H + + B O N N * O O B CO2Et Pr CO2Et OPh Pr 114o AZIRIDINO-BOROX B3 239o B(OPh)3 and OH + OEt + * other OH N2 unknown boron compounds 58 85 O Reaction mixture towards the end of the reaction Path X Ar OH * + OH O Ar + N Pr 58 or Path Y ? 1140 O * CO2Et End result B(OPh)3 and + other unknown boron compounds OEt OH 230 Path X O OPh Ar borate O Ar Ar Ar species O B O O H + OEt + OEt B O N * N * O OH O B N2 CO2Et Pr CO2Et OPh Pr AZIRIDINO-BOROX B3 239o 85 114o Path Y O OH * OH 58 + O borate species OEt O * N2 85 230 OEt OH 230 To probe path X, boroxinate 239o was first generated from aziridine 114o in 43% yield (Figure 3.16, entry 1). A decrease to 26% was observed when 0.5 equiv of EDA was added to 224 this AZIRIDINO-BOROX 239o solution after 10 min (Figure 3.16, entry 2). This further decreased to 19% upon the addition of a second 0.5 equiv of EDA (Figure 3.16, entry 4). During this experiment, the spectra suggest that the direct alkylation of free VAPOL is faster than the decomposition of boroxinate 239o (Figure 3.16, entries 1-4). In fact, both path X and Y appear to be operating at the same time. It was strongly suspected that there is no decomposition of IMINO-BOROX 190 into alkylated adduct 230 in order to get the turnover. In order to test this, a simple experiment was carried out. Aziridination with imine 111h (R = 4-NMe2-C6H4) was attempted. No aziridine was observed along with no signs of 230. 1 Figure 3.16 Probing path X for the generation of the adduct 230. (A) H NMR spectra of the bay region in CDCl3 with Ph3CH as internal standard. Entry 1: (S)-VAPOL (0.1 mmol) plus 3 equiv commercial B(OPh)3 and 3 equiv H2O were heated at 80 °C in THF for 1 h followed by removal of volatiles under vacuum for 0.5 h. Thereafter, 1.0 equiv of aziridine 114o was added to the pre-catalyst as a solution in CDCl3 (1 mL) for 10 min at 25 °C. Entry 2: 0.5 equiv of EDA 85 was added to entry 1. Entry 3: entry 2 after 30 min. Entry 4: 0.5 equiv EDA 85 was added to entry 3. Entry 5: entry 3 after 90 min. Entry 6: entry 3 after 200 min. Entry 7: entry 1 1 3 after 3 days. (B) H NMR spectra of the methyl and methoxy region corresponding to H NMR spectra in Figure 3.16A. 225 Figure 3.16 cont’d A 230 <1% 239o E-4 (3 days) 230 E-4 (200 min) 05% 239o E-4 (90 min) 12% 239o 230 E-3 + 0.5 equiv EDA 85 (10 min) 19% 239o 58 E-2 (30 min) 22% 239o 58 E-1 + 0.5 equiv EDA 85 (10 min) 26% 239o 58 58 43% 239o E-1 B 230 230 230 239o 239o 230 239o 230 239o 230 239o 239o 226 230 230 230 As of now, it is quite evident that path Y is also operating. So we decided to further examine this pathway in a separate experiment. First of all, it was found that (S)-VAPOL 58 and EDA 85 do not react in absence of boron compounds (Figure 3.17, entry 1). However, both of them react quickly in the presence of commercial B(OPh)3 at room temperature by simple mixing all of them together in CDCl3 to afford 230 in 80% yield within 10 minutes (Figure 3.17, entry 2). It was also found that if a mixture of (S)-VAPOL 58 and commercial B(OPh)3 was heated prior to treating with EDA 85, then the reaction is slow in generating only 18% of 230 in 10 minutes (Figure 3.17, entry 3). An unknown compound 241 with a peak at δ = 9.71 ppm (CDCl3) is also observed in 8% yield. After 24 h, the unknown compound increases up to 20% yield where as 230 decreases to 5% yield (Figure 3.17, entry 4). Treatment of this mixture with one equiv of H2O gave a 92% isolated yield of 230 (Figure 3.17, entry 5). As discussed earlier, an aziridination reaction between imine 111a and 1.2 equiv of EDA 85 is also monitored (Figure 3.17, entry 6). After quenching, a 95% yield of 230 was isolated from the crude reaction 5a mixture. It must be noted that (S)-VAPOL 58 can be easily recovered from 230 using SmI2. Figure 3.17 Probing path Y for the generation of 230. 1 H NMR spectra of the bay region in CDCl3 with Ph3CH as internal standard and the yields of the respective species in the parenthesis. Entry 1: (S)-VAPOL (0.1 mmol) plus 2 equiv EDA 85 at 25 °C for 10 min. Entry 2: (S)-VAPOL (0.1 mmol) plus 3 equiv commercial B(OPh)3 and 2 equiv EDA 85 at 25 °C for 10 min. Entry 3: (S)-VAPOL (0.1 mmol) plus 3 equiv commercial B(OPh)3 were heated at 80 °C in toluene for 1 h followed by removal of volatiles under vacuum for 0.5 h. Thereafter, 2 227 Figure 3.17 cont’d equiv of EDA 85 and CDCl3 (1 mL) was added to the pre-catalyst at 25 °C for 10 min. Entry 4: entry 3 after 24 h. Entry 5: entry 4 plus 1 equiv of H2O. Entry 6: (S)-VAPOL (0.1 mmol) plus 3 equiv commercial B(OPh)3 were heated at 80 °C in toluene for 1 h followed by removal of volatiles under vacuum for 0.5 h. Thereafter, 10 equiv of imine 111a and 12 equiv of EDA 85 1 were added to the pre-catalyst at 25 °C and kept for 95 min (Scheme 3.2). Entry 7: H NMR spectrum of the bay region of the pure 230 in CDCl3. 230 E-7 (isolated pure 230) E-6 (Pre-catalyst + imine 111a + EDA 85 (1:10:12)) 58 230 (95%, isolated) 230 (92%, isolated) E-5 (E-4 + 1 equiv H2O) 108 (51%) 241 (20%) 230 (05%) E-3 (after 24 h) 108 (55%) E-3 (Pre-catalyst + EDA) 241 (08%) 230 (18%) 230 (80%) E-2 (VAPOL + EDA + B(OPh)3) 58 (98%) E-1 (VAPOL + EDA) 228 3.2.6 Possibility of ‘free’ BOROX complex 23-H Path I of the catalytic cycle involves the possibility of free BOROX 23-H (Scheme 3.3). Hence, we were interested in finding the support for the existence of the free BOROX catalyst 23-H. So far, there is no evidence for the existence of such kind of species either by NMR or Xray crystallography. The help of computational chemistry was then sought. To begin, the energy minimized structure of the boroxinate anion 23 was computed by DFT calculations using 6 Gaussian ʹ′03 at B3LYP/6-31g* level of theory and the result is shown in Figure 3.18A. A free proton was then placed on either of the two oxygens O1 and O2 as they were found to posses the maximum electron densities. Interestingly, in both cases, the spiro-borate ring was no longer favorable and the tetra-coordinate boron transformed itself into a tri-coordinate boron (Figure 3.18B and 3.18C). This suggests that protonated form of 23 might not exist or they might have very short lifetimes. In both the cases, the distance (B-O1 or B-O2) between the O1/O2 and former tetra-coordinate boron was found to more than 2.5 Å (Figure 3.18B and 3.18C). Additionally, the former tetra-coordinate boron is found to be out of the plane by ~ <1–2.6º (Figure 3.18B and 3.18C). Out of both the structures 23-Ha is found to be more stable than 23Hb by +8.6 kcal/mol. In the case of the boroxinate anion, the ∠oop and B-O2 was found to be 20.2º and 1.43 Å respectively (Figure 3.18A). Figure 3.18 All calculations are performed using Gaussian ʹ′03 at B3LYP/6-31g* level of theory. All structures are visualized by the Mercury program (C, gray; O, red; B, yellow; H, light blue). Hydrogens are omitted for clarity (except O-H). ∠oop = angle out of plane for the current/former tetra-coordinate boron, B-O2 = the distance between O-2 and the former tetra- 229 Figure 3.18 cont’d coordinate boron. B-O1 = the distance between O-1 and the current/former tetra-coordinate boron. (A) Calculated structure of BOROX anion 23 (B) Calculated structure of the neutral BOROX catalyst 23-Ha resulting from protonation of 23 on O1. (C) Calculated structure of the neutral BOROX catalyst 23-Hb resulting from protonation of 23 on O2. A O2 O1 B 23 (∠oop = 20.2º, B-O1 = 1.50 Å, B-O2 = 1.43 Å) B C O2 B B O1 23-Hb (∠oop = 2.6º, B-O2 = 2.57 Å) (ΔΔG = +8.6 Kcal/mol) 23-Ha (∠oop < 1º, B-O1 = 3.43 Å) (ΔΔG = 0 Kcal/mol) 230 It was then undertaken to prepare the boroxinate anion in vitro followed by its protonation in order to observe 23-H. Hence, the boroxinate anion core was prepared utilizing 5e tetra-methyl ammonium acetate as the base to generate BOROX 242. Several equivalents of TfOH were added to 242 (Figure 3.19B). Two new pair of doublets were observed at δ = 10.40 ppm and δ = 10.46 ppm in CDCl3 (Figure 3.19B, entries 3 and 4). However, a free BOROX catalyst 23-H would be expected to give a single doublet for a spiro structure due to the fast exchange of the free proton. Species 23a-H and 23b-H would be expected to exist as two 1 doublets. Protonation of 242 does result in significant changes in the bay region of H NMR spectrum but the structure of this protonated species is still uncertain. The next chapter has been devoted to address this issue. Figure 3.19 (A) Design of the experiment to observe the free neutral BOROX 23-H. (B) NMR spectra of the bay region in CDCl3. (C) 11 a 1 H 1 B NMR spectra corresponding to the H NMR spectra in Figure 3.19B A 1. B(OPh)3 (3 equiv) H2O (3 equiv) THF, 80 °C, 1 h Ph Ph OH Ph Ph OH 2. 0.1 mm Hg 80 °C, 0.5 h 3. Me4NOAc (1equiv) CDCl3 (S)-VAPOL 58 25 °C, 10 min [NMe4] OPh TfOH Ph O O B B O Ph O O B OPh BOROX B3 242 231 [H] OPh O B O B O O O B OPh free BOROX 23-H B Figure 3.19 cont’d 242 + TfOH (1:4, 10 min) 242 + TfOH (1:2, 10 min) 242 + TfOH (1:1, 10 min) 242 + TfOH (1:1, 5 min) 242 C 232 a Note for Figure 3.19B: Entry 1: (S)-VAPOL (0.1 mmol) plus 3 equiv commercial B(OPh)3 and 3 equiv H2O were heated at 80 °C in toluene for 1 h followed by removal of volatiles under vacuum for 0.5 h. Thereafter, 1 equiv of Me4NOAc and CDCl3 (1 mL) was added to the precatalyst at 25 °C for 10 min. Entry 2: 1 equiv of TfOH was added to entry 1 at 25 °C for 5 min. Entry 3: 1 equiv of TfOH was added to entry 1 at 25 °C for 10 min. Entry 4: 2 equiv of TfOH was added to entry 1 at 25 °C for 5 min. Entry 5: 4 equiv of TfOH was added to entry 1 at 25 °C for 5 min. 3.3 Conclusions In this chapter, we have been able to characterize species in which a substrate is bound to the catalyst (S-BA) and in which a product is bound to the catalyst (P-BA) utilizing NMR spectroscopy. Also, their equilibrium was studied. Finally, it was possible to qualitatively and quantitatively analyze the process of depletion of the P-BA in presence of the substrate. The binding affinity of the substrate (imine) was found to be very high compared to that of the product (aziridine). All the above-mentioned observations have been achieved for the first time in case of a Brønsted acid catalyzed aziridination reaction. Given the results from the present work, it should be possible to study the relative binding of various imines and of various aziridines as well as the relative binding between imines and aziridines and to probe the dynamics of their interchange. 233 APPENDIX 234 3.4 Experimental 3.4.1   General Information ........................................................................................................ 236   3.4.2   Synthesis of Imines 111a, 111o, 111v, 111w and 114oʹ′ and triphenoxyboroxine 191a 236   3.4.3   Synthesis of aziridines 114a, 114o, 114v, 114w and 115oʹ′ ........................................... 238   3.4.4   NMR analysis of a mixture of VAPOL, B(OPh)3 and imines 111a, 111o and 114oʹ′ with and without water (pre-catalyst methods A and B, Figure 3.2).................................................. 241   3.4.5   Monitoring the AZ reaction with imine 111a by NMR spectroscopy (Table 3.1) ......... 244   3.4.6   NMR analysis of a mixture of VAPOL, B(OPh)3 and aziridines 114a, 114o, 114v, 114w and 115oʹ′ (pre-catalyst method B, Figure 3.5 and 3.10 )........................................................... 245   3.4.7   NMR analysis of a mixture of VAPOL, boron sources & aziridine 114o (Table 3.2 ) .. 247   3.4.8   NMR analysis of a mixture of VAPOL, B(OPh)3 and a base (111a, 111o, 114a and 114o) by simple mixing at room temperature (Figure 3.9)................................................................... 248   3.4.9   Temperature studies of 239a & 239o and recovery of 114o (Figure 3.4, 3.7, 3.8) ..... 249   3.4.10  Equilibrium studies of 239o, 58 and boron compounds (Figure 3.11 and 3.12) ............. 251   3.4.11  Probing the path II of the catalytic cycle (Figure 3.14 and 3.15) .................................... 253   3.4.12  Termination of the catalytic cycle i.e. Path X and path Y (Figure 3.16 and 3.17) .......... 254   3.4.13  NMR analysis of the addition of TfOH to boroxinate 242 (Figure 3.19)........................ 258   3.4.14  DFT calculations (Figure 3.6) ......................................................................................... 259 235 3.4.1 General Information Same as Chapter 2. 3.4.2 Synthesis of Imines 111a, 111o, 111v, 111w and 114oʹ′ and triphenoxyboroxine 191a See Chapter 2 for the synthesis for the imine 111a and triphenoxyboroxine 191a. Imine 114oʹ′ was prepared according to published procedure. 5b All aldehydes were distilled prior to use. OMe N-Cyclohexylmethylidene-bis(3,5-dimethyl-4-methoxyphenyl )methylamine 111v: Imine 111v was prepared according to the procedure described in Chapter 2 for imine 111a. Crystallization (1: 60 EtOAc/hexanes) and collection of the first crop afforded N OMe 111v as white solid crystals (mp 108-109 ºC) in 71% isolated yield (1.40 g, 3.55 mmol). 111v 1 Spectral data for 111v: H NMR (CDCl3, 300 MHz) δ 1.17-1.34 (m, 5H), 1.64-1.84 (m, 5H), 2.19-2.35 (m, 1H), 2.23 (s, 12H), 3.67 (s, 6H), 5.05 (s, 1H), 6.91 (s, 4H), 7.59 (d, 1H, J = 5.1 Hz); 13 C NMR (CDCl3, 75 MHz) δ 16.19, 25.42, 26.01, 29.79, 43.51, 59.59, 77.44, 127.74, -1 130.49, 139.39, 155.69, 168.59; IR (thin film): 2926s, 1665m, 1483s 1221s, 1142m, 1017s cm ; Mass spectrum m/z (% rel intensity) 393 M+ (0.22), 283 (100), 268 (15), 163 (54), 142 (24), 134 5c (15), 77 (11), 44 (10). These spectral data match those previously reported for this compound. 236 N-(1,1′-dimethylethylidene)-bis(4-methoxy-3,5-dimethyl OMe phenyl)methylamine 111w: Imine 111w was prepared according to the procedure described above for imine 111a. Crystallization (1: 100 CH2Cl2/hexanes) and collection of the first crop afforded N 111w as white solid crystals (mp 90-91 ºC) in 85% isolated yield OMe (1.56 g, 4.25 mmol). 111w 1 Spectral data for 111w: H NMR (CDCl3, 300 MHz) δ 1.09 (s, 9H), 2.23 (s, 12H), 3.68 (s, 6H), 5.08 (s, 1H), 6.91 (s, 4H), 7.61 (s, 1H); 13 C NMR (CDCl3, 75 MHz) δ 16.22, 27.04, 36.33, 59.59, 76.75, 127.71, 130.41, 139.63, 155.62, 171.11; IR (thin film): 2955vs, 1663m, 1483s, -1 1221s, 1017s cm ; Mass spectrum m/z (% rel intensity) 367 M+(0.8), 283 (100), 268 (22), 253 (12), 210 (11), 195 (14), 178 (8), 141 (34), 133 (11), 118 (19), 41 (10). These spectral data 5c match those previously reported for this compound. OMe MeO O 4Å MS + OMe H2N 127o Toluene 25 °C, 3 h N OMe 111o 126c (E)-N-butylidene-1,1-bis(4-methoxy-3,5-dimethylphenyl)methanamine 111o: To a 50 mL flame-dried round bottom flask filled with argon was added bis(2,6-di-methyl-4methoxyphenyl)methylamine 126c (1.49 g, 5.00 mmol), 4 Å Molecular Sieves (1.2 g, freshly dried) and dry toluene (5 mL). After stirring for 10 min, n-butanal 127o (473 µL, 5.25 mmol, 1.05 equiv, freshly distilled) was added. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was filtered through Celite and the Celite bed was washed with 237 CH2Cl2 (10 mL × 3) and then the filtrate was concentrated by rotary evaporation to give the crude imine as an off-white solid. Crystallization (hexanes) and collection of the first crop afforded 111o as white solid crystals (mp 102-103 ºC) in 80 % isolated yield (1.4 g, 4.0 mmol). 1 Spectral data for 111o: H NMR (CDCl3, 500 MHz) δ 0.94 (t, 3H, J = 7.3 Hz), 1.58 (sextet, 2H, J = 7.3 Hz), 2.23 (s, 12H), 2.28-2.32 (m, 2H), 3.67 (s, 6H), 5.09 (s, 1H), 6.92 (s, 4H), 7.75 (t, 1H, J = 4.9 Hz); 13 C NMR (125 MHz, CDCl3) δ 13.81, 16.17, 19.50, 37.84, 59.59, 77.71, 127.75, 130.55, 139.24, 155.73, 164.88; HRMS (ESI-TOF) m/z 354.2433 [(M+H+); calcd. for C23H32NO2 : 354.2433]. These spectral data match those previously reported for this 5c compound. 3.4.3 Synthesis of aziridines 114a, 114o, 114v, 114w and 115oʹ′ All aziridines but 115oʹ′ have been prepared using procedure IV (pre-catalyst method C) of Table 2.1 in Chapter 2. The representative procedures for two aziridines 114a and 114o are given here and the details for the aziridines 114v and 114w can be found in reference 5c. Aziridine 115oʹ′ have been prepared using procedure I (pre-catalyst method A) and is already reported. 238 5b Synthesis of aziridine 114a using imine 111a: IMINO-BOROX catalyst 190a (5 mol %) O MEDAM Ph N + 111a OEt N2 toluene 25 °C, 24 h MEDAM MEDAM N + Ph CO2Et 85 114a B(OPh)3 (4 equiv) H2O (1 equiv) pre(S)-VAPOL catalyst (5 mol%) toluene, 80 °C, 1 h (Method C) then 05 mm Hg 80 °C, 0.5 h Imine 111a NH CO2Et (Ph)H Ph(H) 118a(119a) OPh MEDAM O B O – N+ B O * H O O B OPh Ph IMINO-BOROX catalyst 190a (2R,3R)-ethyl-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-phenylaziridine-2carboxylate 114a: Imine 111a (387 mg, 1 mmol) was reacted according to the general procedure IV (pre-catalyst method C) described above (Chapter 2) with (S)-VAPOL (5 mol%) as the ligand. Purification of the crude aziridine by silica gel chromatography (30 mm × 300 mm column, 9:1 hexanes/EtOAc as eluent, gravity column) afforded pure cis-aziridine 114a as a white solid (mp 107-108 ºC on 99.8% ee material) in 98 % isolated yield (464 mg, 0.980 mmol); cis/trans: >50:1. Enamine side products: 1 % yield of 118a and 1 % yield of 119a. The optical purity of 114a was determined to be 99.8 % ee by HPLC analysis (CHIRALCEL OD-H column, 99:1 hexane/2-propanol at 226nm, flow-rate: 0.7 mL/min): retention times; Rt = 9.26 min (major enantiomer, 114a) and Rt = 12.52 min (minor enantiomer, ent-114a). 1 Spectral data for 114a: Rf = 0.42 (1:9 EtOAc/hexane); H NMR (CDCl3, 500 MHz) δ 0.98 (t, 3H, J = 7.1 Hz), 2.18 (s, 6H), 2.24 (s, 6H), 2.55 (d, 1H, J = 6.8 Hz), 3.10 (d, 1H, J = 6.6 Hz), 3.62 (s, 3H), 3.66 (s, 1H), 3.68 (s, 3H) 3.87-3.97 (m, 2H), 7.09 (s, 2H), 7.18 (s, 2H), 7.21-7.24 239 (m, 3H), 7.36 (d, 2H, J = 7.3 Hz); 13 C (CDCl3, 125 MHz) δ 14.01, 16.16, 16.22, 46.26, 48.20, 59.52, 59.58, 60.47, 77.04, 127.21, 127.41, 127.70, 127.80,127.85, 130.59, 130.60, 135.33, -1 137.79, 137.96, 155.95, 156.10, 168.01; IR (thin film) 2961 vs, 1750 vs, 1414 vs, 1202 vs cm ; Mass spectrum: m/z (% rel intensity) 473 M+ (0.27), 284(78), 283 (100), 268 (34), 253 (20), 237 (11), 210(10), 117 (18), 89 (11); Anal calcd for C30H35NO4: C, 76.08; H, 7.45; N, 2.96. Found: C, 76.31; H, 7.28; N, 2.82; [α ]23 +41.3 (c 1.0, EtOAc) on 99% ee material (HPLC). These D spectral data match those previously reported for this compound. 5c Synthesis of aziridine 114o using imine 111o: IMINO-BOROX catalyst 190o (10 mol %) O MEDAM nPr N + 111o OEt N2 toluene 25 °C, 24 h 85 N + nPr CO2Et 114o B(OPh)3 (4 equiv) H2O (1 equiv) pre(S)-VAPOL catalyst (10 mol%) toluene, 80 °C, 1 h (Method C) then 05 mm Hg 80 °C, 0.5 h MEDAM MEDAM Imine 111o NH CO2Et (nPr)H nPr(H) 118o(119o) OPh MEDAM O B O – N+ B O * H O O B OPh nPr IMINO-BOROX catalyst 190o (2R,3R)-ethyl-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-phenylaziridine-2carboxylate 114o: Imine 111o (353 mg, 1 mmol) was reacted according to the general procedure IV (pre-catalyst method C) described above (Chapter 2) with (S)-VAPOL (10 mol%) as the ligand. Purification of the crude aziridine by silica gel chromatography (20 mm × 250 mm 240 column, 4:2:0.1 hexanes/CH2Cl2/EtOAc, gravity column) afforded pure cis-aziridine 114o as a yellow oil in 64 % isolated yield (281 mg, 0.640 mmol); cis/trans: not determined. Enamine side products: not observed. The optical purity of 114o was determined to be 93% ee by HPLC analysis (CHIRALCEL OD-H column, 99:1 hexane/2-propanol at 226 nm, flow-rate: 0.7 mL/min): retention times; Rt = 4.73 min (major enantiomer, 114o) and Rt = 5.68 min (minor enantiomer, ent-114o). Spectral data for 114o: Rf = 0.28 (4:2:0.1 hexanes/CH2Cl2/EtOAc); 1H NMR (CDCl3, 500 MHz) δ 0.72 (t, 3H, J = 7.6 Hz), 0.98-1.08 (m, 1H), 1.11-1.20 (m, 1H), 1.23 (t, 3H, J = 7.1 Hz), 1.381.45 (m, 1H), 1.49-1.55 (m, 1H), 1.95 (q, 1H, J = 6.6 Hz), 2.18 (d, 1H, J = 6.8 Hz) 2.22 (s, 12H), 3.39 (s, 1H), 3.65 (s, 3H), 3.67 (s, 3H), 4.12-4.23 (m, 2H), 6.99 (s, 2H), 7.07 (s, 2H); 13 C NMR (CDCl3, 125 MHz) δ 13.57, 14.33, 16.09, 16.16, 20.33 29.93, 43.53, 46.76, 59.56, 59.60, 60.64, 77.32, 127.41, 128.07, 130.44, 130.47, 137.75, 138.18, 155.81, 156.12, 169.69; IR (thin film) -1 + 2957vs, 1744s, 1483s, 1221s, 1182vs cm ; HRMS (ESI-TOF) m/z 440.2817 [(M+H ); calcd. for C27H38NO4 : 440.2801]; [α ]23 +95.3 (c 1.0, EtOAc) on 97 % ee material (HPLC). These D spectral data match those previously reported for this compound. 5c 3.4.4 NMR analysis of a mixture of VAPOL, commercial B(OPh)3 and imines 111a, 111o and 114oʹ′ with and without water (pre-catalyst methods A and B, Figure 3.2) 241 As shown in Figure 3.2 of this chapter, a mixture of (S)-VAPOL 58 and commercial B(OPh)3 187a gives different yields of unreacted VAPOL 58, mesoborate B1 106 and pyroborate B2 108 employing different reaction conditions (pre-catalyst methods A and B). 1 Also, it was evident from the H NMR and 11 B NMR that no boroxinate B3 190a was formed unless imine 111a was added irrespective of the methods used. The characteristic peaks i.e. δ 1 10.2-10.4 and δ 5.5-5.7 were missing in H NMR and 11 B NMR respectively. The same observation was made when alkyl imines 111o and 114oʹ′ were used. Unless otherwise noted, commercial B(OPh)3 is used in all the experiments. Also, Ph3CH is used as the internal standard. Experimental: P R N (1 equiv) * OH OH 58 B(OPh)3 Method A-B CDCl3 25 °C, 10 min 0.1 M + [imine-H] OPh OPh OH O –O B O O + * + * B B O B B OPh + * O * OH O O B O O OPh OPh B3 B2 B1 58 (unreacted) 108 106 190a (imine = 111a, R = Ph and P = MEDAM) B3 = 190o (imine = 111o, R = Pr and P = MEDAM) 213o' (imine = 112o', R = Et and P = BUDAM) Entry 1, Figure 3.2: The pre-catalyst was made using method A (see Chapter 2) employing (S)VAPOL (54 mg, 0.1 mmol) and commercial B(OPh)3 (87 mg, 0.3 mmol). To the flask containing the pre-catalyst was first added the Ph3CH (12.22 mg, 0.05 mmol) and then CDCl3 (1 242 mL) under an argon flow through side-arm of the Schlenk flask. The reaction mixture was then stirred for 10 min. The off-white colored solution was then directly transferred to a quartz NMR 1 tube and was subjected to H NMR and 11 B NMR analysis. Entry 2, Figure 3.2: The pre-catalyst was made using method A (see Chapter 2) employing (S)-VAPOL (54 mg, 0.1 mmol) and commercial B(OPh)3 (87 mg, 0.3 mmol). To the flask containing the precatalyst was first added the imine 111a (39 mg, 0.1 mmol), Ph3CH (12.22 mg, 0.05 mmol) and then CDCl3 (1 mL) under an argon flow through side-arm of the Schlenk flask. The reaction mixture was then stirred for 10 min. The red colored solution was then directly transferred to a 1 quartz NMR tube and was subjected to H NMR and 11 B NMR analysis. Entry 3, Figure 3.2: Same as entry 1 except that the pre-catalyst was made using method B (see Chapter 2) employing (S)-VAPOL (54 mg, 0.1 mmol), commercial B(OPh)3 (87 mg, 0.3 mmol) and H2O (5.4 µL, 0.3 mmol). Entry 4, Figure 3.2: Same as entry 2 except that the pre-catalyst was made using method B (see Chapter 2) employing (S)-VAPOL (54 mg, 0.1 mmol), commercial B(OPh)3 (87 mg, 0.3 mmol) and H2O (5.4 µL, 0.3 mmol). Entry 5, Figure 3.2: Same as entry 4 except that imine 111o (1 equiv) was used. Entry 6, Figure 3.2: Same as entry 4 except that imine 114oʹ′ (1 equiv) was used. 243 3.4.5 Monitoring the aziridination reaction with imine 111a by NMR spectroscopy (Table 3.1) Procedure (i) OH 1. Toluene, 80 °C, 1 h 2. 80 °C, 0.5 h 0.1 mmHg B(OPh)3 * (0.3 mmol) 3. imine 111a OH (0.2 or 1 mmol) (S)-VAPOL 58 4. CDCl3, stir, 10 min (0.1 mmol) 5. EDA 85 (0.24 or 1.2 mmol) + O MEDAM N Ph + * CO2Et 114a O OEt 1H NMR Analysis OH 230 The pre-catalyst was made using method A (see Chapter 2) employing (S)-VAPOL (54 mg, 0.1 mmol) and commercial B(OPh)3 (87 mg, 0.3 mmol). To the flask containing the pre-catalyst was first added the imine 111a (78 mg, 0.2 mmol), Ph3CH (12.22 mg, 0.05 mmol) and then CDCl3 (1 mL) under an argon flow through side-arm of the Schlenk flask. The reaction mixture was then stirred for 10 min. The red colored solution was then directly transferred to a quartz 1 NMR tube and was subjected to H NMR and 11 B NMR analysis. After initial analysis, EDA 85 (25 µL, 0.24 mmol) was added to the NMR tube and the NMR tube was shaken for 1 min. Thereafter the NMR was taken at regular intervals. The reaction with 1.0 mmol was followed in the similar way. All details are given in Table 3.1 of the Chapter. Procedure (ii) O MEDAM 1. imine 111a O 1 (0.2 mmol) OH OEt H NMR N + * + Boroxine * Analysis (0.1 mmol) 2. CDCl3, stir, 10 min OH OH Ph CO2Et 3. EDA 85 (0.24 mmol) (S)-VAPOL 58 230 114a (0.1 mmol) 244 Same as procedure (i) except that the pre-catalyst was made using method D (see Chapter 2) employing (S)-VAPOL (54 mg, 0.1 mmol) and triphenoxyboroxine 191a (360 mg, 0.1 mmol). All details are given in Table 3.1 of the Chapter. Procedure (iii) OH B(OPh)3 * (0.3 mmol) 2. CDCl3, stir, 10 min OH 3. EDA 85 (1.2 mmol) (S)-VAPOL 58 (0.1 mmol) + O MEDAM 1. imine 111a (1 mmol) N Ph + * CO2Et 114a O OEt 1H NMR Analysis OH 230 To a 10 mL flame-dried round bottom flask, equipped with a stir bar, filled with argon was added (S)-VAPOL 58 (54 mg, 0.1 mmol, 1 equiv.), commercial B(OPh)3 (87 mg, 0.3 mmol, 3 equiv.), imine 111a (387 mg, 1.00 mmol, 10 equiv.), Ph3CH (12.22 mg, 0.05 mmol) and CDCl3(1 mL). The resultant mixture was stirred for 10 min at room temperature. The red 1 colored solution was then directly transferred to a quartz NMR tube and was subjected to H NMR and 11 B NMR analysis. After initial analysis, EDA 85 (124 µL, 1.2 mmol) was added to the NMR tube and the NMR tube was shaken for 1 min. Thereafter the NMR was taken at regular intervals. All details are given in Table 3.1 of the Chapter. 3.4.6 NMR analysis of a mixture of VAPOL, commercial B(OPh)3 and aziridines 114a, 114o, 114v, 114w and 115oʹ′ (pre-catalyst method B, Figure 3.5 and 3.10 ) 245 * OH OH (S)-VAPOL 58 (0.1 mmol) B(OPh)3 (3 equiv) H2O (3 equiv) THF, 80 °C, 1 h then 80 °C, 0.5 0.1 mmHg pre-catalyst (method B) P N + [aziridine-H] OPh R CO2Et OPh O B OH (1 equiv) O – O O pre+ * + * B B O B B OPh + * O * catalyst OH CDCl3 O O B O O OPh 25 °C, 10 min OPh 0.1 M B3 B2 B1 58 (unreacted) 108 106 239a (aziridine = 114a, R = Ph and P = MEDAM) 239o (aziridine = 114o, R = Pr and P = MEDAM) B3 = 239v (aziridine = 114v, R = Cy and P = MEDAM) 239w (aziridine = 114w, R = tBu and P = MEDAM) 240o' (aziridine = 115o', R = Et and P = BUDAM) The pre-catalyst was made using method B (see Chapter 2) employing (S)-VAPOL (54 mg, 0.1 mmol), commercial B(OPh)3 (87 mg, 0.3 mmol) and H2O (5.4 µL, 0.3 mmol). To the flask containing the pre-catalyst was first added the Ph3CH (12.22 mg, 0.05 mmol) and then the aziridine 114o (44 mg, 0.1 mmol) as a solution in CDCl3 (1 mL) under an argon flow through side-arm of the Schlenk flask. The reaction mixture was then stirred for 10 min. The yellow 1 colored solution was then directly transferred to a quartz NMR tube and was subjected to H NMR and 11 B NMR analysis. A similar analysis was performed in d8-toluene. Other aziridines (114a, 114v, 114w and 115oʹ′) were also examined following the same procedure. 246 3.4.7 NMR analysis of a mixture of VAPOL, different boron sources and aziridine 114o (pre-catalyst methods C, D and E, Table 3.2 ) * OH Boron source OH Method C-E pre-catalyst (S)-VAPOL 58 (0.1 mmol) MEDAM N + [aziridine-H] OPh nPr CO2Et OPh O B OH (1 equiv) O – O O pre+ * + * B B O B B OPh + * O * catalyst OH CDCl3 O O B O O OPh 25 °C, 10 min OPh 0.1 M B3 B2 B1 58 (unreacted) 108 106 239o Entry 4, Table 3.2 (method C): The pre-catalyst was made using method C (see Chapter 2) employing (S)-VAPOL (54 mg, 0.1 mmol), commercial B(OPh)3 (116 mg, 0.4 mmol) and H2O (1.8 µL, 0.1 mmol). To the flask containing the pre-catalyst was first added the Ph3CH (12.22 mg, 0.05 mmol) and then the aziridine 114o (44 mg, 0.1 mmol) as a solution in CDCl3 (1 mL) under an argon flow through side-arm of the Schlenk flask. The reaction mixture was then stirred for 10 min. The yellow colored solution was then directly transferred to a quartz NMR 1 tube and was subjected to H NMR and 11 B NMR analysis. All details are given in Table 3.2 of the Chapter. 247 Entry 5, Table 3.2 (method D): Same as entry 4 except that the pre-catalyst was made using method D (see Chapter 2) employing (S)-VAPOL (54 mg, 0.1 mmol), and triphenoxyboroxine 191a (360 mg, 0.1 mmol). All details are given in Table 3.2 of the Chapter. Entry 6, Table 3.2 (method E): Same as entry 4 except that the pre-catalyst was made using method E (see Chapter 2) employing (S)-VAPOL (54 mg, 0.1 mmol) and BH3•Me2S (150 µL, 0.3 mmol, 2.0 M in toluene), PhOH (18.8, 0.2 mmol) and H2O (5.4 µL, 0.3 mmol). All details are given in Table 3.2 of the Chapter. 3.4.8 NMR analysis of a mixture of VAPOL, commercial B(OPh)3 and a base (111a, 111o, 114a and 114o) by simple mixing at room temperature (Figure 3.9) Base (2 equiv) * OH OH 58 R B(OPh)3 (3 equiv) CDCl3 25 °C, 10 min 0.1 M N imine P + [Base-H] OPh OPh OH O –O B O O + * + * B B O B B OPh + * O * OH O O B O O OPh OPh B3 B2 B1 58 (unreacted) 108 106 P N R CO2Et aziridine 190a (imine = 111a, R = Ph and P = MEDAM) B3 = 190o (imine = 111o, R = Pr and P = MEDAM) 239a (aziridine = 114a, R = Ph and P = MEDAM) 239o (aziridine = 114o, R = Pr and P = MEDAM) Entry 1, Figure 3.9: To a 10 mL flame-dried round bottom flask, equipped with a stir bar, filled with argon was added (S)-VAPOL 58 (54 mg, 0.1 mmol, 1 equiv.), commercial B(OPh)3 (87 mg, 248 0.3 mmol, 3 equiv.), Ph3CH (12.22 mg, 0.05 mmol) and CDCl3(1 mL). The resultant mixture was stirred for 10 min at room temperature. The off-white colored solution was then directly 1 transferred to a quartz NMR tube and was subjected to H NMR and 11 B NMR analysis. Entry 2, Figure 3.9: To a 10 mL flame-dried round bottom flask, equipped with a stir bar, filled with argon was added (S)-VAPOL 58 (54 mg, 0.1 mmol, 1 equiv.), commercial B(OPh)3 (87 mg, 0.3 mmol, 3 equiv.), imine 111a (78 mg, 0.2 mmol, 2 equiv.), Ph3CH (12.22 mg, 0.05 mmol) and CDCl3(1 mL). The resultant mixture was stirred for 10 min at room temperature. The red 1 colored solution was then directly transferred to a quartz NMR tube and was subjected to H NMR and 11 B NMR analysis. Entry 3, Figure 3.9: Same as entry 2 with the imine 111o (2 equiv). Entry 4, Figure 3.9: Same as entry 2 with the aziridine 111a (2 equiv). Entry 5, Figure 3.9: Same as entry 2 with the aziridine 111o (2 equiv). In this case, aziridine 114o was added as solution in CDCl3 (1mL). 3.4.9 Temperature studies of AZIRIDINO-BOROX 239a and 239o and the recovery of the aziridine 114o via hydrolysis of 239o (Figure 3.4, 3.7 and 3.8) Temperature Studies: B(OPh)3 (3 equiv) * OH H2O (3 equiv) OH THF, 80 °C, 1 h then 80 °C, 0.5 0.1 mmHg (S)-VAPOL 58 (0.1 mmol) 249 pre-catalyst (method B) MEDAM N + [aziridine-H] OPh nPr CO2Et OPh O B OH (1 equiv) O – O O pre+ * + * B B O B B OPh + * O * catalyst OH d8-toluene O O B O O OPh 25 °C, 10 min OPh 0.1 M B3 B2 B1 58 (unreacted) 108 106 239o The pre-catalyst was made using method B (see Chapter 2) employing (S)-VAPOL (54 mg, 0.1 mmol), commercial B(OPh)3 (87 mg, 0.3 mmol) and H2O (5.4 µL, 0.3 mmol). To the flask containing the pre-catalyst was first added the Ph3CH (12.22 mg, 0.05 mmol) and then the aziridine 114o (44 mg, 0.1 mmol) as a solution in d8-toluene (1 mL) under an argon flow through side-arm of the Schlenk flask. The reaction mixture was then stirred for 10 min. The yellow colored solution was then directly transferred to a quartz NMR tube and was subjected to 1 H NMR and 11 B NMR analysis at various temperatures. A similar analysis was performed for boroxinate 239a. Recovery of aziridine 114o via hydrolysis of 239o: + [aziridine-H] OPh O –O B B O * O O B OPh 239o H2O (1-10 equiv) 25 °C, 10 min * OH OH 58 B3 250 + MEDAM N nPr CO2Et 114o + unknown boron compounds Entry 1, Figure 3.8: The boroxinate is formed in 43% yield in CDCl3 using the protocol shown in section 3.4.6. Entry 2-4, Figure 3.8: 1, 2 and 4 equiv of the H2O is added to the NMR tube (entry 1) for entries 2, 3 and 3 respectively. Entry 5, Figure 3.8: 10 equiv of the H2O is added to the NMR tube and then the aziridine 114o was recovered in 85% yield by silica gel chromatography. 3.4.10 Equilibrium studies of 239o, (S)-VAPOL 58 and boron compounds (Figure 3.11 and 3.12) A) via dilution of 239o: B(OPh)3 (3 equiv) * OH H2O (3 equiv) OH THF, 80 °C, 1 h then 80 °C, 0.5 0.1 mmHg (S)-VAPOL 58 (0.1 mmol) MEDAM N precatalyst nPr CO2Et (1 equiv) d8-toluene 25 °C, 10 min 0.1 M + [aziridine-H] OPh O –O B B O * O O B OPh B3 239o 251 dilution pre-catalyst (method B) 1H NMR and 11B NMR analysis Entry 1, Figure 3.11: The boroxinate is formed in 56% yield in d8-toluene using the protocol shown in section 3.4.6. The concentration of the solution is 0.2 M as 0.2 mmol of (S)-VAPOL 58 was used in 1 mL of d8-toluene. Entry 2, Figure 3.11: entry 1 after 24 h. Entry 3, Figure 3.11: An additional 1 mL of d8-toluene was added to entry 2 and the NMR was taken. The concentration is 0.1 M. Entry 4, Figure 3.11: The boroxinate is formed in 47% yield in d8-toluene using the protocol shown in section 3.4.6. Entry 5, Figure 3.11: entry 4 after 24 h. Entry 6-8, Figure 3.11: An additional 0.25 mL, 0.75 mL and 0.5 mL of d8-toluene was added to entry 5, 6 and 7 respectively and then the NMR was taken. The concentration of the solution (with respect to the ligand 58) is 0.08 M, 0.05 M and 0.04 M for entries 6,7 and 8 respectively. B) via increase in the concentration of aziridine 114o: B(OPh)3 (3 equiv) * OH H2O (3 equiv) OH THF, 80 °C, 1 h then 80 °C, 0.5 0.1 mmHg (S)-VAPOL 58 (0.1 mmol) 252 pre-catalyst (method B) MEDAM N precatalyst nPr CO2Et (1 equiv) CDCl3 25 °C, 10 min 0.1 M + [aziridine-H] OPh O B O – B O * O O B OPh B3 aziridine 114o 1H NMR and 11B NMR analysis 239o Entry 1, Figure 3.12: The boroxinate is formed in 35% yield in CDCl3 using the protocol shown in section 3.4.6. The concentration of the solution is 0.4 M as 0.4 mmol of (S)-VAPOL 58 was used in 10 mL of CDCl3. An aliquot of 1mL of this solution was withdrawn for NMR analysis. Entry 2-5, Figure 3.12: An additional 0.36 mmol, 0.32 mmol, 0.28 mmol and 0.24 mmol of aziridine 114o was added to the remaining solution in entries 1, 2, 3, and 4 respectively. After each addition, an aliquot of 1mL of the resulting CDCl3 solution was withdrawn and subjected to NMR analysis. The concentration of the solution (with respect to aziridine 114o) is 0.04 M, 0.08 M, 0.12 M, 0.16 M and 0.2 M for entries 1-5 respectively. 3.4.11 Probing the path II of the catalytic cycle i.e. the depletion of 239o in the presence of 111o (Figure 3.14 and 3.15) OPh O B O B O * O O B OPh H Ar aziAr H N CO2Et OPh imine 111o O * aziridine 114o AZIRIDINO-BOROX B3 239o O O B B O O B OPh H Ar imiAr N IMINO-BOROX B3 190o 253 H Entry 1, Figure 3.14 and Entry 1, Figure 3.15: The boroxinate 239o is formed in 43% yield in CDCl3 using the protocol shown in section 3.4.6. Entry 2, Figure 3.14: 1 equiv of imine 111o (36 mg, 0.1 mmol) was added to entry 1 of Figure 3.14. Entry 2, Figure 3.15: 0.5 equiv of imine 111o (18 mg, 0.1 mmol) was added to entry 1 of Figure 3.15. Entry 4, Figure 3.14: 1.1 equiv of EDA 85 (12 µL, 0.1 mmol) was added to entry 2 of Figure 3.14, which was stored for 24 h (entry 3, Figure 3.14) prior to the addition. Entry 4, Figure 3.15: 0.5 equiv of EDA 85 (5.2 µL, 0.05 mmol) was added to entry 2 of Figure 3.15, which was stored for 1 h (entry 3, Figure 3.15) prior to the addition. 3.4.12 Termination of the catalytic cycle i.e. Path X and path Y (Figure 3.16 and 3.17) A) Path X: Treatment of AZIRIDINO-BOROX 239o with EDA 85: OPh O * O O B B O O B OPh Ar H Ar Ar EDA 85 N N CDCl3 114o 254 + CO2Et CO2Et AZIRIDINO-BOROX B3 239o O Ar O * OEt OH 230 The boroxinate 239o is formed in 43% yield in CDCl3 using the protocol shown in section 3.4.6. Thereafter, 0.5 equiv of EDA 85 (5.2 µL, 0.05 mmol) was added after 10 min. Another 0.5 equiv of EDA 85 (5.2 µL, 0.05 mmol) was added after 30 min. The NMR spectra were recorded at regular time intervals. All details are given in Figure 3.16. B) Path Y: Reaction between (S)-VAPOL 58 and EDA 85 under various conditions: * OH EDA 85 (2 equiv) OH CDCl3 (1 mL) No reaction (S)-VAPOL 58 (0.1 mmol) Entry 1, Figure 3.17: To a 10 mL flame-dried single-necked round bottom flask, equipped with a stir bar and a rubber septum and filled with argon was added (S)-VAPOL 58 (54 mg, 0.10 mmol, 1.0 equiv) and EDA 85 (21 µL, 0.20 mmol, 2.0 equiv), Ph3CH (12.2 mg, 0.500 mmol) and CDCl3 (1 mL). The resultant mixture was stirred for 10 min at room temperature. The resulting solution was then directly transferred to a quartz NMR tube (freshly flame-dried) and was subjected to NMR analysis. B(OPh)3 (3 equiv) * OH EDA 85 (2 equiv) OH CDCl3 (1 mL) O (S)-VAPOL 58 (0.1 mmol) O * OEt OH 230 Entry 2, Figure 3.17: Same as entry 1 except that commercial B(OPh)3 (87 mg, 0.30 mmol, 3.0 equiv) was aslo added. 255 * OH B(OPh)3 (3 equiv) OH Toluene, 80 °C, 1 h then 80 °C, 0.5 0.1 mmHg (S)-VAPOL 58 (0.1 mmol) pre-catalyst (method A) O pre-catalyst (method A) EDA 85 (2 equiv) O * CDCl3 (1 mL) OH 230 OEt + unknown 241 Entry 3, Figure 3.17: The precatalyst was made by method A (see Chapter 1) employing (S)VAPOL 58 (54 mg, 0.10 mmol) and commercial B(OPh)3 (87 mg, 0.30 mmol, 3.0 equiv). To the flask containing the pre-catalyst was first added the Ph3CH (12.22 mg, 0.05 mmol) and then the CDCl3 (1 mL) under an argon flow through side-arm of the Schlenk flask. The reaction mixture was then stirred for 10 min. The off-white colored solution was then directly transferred to a 1 quartz NMR tube and was subjected to H NMR and 11 B NMR analysis. After initial analysis, EDA 85 (21 µL, 0.20 mmol, 2.0 equiv) was added and the mixture was shaken for 5 min. Entry 4, Figure 3.17: Entry 4 after 24 h. Entry 5, Figure 3.17: 1 equiv of H2O (1.8 µL, 0.1 mmol) was added to the NMR tube containing entry 4. 256 OH 1. Toluene, 80 °C, 1 h 2. 80 °C, 0.5 h 0.1 mmHg B(OPh)3 * (0.3 mmol) 3. imine 111a (1 mmol) OH 4. CDCl3, stir, 10 min (S)-VAPOL 58 5. EDA 85 (1.2 mmol) (0.1 mmol) 90 min + MEDAM N Ph O + CO2Et 114a O * OEt OH 230 Entry 6, Figure 3.17: The pre-catalyst was made using method A (see Chapter 2) employing (S)-VAPOL (54 mg, 0.1 mmol) and commercial B(OPh)3 (87 mg, 0.3 mmol). To the flask containing the pre-catalyst was first added the imine 111a (387 mg, 1.00 mmol), Ph3CH (12.22 mg, 0.05 mmol) and then CDCl3 (1 mL) under an argon flow through side-arm of the Schlenk flask. The reaction mixture was then stirred for 10 min. The red colored solution was then 1 directly transferred to a quartz NMR tube and was subjected to H NMR and 11 B NMR analysis. After initial analysis, EDA 85 (124 µL, 1.20 mmol) was added to the NMR tube and the NMR tube was shaken for 2 min. Thereafter the NMR sample was kept for 90 min. The NMR sample was then poured into a 25 mL round bottom flask containing 6 mL of hexanes. The resulting solution was then concentrated in vacuo followed by exposure to high vacuum (0.05 mm Hg) for 1 h to afford the adduct as a white solid. Purification of the mono-alkylated adduct 230 by silica gel chromatography (35 mm × 400 mm column, 9:1 hexanes/EtOAc as eluent, under gravity) afforded pure 230 as a white solid (mp. 101-102 °C) in 95% isolated yield (59.3 mg, 0.095 mmol). 257 1 Spectral data for 230: Rf = 0.25 (1:9 EtOAc/hexanes); H NMR (CDCl3, 300 MHz) δ 0.77 (t, 3H, J = 7.1Hz), 1.25 (brs, 1H), 2.74-3.68 (m, 2H), 4.40 (dd, 2H, J = 14.8, 37.6Hz), 6.70 (s, 1H), 6.79-6.85 (m, 4H), 6.93-7.12 (m, 6H), 7.44 (s, 1H), 7.56-7.82 (m, 8H), 7.88-7.94 (m, 2H), 9.559.58 (m, 1H), 9.83 (d, 1H, J = 8.5 Hz); 13 C NMR (CDCl3, 75 Hz) δ 13.48, 60.91, 68.44, 120.48, 123.01, 123.19, 125.97, 126.35, 126.50, 126.67, 126.91, 126.96, 127.13, 127.48, 127.55, 127.64, 127.76, 128.19, 128.36, 128.66, 128.90, 129.08, 129.19, 129.33, 130.66, 132.79, 133.08, 134.41, 2 135.05, 139.37, 140.10, 140.62, 142.27, 152.26, 155.04, 167.66 (four sp carbons not located). These spectral data match those previously reported for this compound. 5a,9 3.4.13 NMR analysis of the addition of TfOH to boroxinate 242 (Figure 3.19) * OH OH (S)-VAPOL 58 (0.1 mmol) pre-catalyst (method B) Me4NOAc (1 equiv) CDCl3 (1 mL) 25 ºC, <5 min B(OPh)3 (3 equiv) H2O (3 equiv) THF, 80 °C, 1 h then 80 °C, 0.5 0.1 mmHg pre-catalyst (method B) + [Me4N] OPh O B O – B O * O O B OPh B3 242 TfOH 1H NMR and 11B NMR analysis The pre-catalyst was made using method B (see Chapter 2) employing (S)-VAPOL (54 mg, 0.1 mmol) commercial B(OPh)3 (87 mg, 0.3 mmol) and H2O (5.4 µL, 0.3 mmol). To the flask containing the pre-catalyst was first added the Me4NOAc (13.3 mg, 0.100 mmol), Ph3CH (12.22 258 mg, 0.05 mmol) and then CDCl3 (1 mL) under an argon flow through side-arm of the Schlenk flask. The reaction mixture was then stirred for 10 min. The red colored solution was then 1 directly transferred to a quartz NMR tube and was subjected to H NMR and 11 B NMR analysis. Thereafter, 1–4 equivalents of TfOH were added at regular intervals. All details are given in Figure 3.19. 3.4.14 DFT calculations: 6 All quantum mechanical calculations were performed using the GAUSSIAN 03. The B3LYP density functional was used along with 6-31G* basis sets. 3.4.14.1 Prediction of the structure of AZIRIDINO-BOROX complex 239o (Figure 3.6) Coordinates of AZIRIDINO-BOROX complex 239o: B3LYP/6-31G* Energy = -4011.05566039 hartrees Number of Imaginary frequencies = none Zero-point correction= 1.348532 (Hartree/Particle) Thermal correction to Energy= 1.432808 Thermal correction to Enthalpy= 1.433753 Thermal correction to Gibbs Free Energy= 1.218432 Sum of electronic and zero-point Energies= -4009.707128 Sum of electronic and thermal Energies= -4009.622852 Sum of electronic and thermal Enthalpies= -4009.621908 Sum of electronic and thermal Free Energies= -4009.837228 Total E (Thermal) KCal/Mol 899.101 CV Cal/Mol-Kelvin 326.353 S Cal/Mol-Kelvin 453.179 259 10 Standard orientation: --------------------------------------------------------------------Center Atomic Atomic Coordinates (Angstroms) No. No. Type X Y Z --------------------------------------------------------------------1 6 0 -5.656871 -1.810910 1.301347 2 6 0 -5.779938 -0.423740 1.114612 3 6 0 -7.050565 0.097013 0.820102 4 6 0 -8.161181 -0.739691 0.711535 5 6 0 -8.023670 -2.116351 0.896119 6 6 0 -6.766367 -2.647549 1.192164 7 6 0 -4.614247 0.481173 1.322858 8 6 0 -3.321972 0.231947 0.775601 9 6 0 -2.213056 0.969017 1.227232 10 6 0 -2.370229 2.107515 2.086394 11 6 0 -3.708035 2.434593 2.472247 12 6 0 -4.779456 1.588010 2.135707 13 6 0 -3.983901 3.624281 3.223757 14 6 0 -2.995268 4.486392 3.567917 15 6 0 -1.629756 4.189433 3.254573 16 6 0 -1.293501 2.982118 2.558122 17 6 0 -3.151532 -0.777075 -0.313738 18 6 0 -2.257700 -1.839405 -0.104913 19 6 0 -2.207654 -2.974464 -0.972578 20 6 0 -2.994768 -2.897671 -2.161739 21 6 0 -3.804018 -1.773740 -2.412434 22 6 0 -3.915217 -0.719652 -1.515636 23 6 0 -1.438766 -4.194177 -0.719443 24 6 0 -1.414657 -5.215657 -1.724417 25 6 0 -2.165825 -5.052168 -2.935579 26 6 0 -2.937352 -3.952410 -3.133652 27 8 0 -1.471940 -1.778585 0.994567 28 5 0 -0.454976 -0.716368 1.080922 29 8 0 -0.982213 0.618355 0.747225 30 6 0 -4.772541 0.437364 -1.904912 31 6 0 -4.345129 1.767531 -1.745208 32 6 0 -5.123524 2.832578 -2.198237 33 6 0 -6.351519 2.595369 -2.819202 34 6 0 -6.794462 1.281257 -2.977725 35 6 0 -6.015134 0.217556 -2.524666 36 8 0 0.651373 -0.984195 0.094745 37 5 0 1.651458 -1.838704 0.462054 38 8 0 1.876094 -2.167880 1.776496 260 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 5 8 6 6 6 6 6 6 8 6 6 6 6 6 6 8 6 6 6 8 8 6 7 6 6 6 6 6 6 6 6 8 6 6 6 6 6 6 6 6 6 8 6 6 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1.114217 1.567557 0.984483 -0.380727 -0.877616 -0.036237 1.323633 1.834285 2.457592 3.481020 4.428031 5.467170 5.574035 4.623921 3.574999 0.066312 1.897877 0.581119 2.121507 3.120762 1.130044 1.267959 1.389023 2.080216 3.331440 3.419637 4.543958 5.608069 5.563513 4.417716 4.597780 6.757613 6.714002 6.740879 2.228670 3.350644 3.435530 2.368644 1.225433 1.179110 4.636851 2.433713 2.911274 0.078885 2.724014 -1.539989 -1.769810 -1.390519 -1.120382 -0.786924 -0.723809 -1.000501 -1.334793 -2.320575 -3.236516 -3.189684 -4.119743 -5.099907 -5.141156 -4.220661 -0.761212 0.677720 1.357114 -0.733296 -1.022987 -1.551183 -2.969655 0.890563 1.819364 1.156530 0.999530 0.443028 0.031814 0.184567 0.738549 0.290213 -0.479140 -1.880713 -0.231652 3.237816 3.690653 5.005144 5.880031 5.460833 4.136158 5.481831 7.165858 8.152883 6.406563 1.331274 2.762942 4.043265 5.231192 5.375559 6.636726 7.748638 7.593445 6.340547 -0.555043 -0.482465 -1.513124 -1.550014 -0.560577 0.461560 0.508644 2.445162 -3.157298 -2.933875 -3.646884 -4.271529 -3.308054 -3.637504 -1.775546 -0.762784 -0.206967 1.179900 1.799316 0.982906 -0.414052 -0.990487 3.299642 1.550200 1.845762 -1.260898 -1.288713 -1.994588 -2.462746 -2.196259 -1.495534 -1.050910 -3.242860 -2.698240 -1.781839 -1.232452 -3.412184 261 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 1 1 1 1 1 1 1 1 1 1 1 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 4.336808 -2.425866 -2.278714 6.191017 -4.077927 -2.360026 6.381588 -5.826025 -0.590249 4.690375 -5.902861 1.234351 2.842105 -4.257675 1.303036 2.887333 -1.561104 6.202469 1.992070 -0.958736 8.449756 -0.435471 -0.462724 8.724812 -1.937987 -0.573601 6.744701 -1.034015 -1.156912 4.513182 -3.215883 5.401734 4.112042 -5.018020 3.828795 3.490054 -5.759389 1.804708 2.551771 -7.159946 1.164560 0.651763 -9.133697 -0.314777 0.475590 -8.888239 -2.769771 0.811574 -6.648507 -3.717026 1.346625 -4.687393 -2.229548 1.551979 -6.382308 -0.799215 -2.626283 -7.754692 1.081778 -3.446636 -6.958476 3.425849 -3.170177 -4.768016 3.851200 -2.064542 -3.396753 1.967352 -1.257374 -4.343907 -1.731812 -3.354066 -3.534712 -3.849105 -4.036656 -2.129681 -5.846463 -3.677836 1.332201 1.845827 0.030790 1.022148 0.042802 -1.267929 0.652943 2.436334 -3.040879 4.193967 3.028464 -2.160287 5.226206 6.212945 -2.675768 4.332749 5.974579 -4.171996 5.298128 4.646201 -3.490501 2.930150 9.096883 -2.330862 3.923774 7.916091 -1.430830 2.248766 8.252533 -0.913349 -0.855997 5.856095 -1.091362 -0.046901 7.110643 -2.059945 0.244274 6.994559 -0.320405 0.307364 3.800544 -0.493782 2.589210 1.309814 1.806834 5.630317 0.314437 3.657635 4.146732 -0.658615 3.616026 4.035921 1.089742 3.793170 7.682591 -2.126545 2.287327 262 129 1 0 6.561135 -2.476638 0.938853 130 1 0 5.917307 -2.114922 2.561158 131 1 0 6.867238 -1.320351 -1.261966 132 1 0 7.671519 0.198757 -0.877098 133 1 0 6.608766 0.088450 -2.299147 134 1 0 4.394266 0.818742 -2.072582 135 6 0 0.750667 -3.252143 -5.036825 136 1 0 2.317592 -3.242696 -3.524549 137 1 0 0.676383 -3.469507 -2.871362 138 1 0 0.818726 -4.327931 -5.233798 139 1 0 -0.298864 -2.957345 -5.132989 140 1 0 1.346173 -2.729013 -5.791144 141 6 0 -0.781836 0.783951 -3.244349 142 1 0 -0.846828 -0.266350 -2.955235 143 1 0 -1.525223 1.329267 -2.652983 144 6 0 -1.073287 0.953351 -4.747687 145 1 0 -0.957943 2.011241 -5.023776 146 1 0 -0.316217 0.402385 -5.322222 147 6 0 -2.470012 0.471412 -5.147777 148 1 0 -2.598160 -0.592062 -4.919789 149 1 0 -3.250276 1.020766 -4.610842 150 1 0 -2.633933 0.610762 -6.222097 151 6 0 -0.679315 -6.404617 -1.510788 152 1 0 -0.674836 -7.157182 -2.296485 153 6 0 -0.751162 -4.466972 0.491882 154 1 0 -0.798258 -3.741946 1.289630 155 6 0 -0.000675 -6.624847 -0.328926 156 1 0 0.555577 -7.545704 -0.176115 157 6 0 -0.054963 -5.649451 0.681123 158 1 0 0.447388 -5.822824 1.629240 159 6 0 0.087638 2.706430 2.398078 160 1 0 0.366416 1.760571 1.963908 161 6 0 -0.612605 5.077432 3.673579 162 1 0 -0.906136 5.988701 4.190223 163 6 0 1.065880 3.587989 2.829128 164 1 0 2.114005 3.337452 2.688351 165 6 0 0.720854 4.796101 3.456925 166 1 0 1.493018 5.484811 3.789402 --------------------------------------------------------------------- 263 REFERENCES 264 REFERENCES (1) (a) Tokunaga, N.; Yoshida, K.; Hayashi, T. Proc. Nat. Acad. Sci. U.S.A 2004, 101, 54455449. (b) Uyeda, C.; Jacobsen, E. N. J. Am. Chem. Soc. 2011, 133, 5062-5075. (2) (a) Amarante, G. W.; Benassi, M.; Milagre, H. M. S.; Braga, A. A. C.; Maseras, F.; Eberlin, M. N.; Coelho, F. Chem.–Eur. J. 2009, 15, 12460-12469. (b) Schrader, W.; Handayani, P. P.; Zhou, J.; List, B. Angew. Chem., Int. Ed. 2009, 48, 1463-1466. (3) (a) Daniel, C.; Koga, N.; Han, J.; Fu, X. Y.; Morokuma, K. J. Am. Chem. Soc. 1988, 110, 3773-3787. (b) Kozuch, S.; Martin, J. M. L. ACS Catal. 2011, 1, 246-253. (c) Kozuch, S.; Martin, J. M. L. Chem. Commun. 2011, 47, 4935-4937. (4) (a) Rueping, M.; Nachtsheim, B. J.; Ieawsuwan, W.; Atodiresei, I. Angew. Chem., Int. Ed. 2011, 50, 6706-6720. (b) Schenker, S.; Zamfir, A.; Freund, M.; Tsogoeva, S. B. Eur. J. Org. Chem. 2011, 2209-2222. (c) Rueping, M.; Kuenkel, A.; Atodiresei, I. Chem. Soc. Rev. 2011, 40, 4539-4549. (d) List, B.; Kampen, D.; Reisinger, C. M. Top Curr Chem 2010, 291, 395-456. (e) Rueping, M.; Koenigs, R. M.; Atodiresei, I. Chem.–Eur. J. 2010, 16, 9350-9365. (f) Sohtome, Y.; Nagasawa, K. Synlett 2010, 1-22. (g) Terada, M. Synthesis 2010, 1929-1982. (h) Terada, M. Bull. Chem. Soc. Jpn. 2010, 83, 101-119. (i) Zamfir, A.; Schenker, S.; Freund, M.; Tsogoeva, S. B. Org. Biomol. Chem. 2010, 8. (j) Yamamoto, H.; Payette, J. N. In Hydrogen Bonding in Organic Synthesis; Wiley-VCH 2009, p 73-140. (k) Terada, M. Chem. Commun. (Cambridge, U. K.) 2008, 4097-4112. (l) Yu, X.; Wang, W. Chem.–Asian. J. 2008, 3, 516-532. (m) Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713-5743. (n) Akiyama, T. Chem. Rev. 2007, 107, 57445758. (o) Taylor, M. S. J., E. N. Angew. Chem., Int. Ed. 2006, 45, 1520-1543. (p) Akiyama, T.; Itoh, J.; Fuchibe, K. Adv. Synth. Catal. 2006, 348, 999-1010. (q) Connon, S. J. Angew. Chem., Int. Ed. 2006, 45, 3909-3912. (5) (a) Zhang, Y.; Desai, A.; Lu, A.; Hu, G.; Ding, Z.; Wulff, W. D. Chem. –Eur. J. 2008, 14, 3785-3803. (b) Zhang, Y.; Lu, Z.; Desai, A.; Wulff, W. D. Org. Lett. 2008, 10, 5429-5432. (c) Mukherjee, M.; Gupta, A. K.; Lu, Z.; Zhang, Y.; Wulff, W. D. J. Org. Chem. 2010, 75, 56435660. (d) Ren, H.; Wulff, W. D. Org. Lett. 2010, 12, 4908-4911. (e) Hu, G.; Huang, L.; Huang, R. H.; Wulff, W. D. J. Am. Chem. Soc. 2009, 131, 15615-15617. (f) Hu, G.; Gupta, A. K.; Huang, R. H.; Mukherjee, M.; Wulff, W. D. J. Am. Chem. Soc. 2010, 132, 14669–14675. (g) Gupta, A. K.; Mukherjee, M.; Wulff, W. D. Org. Lett. 2011, 13, 5866-5869. (h) Newman, C. A.; Antilla, J. C.; Chen, P.; Predeus, A. V.; Fielding, L.; Wulff, W. D. J. Am. Chem. Soc. 2007, 129, 7216-7217. (i) Desai, A. A.; Wulff, W. D. J. Am. Chem. Soc. 2010, 132, 13100-13103. (j) Vetticatt, M. J.; Desai, A. A.; Wulff, W. D. J. Am. Chem. Soc. 2010, 132, 13104-13107. (k) Desai, A. A.; Morán-Ramallal, R.; Wulff, W. D. Org. Synth. 2011, 88, 224-237. (l) Ren, H.; Wulff, W. D. J. Am. Chem. Soc. 2011, 133, 5656-5659. (m) Desai, A. A.; Ren, H.; Mukherjee, M.; Wulff, W. D. Org. Process Res. Dev. 2011, 15, 1108-1115. 265 (6) Gaussian 03, Revision D.01 M. J. Frisch, G. W. T., H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman, J. A. Montgomery, Jr., T. Vreven, K. N. Kudin, J. C. Burant, J. M. Millam, S. S. Iyengar, J. Tomasi, V. Barone, B. Mennucci, M. Cossi, G. Scalmani, N. Rega, G. A. Petersson, H. Nakatsuji, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, M. Klene, X. Li, J. E. Knox, H. P. Hratchian, J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R. E. Stratmann, O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli, J. W. Ochterski, P. Y. Ayala, K. Morokuma, G. A. Voth, P. Salvador, J. J. Dannenberg, V. G. Zakrzewski, S. Dapprich, A. D. Daniels, M. C. Strain, O. Farkas, D. K. Malick, A. D. Rabuck, K. Raghavachari, J. B. Foresman, J. V. Ortiz, Q. Cui, A. G. Baboul, S. Clifford, J. Cioslowski, B. B. Stefanov, G. Liu, A. Liashenko, P. Piskorz, I. Komaromi, R. L. Martin, D. J. Fox, T. Keith, M. A. Al-Laham, C. Y. Peng, A. Nanayakkara, M. Challacombe, P. M. W. Gill, B. Johnson, W. Chen, M. W. Wong, C. Gonzalez, and J. A. Pople, Gaussian, Inc., Wallingford CT, 2004 (7) (a) Nishio, M. Tetrahedron 2005, 61, 6923-6950. (b) Nishio, M. H., M.; Umezawa, Y. The CH/π Interaction: Evidence, Nature, and Consequences; Wiley-VCH, 1998. (c) Plevin, M. J.; Bryce, D. L.; Boisbouvier, J. Nat Chem 2010, 2, 466-471. (8) This work was presented at the 241th American Chemical Society National Meeting, Anaheim (2011), ORGN 648. (9) Lu, Z.; Zhang, Y.; Wulff, W. D. J. Am. Chem. Soc. 2007, 129, 7185-7194. (10) (a) Becke, A. D. Phys. Rev. A 1988, 38, 3098. (b) Lee, C. Y., W.; Parr, R. G. Phys. Rev. B 1988, 37, 785. 266 CHAPTER 4 CAN “FREE” PROTON BE THE COUNTER CATION OF CHIRAL BORATE ANIONS IN THE ABSENCE OFA BASE IN NON-AQUEOUS MEDIA If you think that this is wrong then you should give it a shot and nail it! I hate to publish anything, which is wrong even accidently!!! -William D. Wulff 4.1 Introduction In the preceding Chapter 3, various intermediates were characterized of the proposed catalytic cycle (Scheme 3.3, Chapter 3) of the Brønsted acid catalyzed aziridination reaction 1 between imines and stabilized diazo compounds. In the process, for the first time, the existence of the AZIRIDINO-BOROX complex 239 was demonstrated where product is bound to the catalyst (Scheme 3.3, Chapter 3). While discussing path II of the catalytic cycle, the possible existence of “free” Brønsted Acid 23-H was proposed (Figure 4.1A). As discussed earlier (Chapter 3), there is no NMR or X-ray evidence in the support of the existence of 23-H as of this time. Additionally, the calculated structure of 23-H reveals that a species with a tri-coordinate boron is energetically more favorable than one with a tetra-coordinate boron (Figure 3.18, Chapter 3). It was then decided to revisit the literature to find if anything similar has ever been reported. This was extremely important, as it would help to find an optimum protocol for generating a species like 23-H. Two such systems were identified which were reported from the 2 field of asymmetric catalysis. One of such system includes the spiroborates (SB) 20-H and 21H 2e,2f 3 and the other is the fused-spiroborate (FSB) 22-H (Figure 4.1B). Both kinds of borates 267 were reported to posses a tetra-coordinate boron and a “free” proton as the counter cation. In search of an optimized protocol to generate 23-H, the cases of 20-H and 22-H were examined in more detail. In order to examine these systems, techniques including computational chemistry, NMR spectroscopy and X-ray crystallography were used. Figure 4.1 (A) Free BOROX 23-H. (B) Spiroborates 20-H and 21-H and Fused-spiroborate 22-H A + H OPh O B O– B O O O B OPh Ph Ph 23-H B R R + H O O – O B O O O O + H – B O R In the present work, R 20-H (R=H) 21-H (R=Br) 11 22-H B NMR spectroscopy has been used as one of the most important tools to characterize borate intermediates. Out of all the borates shown in Figure 4.1, the only protonated neutral borate for which 11 B NMR spectrum is reported is for the fused-spiroborate 268 3a 22-H. In the 11 B NMR analysis of borate anions, the chemical shift depends on the cation, concentration and the solvent. Hence, a list of 11 B NMR chemical shifts for some known achiral 4 and chiral borate anions is given in Figure 4.2. This provides us an idea of the general range of the chemical shift values for different types of borate anions and would help in the identification of the three systems listed in Figure 4.1. The detailed analysis of each system is described in subsequent sections. Figure 4.2 11 B NMR chemical shifts of B(OPh)3 187a, triphenoxy boroxine 191a, various achiral and chiral borate anions. PhO B O O B O OPh PhO B OPh 191a δ = 18.5 ppm, br CDCl3 (Ref 4a) 187a δ = 16.2 ppm, br CDCl3 (Ref 4a) + X PhO – OPh B OPh PhO 244a-d X + + Na + Li + Me2NH2 + C5H11NH2 δ, ppm Solvent Ref 2.79 2.00 1.40 2.60 OPh B OPh CD3CN CDCl3 C6D6 THF-d8 4b 4c 4d 4e excess PhOH + PhO OPh B OPh 243 δ = 14.5 ppm, br (Ref 3a) + [Rh(PMe3)4] ArO OAr B O – O B B O O B O O B ArO OAr + [Rh(PMe3)4] HO OH B O – O B B O O B O O B HO OH 245 (Ar=4-MeO-C6H4) δ = 4.76 ppm acetone-d6 (Ref 4f) 246 δ = 2.24 ppm, br acetone-d6 (Ref 4f) 269 Figure 4.2 cont’d + [Imine-H] + A O – O B O O OPh O B O– B O O O B OPh Ph Ph 247a-c + δ, ppm Solvent Ref + Na Li + Diglyme 4g THF-d8 4h C6D6 4i A 14.6 + 11.9 Me2NH2 14.0 104a δ = 5.5-5.7 ppm CDCl3 (Ref 1f) + C O O O + H – B O – O B O O O 147a-d + C + Et3NH + Me2NH2 + (R)-Ph(Me)CHNH3 + Na 22-H δ = 10 ppm, br CD2Cl2 (Ref 3a) 4.2 δ, ppm Solvent 8.98 8.96 9.01 9.20 DMSO-d6 DMSO-d6 DMSO-d6 DMSO-d6 Ref 4j 4j 4j 4k The case of the chiral spiroborates 20-H and 21-H In 1994, Yamamoto and co-workers reported the preparation of the spiroborate 20-H and its utilization for Mannich reactions imines (Scheme 4.1B). 2a,2d 2a-2c (Scheme 4.1A) and heteroatom Diels-Alder reactions of In the year 1997, the same catalyst was purported to effect an 270 asymmetric Pictet-Spengler reaction (Scheme 4.1C). 2e,2f In all three reactions, excellent yields and enantioselectivities and diasteroselectivities were obtained, although stoichiometric amounts of the catalyst were required. Scheme 4.1 Asymmetric reactions reported to be catalyzed by 20-H A Asymmetric imino-aldol reaction N R1 + 2a-2c OTMS OtBu Ph 75 76 catalyst 20-H (100 mol %) 4 Å MS, CH2Cl2 –78 °C, 20 h R1 = Ph, Bn, Bh, (S)PhMeCH 1-NpCH2 Ph OTMS N Ph + R2 78 OtBu 76 catalyst 20-H (100 mol %) 4 Å MS, CH2Cl2 –78 °C, 20 h R2 = Ph, 2-naphthyl, p-Me-C6H4, p-Cl-C6H4, p-OAc-C6H4, 2,4-Cl2-C6H4 HN R1 CO2tBu Ph 77 5 examples ee = < 5 – > 90% de = 95 (for chiral amine) Ph HN R2 Ph CO2tBu 79 6 examples yield = 35 – 58% ee = 95 – 98% 271 Scheme 4.1 cont’d B Asymmetric heteroatom Diels-Alder reaction OMe R1 N catalyst 20-H (100 mol %) + Ph 2a,2d OTMS R1 4 Å MS, CH2Cl2 –78 °C, 12 h Ph N O 80 75 81 R1 y% Bn (S)PhMeCH (S)PhMeCH (with ent-20-H) C Asymmetric Pictet-Spengler reaction + N O– N H R ee/de% 78 64 49 86 99 83 2e,2f catalyst 20-H or 21-H (200 mol %) 4 Å MS, CH2Cl2 25 °C, 48 h 83 N OH N H R 84 6 examples yield = 39 – 94% ee = 15 – 94% R = Ph, p-OMe-C6H4, p-NO2-C6H4, Me, iBu, 1-naphthyl, The reported structure represents the catalyst as a Brønsted acid 20-H containing a tetracoordinate boron atom (Scheme 4.2). 2a,2e However, the mode of catalysis of 20-H was proposed to be as a Brønsted acid assisted Lewis acid (BLA) catalysis. The catalytic function of 20-H was proposed to be as a chiral Lewis acid where interaction with a Lewis base disrupts one of the boron-oxygen bonds to give the Lewis acid-Lewis base complex 71/71ʹ′ (Scheme 4.2). 272 2a,2e Scheme 4.2 Proposed catalytic activity of 20-H + H OH OH B(OPh)3 O – O B O O (0.5 equiv) 55 20-H Brønsted acid LB LB O O H B O O 71 (LB = imine) 71' (LB = nitrone) Brønsted acid assisted Lewis acid (BLA) In the present work, the structure of 20-H was then investigated with the help of computational chemistry. The proposed structure 20-H was computed by DFT calculations using Gaussian ʹ′03 at B3LYP/6-31g* level of theory. 5 First, the structure of spiroborate anion 20 was optimized (Figure 4.3A) which was then followed by optimization of 20-H by putting a proton on each of the four oxygen atoms of the anion 20 (Figure 4.3B). Surprisingly, the calculations suggested the presence of a tri-coordinate boron atom instead of a tetra-coordinate boron atom as proposed in the original structure (Figure 4.3B vs. Figure 4.1B). Interestingly, the optimization converged to only one structure 72 (Figure 4.3B). In the calculated structure 72, there is a hydrogen bonding (2.33 Å) between the O1-H of one of the BINOL units and an oxygen (O2) on the other BINOL unit (Figure 4.3B). As shown in Figure 4.3B, there is another 273 possibility 72ʹ′ (an isomer of 72) where the H-bond is between the O1-H group on one of the BINOL units and an oxygen (O3) on that same BINOL unit. In this case, in order to obtain a geometry corresponding to the 72ʹ′, calculation was initiated with the proton attached to O1 in proximity to O3, with the distance of the proton to O2 fixed at 3 Å. Starting from the optimized geometry 72ʹ′ (H-bond = 1.86 Å) from the fixed distance calculation and releasing the proton-O2 distance resulted in a new optimized geometry 72ʹ′ʹ′ where the H-bond (3.72 Å) is almost lost. The relative energy of each species either from complete minimization or fixed distance minimization is shown in Figure 4.3. Figure 4.3 Calculated structures of 20-H, 72 and 72ʹ′ obtained using Gaussian ʹ′03 at B3LYP/631g* level of theory. All structures are visualized by the Mercury program (C, gray; O, red; B, yellow; H, light blue). Hydrogens are omitted for clarity (except O-H). All the bond distances are in Angstrom and energies in kcal/mol. ∠oop = angle out of plane for the current/former tetracoordinate boron, B-On = the distance between O-n and the current/former tetra-coordinate boron where n = 1-4. (A) Calculated structure of Spiroborate anion 20. (B) Calculated structures 72, 72ʹ′ (from fixed distance calculation) and 72ʹ′ʹ′ obtained by putting a proton on any one of the four oxygen atoms. A boron O2 B oxygen O3 O4 O1 carbon hydrogen 23 (∠oop = 19.4º, B-O1 = B-O2 = B-O3 = B-O4 = 1.47 Å) 274 Figure 4.3 cont’d B 2.33 Å O2 O3 B O4 O1 72 (∠oop < 1º, B-O1 = 3.51 Å, B-O2 = 1.40 Å, B-O3 = 1.35 Å, B-O4 = 1.38 Å) (ΔΔG = 0 Kcal/mol) 1.86 Å O2 B 3.72 Å O1 O2 O3 O4 B O4 72ʹ′ (∠oop < 1º, B-O1 = 3.50 Å, B-O2 = 1.37 Å, B-O3 = 1.37 Å, B-O4 = 1.37 Å) (ΔΔG = +4.2 kcal/mol) * fixed distance calculation (O2-H = 3Å) O3 O1 72ʹ′ʹ′ (∠oop < 1º, B-O1 = 5.41 Å, B-O2 = 1.37 Å, B-O3 = 1.37 Å, B-O4 = 1.38 Å) (ΔΔG = +1.6 kcal/mol) Based on these computational results, the possibility of the existence of spiroborate 20-H seems unlikely. It must be noted that various salts have been reported which contain the spiroborate anion 20 and these include those with protonated amines 275 4j,6 or metal cations 4k in the ion-pair (Figure 4.2). The 11 B NMR spectrum of these salts revealed the chemical shift of the tetra-coordinated boron atom to be ~ 9 ppm. Hence, it was thought that the 11 B NMR spectrum of the proposed structure would give a similar observation. At this point, it must be noted that Gang Hu, a former group member, performed the NMR studies presented in the first 5 entries in Figure 4.4. The entry 6 of Figure 4.4 is the part of this doctoral research. The reaction of B(OPh)3 with two equivalents of BINOL was performed following Yamamoto’s protocol 2a for the preparation of the spiroborate 20-H which involves stirring the two in CD2Cl2 over 4 Å molecular sieves for 1 h at room temperature. The solution was filtered and subjected to NMR 1 analysis. The H NMR and 11 B NMR spectra are shown in Figure 4.4B (entry 2) and Figure 1 4.4C (entry 1), respectively. The H NMR spectrum reveals a complex mixture of species most of which have not been identified, but the 11 B NMR spectrum shows a broad absorption at 16.0 ppm that would be expected for any kind of three coordinate borate ester. Phenol should be present in the mixture as a result of exchange with BINOL. However, this should not be considered as indicative of the extent of exchange since it is our experience that most commercial B(OPh)3 samples contains 20-30 percent phenol (see Figure 4.13, entry 5). In contrast, the reaction of VAPOL and B(OPh)3 shows no reaction under the same conditions. 1f Our observations with the reactions of imines catalyzed by borate derivatives of VANOL and VAPOL are that the actual catalyst species is not formed until the imine is added. The mesoborate 106 (B1) and the pyro-borate 108 (B2) are pre-catalysts that are converted into the poly- 276 borate (BOROX) catalyst 188/189 by the imine 78 (Scheme 2.1, Chapter 2). Thus, it was decided to examine the effect of added imine on this mixture of BINOL and B(OPh)3. When the mixture of 2 equivalents of BINOL and one equivalent of B(OPh)3 is treated with one equivalent of the imine 78a, the complex mixture of compounds is converted cleanly into a single 1 compound within the time that it takes to load an NMR tube and take the H NMR and 11 B NMR spectra (Figure 4.4B, entry 3 and Figure 4.4C, entry 2). This compound is assigned as the ion-pair 74a comprised of a spiroborate anion 20 and the protonated form of imine 78a (Figure 4.4A). The four coordinate anionic borate unit in 74a displays a characteristic sharp absorption at δ = 8.9 ppm in the 11 B NMR spectrum (Figure 4.4C, entry 2) and reveals the complete disappearance of the broad three coordinate borate absorption at δ = 16 ppm, suggesting the formation of 74a in near quantitative yield. Also, similar observations were made when (S)-55 was used instead of (R)-55 (not shown here). Further, the formation of ion-pair 74a/147f was observed when different bases or NMR solvents were used (Figure 4.4B, entries 4-6). Figure 4.4 (A) NMR Analysis of a mixture of (R)-55 with B(OPh)3 and imine 78a or DMAP. (B) a 1 H NMR spectra (aromatic region) of the reaction mixture in CD2Cl2 or CDCl3. (C) 1 NMR spectra corresponding to the H NMR spectra in Figure 4.4B starting from entry 2. 277 11 B Figure 4.4 cont’d A OH OH B(OPh)3 (0.5 equiv) O O O B O H 55 72 Brønsted acid assisted Lewis acid (BLA) Base + [Base-H] O – O B O O 74a (Base = imine 78a) 147f (Base = DMAP) Brønsted acid B 147f (R)-55 + B(OPh)3 + DMAP (2:1:1 in CDCl3) 74a (R)-55 + B(OPh)3 + imine 78a (2:1:1 in CDCl3) 55 (R)-55 + B(OPh)3 (2:1 in CDCl3) 74a (R)-55 + B(OPh)3 + imine 78a (2:1:1 in CD2Cl2) (R)-55 + B(OPh)3 (2:1 in CD2Cl2) 55 (R)-55 (in CD2Cl2) 278 Solvent 25 ºC, 5 min Figure 4.4 cont’d C 147f (R)-55 + B(OPh)3 + DMAP (2:1:1 in CDCl3) 74a (R)-55 + B(OPh)3 + imine 78a (2:1:1 in CDCl3) (R)-55 + B(OPh)3 (2:1 in CDCl3) 74a (R)-55 + B(OPh)3 + imine 78a (2:1:1 in CD2Cl2) (R)-55 + B(OPh)3 (2:1 in CD2Cl2) a Note for Figure 4.4B: Entry 1: pure BINOL (R)-55 in CD2Cl2. Entry 2: (R)-55 (0.1 mmol) plus 0.5 equiv B(OPh)3 and powdered 4Å Molecular Sieves (150 mg) were stirred for 1 h in CD2Cl2 (3 mL) at 25 °C. Entry 3: 0.5 equiv imine 78a was added to the entry 2 for 10 min at 25 °C. Entry 4: Same as entry 2 in CDCl3. Entry 5: Same as entry 3 in CDCl3. Entry 6: 0.5 equiv DMAP was added to the entry 4 for 10 min at 25 °C. It is of course possible that the compound with the proposed structure 74a could also have the structure 71a or 73a in which there is a Lewis acid-Lewis base complex which contains a tetra-coordinate boron atom (Figure 4.5). Support for the structure 74a containing a 279 spiroborate anion and an iminium cation comes from the work of Yamamoto and coworkers who have previously studied heteroatom Diels-Alder and Mannich reactions of imines mediated by a stoichiometric amount of a catalyst prepared from two equivalents of BINOL and one equivalent 2a of B(OPh)3. In support of a spiroborate core in their catalyst they were able isolate and determine the X-ray structure of the complex 248 although no spectral data for 248 was presented (Figure 4.6). 2a This complex consists of the spiroborate anion, a molecule of phenol and the protonated form of imine (S)-139a (Figure 4.6). There is no direct H-bonding between the protonated iminium and the spiroborate anion, but rather the protonated iminium is H-bonded to the phenol, which in turn is H-bonded to the spiroborate anion. This crystal was of the miss- Figure 4.5 Bronsted acid 74a and Brønsted acid assisted Lewis acid 71a or 73a (imine = 78a) + [imine-H] O – O B O O 74 74a (imine = 78a) Brønsted acid imine imine O O H B O O O B O O O H 71 73 73a (imine = 78a) 71a (imine = 78a) Brønsted acid assisted Lewis acid (BLA) Brønsted acid assisted Lewis acid (BLA) 280 matched pair of (S)-BINOL 55 and (S)-139a and perhaps in the matched pair non-covalent contacts between the (S)-BINOL core and protonated (R)-139a would be more favorable. While studying the NMR spectra of the complex 74a with (S)-BINOL 55, Gang Hu observed that a few yellow crystals serendipitously formed in the NMR tube, which provided an opportunity to determine the crystal structure of the ion-pair 74a. It was hoped that non-covalent interactions between the spiroborate core and the iminium could be found in 74a since the imine 78a from which it is derived is not chiral. The complex 74a also crystallized with a molecule of phenol but an X-ray diffraction analysis of these crystals revealed that non-covalent interactions present in complex 249 are much different than in Yamamoto’s complex 248 (Figure 4.6). The details about the crystal structure 249 can be found in Gang Hu’s dissertation (Figure 4.6). 7 Also, the crystal structures of the other salts containing the spiroborate anion 20 and a) protonated amines, 6 b) metal ions 4k are given in literature. 2a Figure 4.6 Schematic drawing of imine (S)-139a, Yamamoto’s structure 248 and Gang Hu’s 7 structure 249 Ph Ph Me Me N + H Ph O H Ph N (S)-139a N + H O – O B O O O – O B O O H O 248 249 281 Based on the above discussion, it is quite clear that there is no spectroscopic evidence for the existence of spiroborate 20-H. The data taken as a whole suggests that perhaps there is no tetra-coordinate boron species unless an imine is added to deprotonate the hydroxyl group in the BINOL 55. Although our interests are in chiral spiroborate species, an achiral spiroborate 251-H similar to 20-H has been reported as a protonated neutral species with a tetra-coordinate boron and was prepared from the reaction between boric acid and 2 equiv of catechol 250 (Scheme 4.3A). 8 However, there was no spectroscopic characterization provided for this compound. After almost a decade, Nöth and co-workers reported a different compound 252 for the same 9 reaction and with the same conditions. They characterized this compound by NMR spectroscopy and X-ray crystallography. As shown in Scheme 4.3A, there is no tetra-coordinate boron atom in 252 which is consistent with the chemical shift observed in the 11 B NMR spectrum (δ = 22.5 ppm, CDCl3). This is in agreement with our observations for the spiroborate 20-H. Scheme 4.3 Common borate esters of catechol 250 A H3BO3 (0.5 equiv) O B O OH toluene, reflux O 252 11B NMR; δ = 22.5 ppm, CDCl 3 (characterized by X-ray) (Ref 9) 11B NMR δ = 7.6 ppm, pH = 11 δ = 8.9 ppm, pH = 7-11 OH H3BO3 (0.5 equiv) + H O –O B O O toluene, reflux OH 250 251-H (no spectroscopic evidence) H3BO3 (Ref 8) (0.25 equiv) D2O/H2O O – OH + H3O B O OH O –O B O O 253 (Ref 10) 254 (Ref 10) 282 11B NMR + H3O δ = 13.1 ppm, pH = 11 δ = 14.3 ppm, pH = 7-11 Scheme 4.3 cont’d B H3BO3 (1 equiv) O B OH OH O OH 256 (Ref 9) H3BO3 (0.5 equiv) toluene, reflux 250 H3BO3 (0.99 equiv) B O OH O 252 (11B NMR; δ = 22.5 ppm) CDCl3 (Ref 9) H3BO3 (2/3 equiv) benzene, reflux O O benzene, reflux O B O B O O O O B O 257 (11B NMR; δ = 22.6 ppm) CDCl3 (Ref 9) O B O O 255 (11B NMR; δ = 22.7 ppm) CDCl3 (Ref 9) 1. B2O3 2. NaBH4 (0.33 equiv) (0.5 equiv) toluene, diglyme reflux B(NMe2)3 (0.5 equiv) Et2O + Na + Me2NH2 O – O B O O O – O B O O 247a 247c (11B NMR; δ = 14.0 ppm) C6D6 (Ref 4i) (11B NMR; δ = 14.6 ppm) Diglyme (Ref 4g) At this point, it was thought that the structure of 251-H could be used to calibrate our computational method. Ideally, after the optimization of the proposed structure of 251-H, the 283 finalized energy minimum structure should be close to that of the X-ray structure of 252. This would validate our calculation method. In fact, the calculated structure was found to be essentially the same as the X-ray structure of 252 (Figure 4.7). Figure 4.7 Calculated structures of 251 and 251-H obtained using Gaussian ʹ′03 at B3LYP/631g* level of theory. All structures are visualized by the Mercury program (C, gray; O, red; B, yellow; H, light blue). Hydrogens are omitted for clarity (except O-H). All the bond distances are in Angstroms and energies in kcal/mol. ∠oop = angle out of plane for the current/former tetra-coordinate boron, B-On = the distance between O-n and the current/former tetra-coordinate boron where n = 1-4. (A) Calculated structure of spiroborate anion 251 (B) Calculated structures of possible spiroborate 251-H obtained by putting a proton on any one of the four oxygen atoms (C) X-ray structure of 252. A O1 O2 B O3 O4 251 (∠oop = 19.4º, B-O1 = B-O2 = B-O3 = B-O4 = 1.49 Å) B C O1 B O4 O3 2.11 Å O2 Calculated structure of 251-H (∠oop < 1º, B-O1 = 1.39 Å, B-O2 = 3.99 Å, B-O3 = 1.39 Å, B-O4 = 1.35 Å) 284 252 Importantly, two compounds 253 and 254 were reported when a mixture containing catechol and boric acid (0.5 equiv) was subjected to NMR analysis in aqueous solutions (Scheme 10 4.3A). 11 In the B NMR spectrum, two peaks at δ = 7.6 ppm and δ = 13.1 ppm were reported 10a for 253 and 254, respectively, at pH = 11. This result was expected as the analysis was performed under aqueous conditions where water is acting as the base. Also, a variety of other products were reported that were a function of the different ratios of both the components 9 (Scheme 4.3B). Similar compounds have also been reported and observed for BINOL 55 (Scheme 5.4, Chapter 5). As shown in Scheme 4.3B, a salt 247c derived from catechol 250, B(NMe2)3 (0.5 equiv) is found to exhibit a peak at δ = 14.0 ppm (in C6D6) in the 4i spectrum. literature. 11 B NMR A number of similar spiroborates from different diols have been reported in the 11 In the end, the results suggest that the spiroborate 20-H is unlikely to exist in the the absence of base. At the same time, ion-pair 74 can be generated as soon as imine is added. However, different ligands might behave differently. Hence, a second case was then examined involving the fused-spiroborate 22-H (Figure 4.1B). 4.3 The case of the chiral fused-spiroborate 22-H As discussed earlier, the fused-spiroborate (FSB) 22-H is another example of a published neutral chiral borate containing a tetra-coordinate borate anion and a “free” proton as the counterion (Scheme 4.1). In 1994, Yamamoto and co-workers reported chiral catalyst 22-H for the first time. 3a They used this catalyst for the asymmetric Diels-Alder reaction between dienes 285 and enals/alkynals (Scheme 4.4A and 4.4B). was provided for the catalyst 22-H except a 3a-3d 11 It must be noted that no spectroscopic data B NMR spectrum (δ = 10 ppm). Scheme 4.4 Asymmetric reactions reported to be catalyzed by 22-H A Asymmetric Diels-Alder reactions of dienes and enals 3a-3c R1 catalyst 22-H (10 mol %) R2 + R3 CHO 93 4 Å MS, CH2Cl2 –78 °C, 4 h exo-endo = 49 − >99:1 94 R2= Br,Me,Et R3= H,Me R1= H, CH2OBn B Asymmetric Diels-Alder reactions of dienes and alkynals + R CHO 96 n = 1,2 R2 95 7 examples yield = > 99% ee = 92 – > 99% n CHO R 3e 1) catalyst (S)-22-H (10 mol%) CH2Cl2, –78 °C R1 + CHO 103 5 examples yield = 28 – 98% ee = 34 – 95% R = I,Me,CO2Et C Formal [4+3] cycloaddition 96b 4 Å MS, CH2Cl2 –78 °C, 3–66 h 102 R1 3d catalyst 22-H or 98 (10-20 mol%) n R3 R2 CHO 97 2) AlCl3 (1.1 equiv) 0 °C, CH2Cl2, 2 h R1= Me,Et, Bn R2= -(CH2)3- O R2 1 R 101 4 examples yield = 72 – 85% ee = 46 – 96% 286 In the year 2006, Davies and coworkers introduced a formal [4+3] cycloaddition by a tandem Diels Alder reaction/ring expansion using 22-H as the catalyst (Scheme 4.4C). 3e The catalyst 22-H was prepared by the reaction of the tetra-phenol 89 with 1 equiv of commercial B(OPh)3 and its structure was proposed to contain a tetra-coordinate borate anion that was protonated at some unspecified location (Scheme 4.5). 3a-3d Similar to the case of 20-H, the mode of catalysis of 22-H was proposed to be that of a Brønsted acid assisted Lewis acid (BLA) catalyst which means that it behaves as a chiral Lewis acid where interaction with a Lewis base disrupts one of the boron-oxygen bonds to give Lewis acid-Lewis base complex 90ʹ′ (Scheme 4.5). This case study is more likely to give 22-H, perhaps, due to the presence of all four oxygens in the same molecule. Scheme 4.5 Proposed catalytic activity of 22-H OH B(OPh)3 OH OH (1 equiv) OH 89 O O O Lewis – + Base B H O 22-H Brønsted acid O O O H B O LB 90' (LB = aldehydes) Brønsted acid assisted Lewis acid (BLA) In the current work, the first step in characterization of the proposed structure 22-H was the optimization by DFT calculations using Gaussian ʹ′03 at B3LYP/6-31g* level of theory. 5 After the optimization of the fused-spiroborate anion 22, energy minimization of 22-H was performed 287 by putting a proton on each oxygens. The two structures 91 and 91ʹ′ were obtained where structure 91ʹ′ was found to be lying +4.3 kcal/mol higher in energy (Figure 4.8B). Additionally, structure 91 is stabilized by an extra hydrogen bond of the OH at O1 to one of the oxygen of the 3-coordinate borate ester. However, in both cases, the calculations revealed the presence of a tricoordinate boron atom instead of a tetra-coordinate boron atom as proposed in the original structure of 22-H. The observation is in agreement with that seen for the case of spiroborate 20H. However, this computational result is not consistent with the fact that a peak at δ = 10 ppm is reported for the 11 B NMR spectrum of 22-H. This chemical shift lies in the range of a tetra- coordinate boron as was observed in the case of BINOL derivatives (Figure 4.2). The calculated value of the chemical shift of boron in 91 (Figure 4.8B) is found to be 19 ppm using Gaussian ʹ′03. Hence, to address this discrepancy it was deemed important to experimentally reproduce Yamamoto’s synthesis of 22-H as it might lead us to a better understanding of finding a protocol towards the trapping of protonated form of VAPOL boroxinate i.e. 23-H. Figure 4.8 Calculated structures of 22, 91 and 91ʹ′obtained using Gaussian ʹ′03 at B3LYP/6-31g* level of theory. All structures are visualized by the Mercury program (C, gray; O, red; B, yellow; H, light blue). Hydrogens are omitted for clarity (except O-H). ∠oop = angle out of plane for the current/former tetra-coordinate boron, B-On = the distance between O-n and the current/former tetra-coordinate boron where n = 1-4. (A) Calculated structure of fused- spiroborate anion 22 (B) Calculated structure 91 obtained by putting a proton on O1 (C) Calculated structure 91ʹ′ obtained by putting a proton on O3 288 Figure 4.8 cont’d A boron O2 O4 B O3 O1 oxygen carbon hydrogen 22 (∠oop = 18.1º–20.9º, B-O1 = B-O4 = 1.45 Å, B-O2 = B-O3 = 1.50 Å) B O4 O2 O3 B O2 1.85 Å O1 O3 91 (∠oop < 1º, B-O1 = 3.94 Å, B-O2 = 1.39 Å, B-O3 = 1.38 Å, B-O4 = 1.37 Å) (ΔΔG = 0 kcal/mol) O4 B O1 91ʹ′ (∠oop < 1º, B-O1 = 1.37 Å, B-O2 = 1.39 Å, B-O3 = 2.50 Å, B-O4 = 1.38 Å) (ΔΔG = +4.2 kcal/mol) The BINOL derivative (R)-89 was prepared by Suzuki coupling of (R)-259 with 2methoxyphenylboronic acid 260 in the presence of Pd(PPh3)4 and subsequent demethylation (Scheme 4.6) 289 Scheme 4.6 Preparation of BINOL derivative 89 I OH OH MeI OMe OMe K2CO3 acetone nBuLi TMEDA OMe OMe I2 71% I 90% 55 258 259 Pd(OAc)2 Ba(OH)2 8H2O OH OH OH OH 89 OMe OMe OMe OMe BBr3 CH2Cl2 85% P(o-tolyl)3 B(OH)2 80 °C, 2 h 260 95% DME:H2O (6:1) MeO 261 In order to independently characterize the structure 22-H proposed by Yamamoto, the synthesis of 22-H was performed following Yamamoto’s protocol, which involves the reaction of the BINOL derivative (R)-89 (0.05 mmol) with one equiv of B(OMe)3. According to the procedure, both of the components were refluxed at 60 °C in CD2Cl2 (3 mL) for 2 h during which the methanol was removed using 4Å Molecular Sieves (pellets) in a Soxhlet thimble. 3a A white precipitate was observed. Thereafter, it was then stirred vigorously for 0.5 h after the addition of extra CD2Cl2 (1.5 mL). Most of the white precipitate was dissolved and the 1 resulting turbid solution was subjected to NMR analysis. The H NMR spectrum reveals a complex mixture of species (Figure 4.9C, entry 2). Interestingly, no peak at δ = 10 ppm was observed in the 11 B NMR spectrum. In fact, the 11 290 B NMR spectrum shows a broad absorption at 19.5 ppm that is very similar to that observed for 20-H and which would be expected for a tricoordinate borate species (Figure 4.9B, entry 2). Figure 4.9 (A) NMR Analysis of a mixture of 89 with various boron sources and imine 78a. (B) 11 a 1 B NMR spectra of the reaction mixture in CD2Cl2. (C) H NMR spectra (aromatic region) corresponding to the 11 B NMR spectra in Figure 4.9B. A OH OH OH OH boron source (1 equiv) O O O Method I-III 89 H O 91 B Ph O imine 78a O O CD2Cl2 25 ºC 5 min – B O 92a Brønsted acid B E-9 + imine 78a (1 equiv) (R)-89 + B(OPh)3 (1 equiv) E-7 + imine 78a (1 equiv) (R)-89 + BH3•Me2S (1 equiv) E-5 + imine 78a (1 equiv) E-2 + MeOH (3 equiv) E-2 + MeOH (1 equiv) E-2 + imine 78a (1 equiv) (R)-89 + B(OMe)3 (1 equiv) (R)-89 291 Ph + N Ph H Figure 4.9 cont’d C a Note for Figure 4.9B: Entry 1: pure BINOL derivative (R)-89. Entry 2: (R)-89 (0.05 mmol) plus 1 equiv B(OMe)3 were refluxed at 60 °C in CD2Cl2 (3 mL) for 2 h. The methanol was removed using 4Å Molecular Sieves (pellets) in a Soxhlet thimble. After cooling to 25 ºC, additional 1.5 mL of CD2Cl2 added and then stirred vigorously for 0.5 h and directly subjected to NMR analysis (Method I). Entry 3: 1.0 equiv imine 78a was added to the entry 2 for 10 min at 25 °C. Entry 4: 1.0 equiv MeOH was added to the entry 2 for 10 min at 25 °C. Entry 5: 3.0 equiv MeOH was added to the entry 2 for 10 min at 25 °C. Entry 6: 1.0 equiv imine 78a was 292 added to the entry 5 for 10 min at 25 °C. Entry 7: (R)-89 (0.05 mmol) plus 1 equiv BH3•Me2S were heated at 80 °C in toluene for 1 h followed by removal of volatiles under vacuum for 0.5 h (Method II). Entry 8: 1.0 equiv imine 78a was added to the entry 7 for 10 min at 25 °C. Entry 9: (R)-89 (0.05 mmol) plus 1 equiv B(OPh)3 and powdered 4Å Molecular Sieves (150 mg) were stirred for 1 h in CD2Cl2 (1.5 mL) at 25 °C (Method III). Entry 10: 1.0 equiv imine 78a was added to the entry 9 for 10 min at 25 °C. These results from the 11 B NMR spectrum suggests that a species like 22-H, if formed at all, are highly unstable and can only be observed by NMR spectroscopy in the presence of a base. Although, the Diels-Alder reaction is performed with enals, which are weak bases, it was decided to use the imine 78a as the base to generate the fused-spiroborate 92a. In fact, a peak at δ = 5.93 ppm in the 11 B NMR spectrum appeared when one equivalent of imine 78a was added to the 1:1 mixture of ligand 89 and B(OMe)3 (Figure 4.9B, entry 3). This compound is assigned as the ion-pair 92a comprised of a fused-spiroborate anion 22 and the protonated form of imine 78a. These observations further supports the hypothesis that a base is needed to induce the formation of these complexes under non-aqueous conditions. It is worth mentioning that methanol is reported to be involved in adduct formation with trimethylborate. of the peak observed at δ = 10 ppm in the 11 12 An explanation B NMR spectrum of the compound that Yamamoto assigned as 22-H (Scheme 4.5) is that a residual amount of methanol might be functioning as a coordinating ligand in the original experiment reported by Yamamoto. To test this an additional 293 equivalent of the methanol was added to the mixture containing ligand 89 and B(OMe)3. The increase in sharpness of the peak in the 11 B NMR spectrum revealed that the electrophilic boron centre might be experiencing a tetragonal environment (Figure 4.9B, entry 4). However, there was no change in the chemical shift and hence the possibility of the coordination of methanol was considered unlikely. In fact, when excess methanol (3 equiv) was added, the reaction furnished pure ligand (Figure 4.9B and 4.9C, entry 5). Addition of 1 equiv of imine 78a to this mixture resulted in the generation of 92a (Figure 4.9B and 4.9C, entry 6). Yamamoto and coworkers have also employed B(OPh)3 and ligand 89 for catalyst formation in a Diels-Alder reaction. As shown by the 11 B NMR spectrum, no formation of a tetra-coordinate boron species occurs until a base (imine in this case) is added irrespective of the boron source being used (Figure 4.9B, entries 7 and 9 vs. 8 and 10). It must noted that a large amount of phenol was observed in the case of catalyst formation with B(OPh)3 (Figures 4.9B and 4.9C, entry 9). This is thought to be due to the exchange of phenol in B(OPh)3 by the ligand. The results from the analysis of 20-H and 22-H suggests that these species have similar structures. Although, no Xray structure was obtained for 92a, its structure was assigned as that shown in Figure 4.10 based on spectral similarities with 74a and the X-ray structure of 74a (Figure 4.5). However, a Lewis acid Lewis base complex of the type 90a cannot be definitively ruled out (Figure 4.9). It must be noted that the original Diels-Alder reaction was performed with enals instead of imines. Hence, since an aldehyde is thought not be basic enough to form an ion-pair of the type 90, it may very well be likely that a Lewis acid Lewis base complex of type 90 may be involved with reactions with enals. 294 Figure 4.10 Brønsted acid 92 and Brønsted acid assisted Lewis acid 90 O O + – B [imine-H] O O O O O H B O imine 90 92 92a (imine = 78a) Brønsted acid 90a (imine = 78a) Brønsted acid assisted Lewis acid (BLA) The results to this point indicate that the compounds 20-H and 22-H do not exist as protonated neutral species to any great extent. However, it is interesting to observe the common trend that theses complexes can be generated upon the addition of bases. Although this study is focused on chiral systems, it was decided to examine at least one achiral system. The structure of the tetraphenoxyborate 262-H (Figure 4.11A) was examined and a discussion of the results is given below. 4.4 The case of the achiral tetraphenoxyborate 262-H Although there is no literature precedent for 262-H, various salts have been reported which 4b-4e have 262 as their anion (Figure 4.11C). + + These salts usually have metal ions like Na , K , + Li and nitrogen bases as the counter cations (Figure 4.11C). 295 Figure 4.11 (A) tetraphenoxyborate anion 262 (B) proposed structure for 262-H (C) common tetraphenoxyborates 244 (D) piperdine-B(OPh)3 244dʹ′ (Lewis acid-Lewis base adduct) (E) + – proposed structure for [imine-H] [B(OPh)4] complex 263/264 A B + H O O– B O O O O– B O O 262 262-H C + X O O– B O O 244a 244b + N H H +N 244 D ion-pair Na+ Li + + X 244c H 244d H E H N O O– B O O O O B O 244d' H + PG N R 263 (PG = Bh) 264 (PG = MEDAM) 296 The proposed structure 262-H was examined theoretically by computing the energy minimum for the anion 262 followed by a similar analysis of the protonated form 262-H. Based on similar results with 20-H and 22-H it was not a surprise that 262-H was found to be highly unstable and dissociated into B(OPh)3 and phenol 182a where phenol is held by hydrogen bonding to B(OPh)3 (Figure 4.12B). Figure 4.12 Calculated structures of 262 and 262-H obtained using Gaussian ʹ′03 at B3LYP/631g* level of theory. All structures are visualized by the Mercury program (C, gray; O, red; B, yellow; H, light blue). Hydrogens are omitted for clarity (except O-H). ∠oop = angle out of plane for the current/former tetra-coordinate boron, B-On = the distance between O-n and the current/former tetra-coordinate boron where n = 1-4. tetraphenoxyborate anion 262 (A) Calculated structure of (B) Calculated structure of 262-H, the protonated tetraphenoxyborate anion 262. A B O1 O2 O1 B O4 O3 1.98 Å O2 O4 B O3 262 (∠oop = 19.4º, B-O1 = B-O2 = B-O3 = B-O4 = 1.47 Å) 262-H (∠oop <1º, B-O1 = 3.51 Å, B-O2 = 1.39 Å, B-O3 = 1.36 Å, B-O4 = 1.37 Å) 297 In order to further confirm that the presence of base is needed for the generation of tetraphenoxyborate anion 262, a detailed study based on NMR experiments was performed. A fresh sample of B(OPh)3 was prepared from BH3•Me2S and PhOH (see experimental). When one equiv of PhOH 194a was added to freshly prepared B(OPh)3, there is no significant change 1 in the H or the 11 B NMR spectra (Figure 4.13, entry 3). However, when one equivalent of 1 DMAP was added to this mixture, H NMR spectrum revealed the upfield shift in the doublet for the ortho hydrogens of the phenol component from 7.15 ppm to 7.03 ppm (Figure 4.13, entry 4). Additionally, appearance of a peak at δ = 2.24 ppm in the 11 B NMR spectrum is suggestive of the formation of 244e. Similar observations were reported when piperidine was used as the base to form 244d (δ = 2.6 ppm (THF-d8), 11 4e B NMR) (Figure 4.11C). However, in the same work, it had been reported that a Lewis acid-base adduct (piperidine->B(OPh)3) 241dʹ′ (δ = 2.3 ppm (nitrobenzene), 11 B NMR) is generated from the reaction between piperidine and B(OPh)3 in 4e absence of phenol (Figure 4.11D). Hence, the 11 B NMR data is similar for the ion-pair 244d and adduct 244dʹ′. Similar can be assumed for the complexes generated for the reaction between DMAP and freshly prepared B(OPh)3. However, the presence of the ion-pair 244e was supported by X-ray analysis described later. In the past, we have observed that commercial B(OPh)3 always has some percentage of phenol in its composition (Figure 4.11, entry 2 vs. 3 and 5). An observation similar to entry 4 of Figure 4.13B and 4.13C was made when one equivalent of DMAP was added to commercial B(OPh)3 (entry 6). In fact, a peak at δ ~ 2-3 ppm in the 298 11 B NMR spectrum has been occasionally observed during the formation of an IMINO-BOROX catalyst from a mixture of a vaulted ligand, B(OPh)3 and an imine. Hence, a similar ion-pair 263/264 can be assumed to be generated when commercial B(OPh)3 and imines 78/111 interact with each other (Figure 4.11E). A racemic reaction between imine 78a and EDA 85 mediated by commercial B(OPh)3 results in 78% yield of aziridine 86a. This is probably a racemic reaction catalyzed by the racemic Brønsted acid 264. Figure 4.13 (A) NMR Analysis of a mixture of PhOH 194a with B(OPh)3 187a and DMAP 216c. (B) a1 H NMR spectra of the reaction mixture in CDCl3 (aromatic region). (C) 11 B NMR 1 spectra corresponding to the H NMR spectra in Figure 4.13B A N OH B(OPh)3 187a (1 equiv) N H N + (1 equiv) 216c CDCl3 25 ºC, 5 min O O– B O O N 194a 244e 299 B Figure 4.13 cont’d DMAP B(OPh)3 (commercial) + DMAP (1:1) 8.4 B(OPh)3 (commercial) B(OPh)3 (freshly prepared) + PhOH + DMAP (1:1:1) 8.4 B(OPh)3 (freshly prepared) + PhOH (1:1) B(OPh)3 (freshly prepared) PhOH (freshly sublimed) C B(OPh)3 (commercial) + DMAP (1:1) B(OPh)3 (commercial) B(OPh)3 (freshly prepared) + PhOH + DMAP (1:1:1) B(OPh)3 (freshly prepared) + PhOH (1:1) B(OPh)3 (freshly prepared) 300 a Note for Figure 4.13B: Entry 1: freshly sublimed PhOH 194a. Entry 2: freshly prepared B(OPh)3; BH3•Me2S (0.1 mmol) plus 3 equiv PhOH were heated at 80 °C in toluene for 1 h followed by removal of volatiles under vacuum for 0.5 h. Entry 3: 1.0 equiv PhOH 194a was added to the entry 2 for 10 min at 25 °C. Entry 4: 1.0 equiv DMAP 216c was added to the entry 3 for 10 min at 25 °C. Entry 5: commercial B(OPh)3. Entry 6: 1.0 equiv DMAP 216c was added to the entry 5 for 10 min at 25 °C. Entry 7: pure DMAP 216c A literature search revealed that there are several ion pairs comprised of the tetraphenoxyborate anion 262 and a protonated nitrogen base with 4e given in some cases (Figure 4.2). 11 B NMR spectroscopic data Although, salts derived from 262 and metal ions have been characterized by X-ray crystallography, no X-ray analysis has been reported for ion-pairs generated from nitrogen bases. To our delight, a few colorless crystals of 244e serendipitously formed in the NMR tube during the analysis of boroxinate complex 217c (Chapter 2, Table 2.9) 13 generated from a mixture of (S)-VAPOL 58, B(OPh)3 and DMAP (this work). This provided an opportunity to confirm our proposed structure for the ion-pair 244e. The X-ray structure of 244e revealed the presence of protonated DMAP in two positions in 75% and 25% probabilities (Figure 4.14A). The key interaction is the hydrogen bond between the protonated nitrogen and one of the oxygens of the tetraphenoxyborate anion (d1 = 1.99 Å, d2 = 2.18 Å, Figure 4.14A). The complete proton transfer to nitrogen was further confirmed by the N-H bond of 0.81 Å. There also appears to be a π–π stacking interaction (d5 = 3.23 Å) between one of the phenoxy 301 rings of the tetraphenoxyborate anion and the pyridinium ion of the protonated DMAP. In addition, there appears to be a CH–π interaction (d3 = 3.64 Å) between an ortho hydrogen on the DMAP ring and a different phenoxy ring (Figure 4.14B). Another CH–π interaction (d4 = 3.71 Å) is between one of the methyl groups on the protonated DMAP and a phenoxy ring. Figure 4.14 (A) Solid state structure of the tetraphenoxyborate 244e visualized by the Mercury program (C, gray; O, red; B, yellow; H, light blue). Calculated hydrogen atoms and solvent molecules were omitted for clarity. Hydrogen attached to nitrogen is shown to highlight the hydrogen bonding (d1 = 1.99 Å and d2 = 2.18 Å). ∠oop = angle out of plane for the current/former tetra-coordinate boron, B-On = the distance between O-n and the current/former tetra-coordinate boron where n = 1-4. (B) Some secondary interactions were proposed and highlighted: d3 = 3.64 Å (CH–π); d4 = 3.71 Å (CH–π) and d5 = 3.23 Å (π–π stack). (C) Spacefilling model of the complex 244e. The color scheme is given in Figure 4.14A. (D) Drawing of the packing along the axis where the dotted lines represent potential hydrogen bonding. A 25% 75% O1 d1 O4 boron oxygen O2 B d2 O3 carbon hydrogen nitrogen 244e (∠oop = 18.2º-19.7º, B-O1 = B-O3 = 1.46 Å, B-O2 = 1.48 Å, B-O4 = 1.47 Å) 302 B C d3 d4 d5 D 4.5 Mode of Catalysis: Lewis Acid Catalysis verses Brønsted Acid Catalysis 1 Based on the above H NMR and computational analysis, it is quite clear that the protonated neutral spiroborates 20-H, 21-H and 22-H are not favorable species. The data suggests that there is no tetra-coordinate boron species unless an imine is added to deprotonate the hydroxyl group in the BINOL 55 or BINOL derivative 89. 303 At this point, it became interesting to explore the mode of catalysis for reactions that have been reported for these chiral catalysts. 4.5.1 Asymmetric Imino-aldol reaction and heteroatom Diels-Alder reactions catalyzed by 20-H As shown in Scheme 4.1, the catalyst 20-H has been proposed to be the active catalyst in asymmetric imino-aldol reactions and in heteroatom Diels Alder reactions. In both cases, the mode of catalysis has been assumed to be as a Brønsted acid assisted Lewis acid (BLA) catalysis (Scheme 4.2). After we collected evidence that suggests that the catalyst is an ion-pair 74 consisting of a chiral borate anion and a protonated iminium ion (Figure 4.5), we became interested as to whether the mode of catalysis for these reactions involves a Brønsted acid (BA) or a Brønsted acid assisted Lewis acid (BLA) catalysis. Another current group member, namely Dr. Mathew Vetticat, initiated theoretical calculations to investigate the transition states for the asymmetric imino-aldol reaction. He found out that it indeed occurs via a Brønsted acid (BA) catalyzed reaction contrary to the proposed Brønsted acid assisted Lewis acid (BLA) mechanism. 14 The energy difference between the BA (TS-263) and BLA (TS-264) type transition states leading to the favored enantiomer was found to be +12 kcal/mol. Furthermore, it must be noted that a similar behavior has been assumed in case of heteroatom Diels-Alder reaction. 304 Figure 4.15 (A) Asymmetric imino-aldol reaction of imine 78a catalyzed by 20-H (B) Diagrammatic representation of TS-263 and TS-264 for BA and BLA type mechanism respectively. A Ph OTMS N Ph + OtBu Ph 78a 76 Ph catalyst 20-H (100 mol %) HN 4 Å MS, CH2Cl2 –78 °C, 20 h Ph CO2tBu Ph 79a 58% yield, 96% ee B Ph TMSO tBuO Ph N + Ph Ph TMSO tBuO H O – O B O O Ph N Ph O O B O O H TS-263 4.5.2 TS-264 Asymmetric Pictet-Spengler reaction catalyzed by 20-H and 21-H. The asymmetric Pictet-Spengler reaction is another reaction that has been reported with 2e,2f the catalyst 20-H but requires the use of two equivalents of 20-H. This reaction was performed using nitrones instead of imines. Hence, the question arises of whether this reaction occurs via BA or BLA type catalysis. As a part of this doctoral research, the transition states for each mode of catalysis were located using Gaussian ʹ′03 and are presented in Figure 4.16. In 305 order to reduce the computational cost, the hydrid DFT:Semi-emperical ONIOM method was implemented. The division of layers for the ONIOM calculations is illustrated by the given color scheme in Figure 4.7A. All the calculated distances are reported in angstroms and the reported ‡ energies are ΔΔG for fully optimized geometries from the ONIOM calculations. Figure 4.16 (A) Asymmetric Pictet-Spengler reaction of nitrone 83a catalyzed by 20-H. (B) Division of layers for the ONIOM(B3LYP/6-31g**:AM1) level of calculations. (C) 3D structures and relative energies of TS-S-265 and TS-R-265 for BA type mechanism. The relative energies given in italics are the energies computed from the full DFT B3LYP/6-31g*. (D) 3D structures and relative energies of TS-S-266 and TS-R-266 for BLA type mechanism. A + N O– N H Ph catalyst 20-H (200 mol %) N OH N H 4 Å MS, CH2Cl2 25 °C, 48 h 83a Ph 84a B 81% yield, 73% ee N H + N O H Ph + N O– N H O – O B O O Ph O O B O O H TS-265 TS-266 Red = B3LYP/6-31g** Green = AM1 306 Figure 4.16 cont’d C 1.86 Å 1.67 Å 1.88 Å 2.02 Å 2.05 Å 1.73 Å boron TS-S-265 TS-R-265 ‡ oxygen ‡ carbon (ΔΔG = +1.0 kcal/mol) (ΔΔG = +1.4 kcal/mol) ‡ (ΔΔG = 0 kcal/mol) ‡ (ΔΔG = 0 kcal/mol) hydrogen nitrogen D 1.85 Å 1.83 Å 1.90 Å 2.06Å TS-S-266 TS-R-266 ‡ ‡ (ΔΔG = 0 kcal/mol) (ΔΔG = +0.6 kcal/mol) 307 In case of the BA type mechanism, the most stable transition state for the formation of both the R and S products from the (S, S)-catalyst were located and are given in Figure 4.16B. Other than the hydrogen bonding (1.67 Å, Figure 4.16B), there was one additional important interaction, a CH-O interaction between the hydrogen in the 2-position of the indole and oxygen of the spiroborate (2.02 Å, Figure 4.16B) in case of S-enantiomer formation. Unfortunately, these calculations do not match the experimental findings as the minor enantiomer (R) is found to be the one with lowest energy. Based of the ONIOM calculations, the major enantiomer (S) is found to be +1.0 kcal/mol higher in energy. In fact, calculations using full DFT (B3LYP/631g*) also predict a similar outcome with S-product formation favored by +1.4 kcal/mol. (Figure 4.16B). It was found that transition state TS-S-265 (BA type mechanism) leading to the favored enantiomer (S) was found to be +5.4 kcal/mol higher in energy than TS-S-266 (BLA type mechanism) also leading to the S-enantiomer of the product (Figure 4.16B and 4.16C). Upon location of the two transition states 266 for the formation of both the R and S products via the BLA mechanism, it was found that the TS leading to the minor enantiomer (R) is 0.6 kcal/mol higher in energy than that for the major enantiomer (S). Single-point energies were then calculated and it was found that the disfavored enantiomer is +2 kcal/mol higher in energy. Hence, these computational studies suggest that a BLA mechanism is operational in case of nitrones for an asymmetric Pictet-Spengler reaction. Thus, a summary of the mode of catalysis for the reactions with 20-H is presented in Scheme 4.7. 308 Scheme 4.7 Current understanding of the catalytic activity of 20-H Catalyst Mode of Catalysis + H Old Proposal (Yamamoto, Nakagawa) LB O – O B O O LB OH OH O H O B O 20-H 2 O 71 (LB = imine) 71' (LB = nitrone) Brønsted acid assisted Lewis acid (BLA) Brønsted acid LB 55 O + O O B B(OPh)3 New Proposal (Wulff) H LB O O 72 Brønsted acid assisted Lewis acid (BLA) O B H O 73' (LB = nitrone) Brønsted acid assisted Lewis acid (BLA) + [LB-H] O O B O H LB O 72 Brønsted acid assisted Lewis acid (BLA) 4.5.3 O O – O B O O 74 (LB = imine) Brønsted acid Asymmetric Diels-Alder reaction catalyzed by 22-H. Although no evidence could be gained for the existence of 22-H by NMR spectroscopy, the mode of catalysis is thought to be more likely to be as a Brønsted acid assisted Lewis acid catalyst in the case of the Diels-Alder reaction between α-methylacrolein 94a and 3a-3c cyclopentadiene 93a (Figure 4.17A). This is possibly due to high acidity of protonated aldehydes. 309 Figure 4.17 (A) Asymmetric Diels-alder reaction of 94a catalyzed by 22-H. (B) Diagrammatic representation of TS-267 and TS-268 for BA and BLA type mechanism respectively. A Me + CHO 93a 94a catalyst 22-H (10 mol %) CHO 4 Å MS, CH2Cl2 –78 °C, 4 h Me 95a >99% yield, 99%ee B O O O O – B O O O + O H H TS-267 B O O TS-268 Dr. Mathew Vetticatt, a current group member, found from computational studies that indeed in this reaction between enals and dienes the catalyst appears to be operating as a 14 Brønsted acid assisted Lewis acid (Figure 4.17B). reaction is presented in Scheme 4.8. 310 Hence, the current understanding of this Scheme 4.8 Current understanding of the catalytic activity of 22-H Catalyst Old Proposal (Yamamoto) OH B(OPh)3 (1 equiv) OH OH OH 89 New Proposal (Wulff) Mode of Catalysis O – + O B H O O LB 22-H Brønsted acid LB 91 Brønsted acid assisted Lewis acid (BLA) 4.6 LB 90' (LB = aldehydes) Brønsted acid assisted Lewis acid (BLA) LB O O B O HO O O B O HO O + – O B [LB-H] O O 92 (LB = imine) Brønsted acid Conclusions In the end, it is quite evident that ion-pairs 20-H, 21-H, 22-H, and 262-H, if they exist at all, are unfavorable with regard to alternative structures not containing a tetra-coordinate boron. In contrast, the ion-pairs 102a, 74a, 90a and 244e have been characterized by NMR spectroscopy and X-ray crystallography. As of now, there is no evidence for the protonated form of the VAPOL boroxinate 23-H, but rather that like the case of 20-H–22-H it appears to be unstable with respect to other structures. One of the biggest advantages of the above-discussed case studies is that it has provided a better understanding of the structure and function of variety of chiral Brønsted acids derived from chiral borate anions from both vaulted and linear biaryl ligands. 311 APPENDIX 312 4.7 Experimental 4.6.1   General information ........................................................................................................ 314   4.6.2   Synthesis of imine 78a, B(OPh)3 187a and (R)-3,3ʹ′-(2-OH-C6H4)2-BINOL 89........... 314   4.6.3   NMR analysis of a mixture of BINOL 55, commercial B(OPh)3 and imine 78a or DMAP 216c (Figure 4.4) ............................................................................................................ 320   4.6.4   NMR analysis of a mixture of (R)-3,3ʹ′-(2-OH-C6H4)2-BINOL 89, various boron sources and imine 78a (Figure 4.9) ............................................................................................. 321   4.6.5   NMR analysis of a mixture of Phenol 194a, commercial and freshly prepared B(OPh)3 and DMAP 216c (Figure 4.14) ....................................................................................... 324   4.6.6   DFT calculations ............................................................................................................. 325 313 4.6.1 General information The general information of this chapter is similar to that of Section 2.6.1 of Chapter 2. All reagents were purified by simple distillation or crystallization with simple solvents unless otherwise indicated. BINOL 55, commercial B(OPh)3 (stored in dessicators), and benzhydrylamine 126a (distilled prior to use) obtained from Aldrich Chemical Co., Inc. and used as received. 4.6.2 Synthesis of Imine 78a, B(OPh)3 187a and (R)-3,3ʹ′-(2-OH-C6H4)2-BINOL 89 a) Imine 78a: The synthesis of imine 78a is given in section 2.6.2 of Chapter 2 b) B(OPh)3 187a: OH BH3•Me2S (1 equiv) 3 194a toluene, 80 °C, 1 h then 0.5 mmHg 80 °C. 0.5 h O B O O 187a Triphenylborate 187a: To a flame dried home-made Schlenk flask equipped with a stir bar and flushed with argon was added PhOH 194a (28.2 mg, 0.300 mmol) and BH3•Me2S (50 µL, 0.10 mmol, 2.0 M in toluene,). Under an argon flow through the side-arm of the Schlenk flask, dry toluene (2 mL) was added. The flask was sealed by closing the Teflon valve, and then placed in an oil bath (80 ºC) for 1 h. After 1 h, a vacuum (0.5 mm Hg) was carefully applied by slightly opening the Teflon valve to remove the volatiles. After the volatiles are removed completely, a 314 full vacuum is applied and is maintained for a period of 30 min at a temperature of 80 ºC (oil bath). The flask was then allowed to cool to room temperature yielding the B(OPh)3 187a as white solid. The resulting freshly prepared B(OPh)3 was directly used for NMR analysis. 1 Spectral data for B(OPh)3 187a: H NMR (CDCl3, 500 MHz) δ 7.13 (t, 3H, J = 7.5 Hz), 7.16 (d, 6H, J = 9.0 Hz), 7.34 (t, 6H, J = 7.5 Hz). 13 C NMR (CDCl3, 125 MHz) δ 120.21, 123.52, 129.26, 152.86. These spectral data match those previously reported for this compound. 4a c) (R)-3,3ʹ′-(2-OH-C6H4)2-BINOL 89: I OH OH MeI OMe OMe K2CO3 acetone nBuLi TMEDA OMe OMe I2 71% I 90% 55 258 259 Pd(OAc)2 Ba(OH)2 8H2O OH OH OH OH 89 OMe OMe OMe OMe BBr3 CH2Cl2 85% P(o-tolyl)3 B(OH)2 80 °C, 2 h 260 95% DME:H2O (6:1) MeO 261 (R)-2,2'-Dimethoxy-1,1'-binaphthalene 258: To 250 mL flame-dried round bottom flask was added (R)-55 (2.5 g, 8.7 mmol) and acetone (80 mL). To this solution were added potassium 315 carbonate (4.0 g, 29 mmol) and methyl iodide (4.94 g, 2.17 mL, 35 mmol), and the mixture was set to reflux for 24 h. Additional methyl iodide (2.07 g, 0.910 mL, 14.6 mmol) was then added and reflux was continued for next 12 h. The solvent was then evaporated to leave a volume of 15 mL and treated with water (80 mL). The mixture was then stirred for 8 h, and the resulting solid was washed with water and dried under vacuum first at 25 °C and then at 95 °C (0.1 mm Hg, for 12 h) to afford (R)-258 as white powder (mp. 225-226 °C) in 90% yield (2.25 g, 7.83 mmol). 1 Spectral data for (R)-258: H NMR (CDCl3, 300 MHz) δ 3.75 (s, 6H), 7.10 (d, J = 8.4 Hz, 2H), 7.17-7.24 (m, 2H), 7.28-7.33 (m, 2H), 7.45 (d, J = 9.0 Hz, 2H), 7.86 (d, J = 8.1 Hz, 2H), 7.97 (d, J = 9.0 Hz, 2H); 13 C NMR (CDCl3, 75 MHz) δ 154.97, 134.00, 129.37, 129.21, 129.90, 126.28, 125.25, 123.48, 119.61, 114.25, 56.89; [α ]25 +54.5 (c 1.0, CHCl3). These spectral data match D those previously reported for this compound. 15 (R)-3,3'-diiodo-2,2'-dimethoxy-1,1'-binaphthalene (R)-259: In a 50 mL flame-dried threenecked round bottomed flask equipped with a N2-inlet were placed dry Et2O (15 mL) and n TMEDA (349 mg, 0.450 mL, 3.00 mmol). To this solution was added BuLi (1.2 mL, 3.0 mmol, 2.5 M in hexanes). The solution was stirred for 30 min at room temperature. To this solution was added solid (R)-258 (314 mg, 1.00 mmol) in one portion and the reaction mixture was stirred for 12 h. The resulting suspension was cooled to –78 °C, and a solution of I2 (1.7 g, 6.5 mmol) in THF (4 mL) was added via syringe over a period of 10 min. The solution was stirred for 1 h at 316 –78 °C and then allowed to warm to room temperature and was left stirring for 18 h. The reaction was quenched with saturated Na2S2O3 solution (10 mL) and stirred for 30 min. The organic layer was separated, and the aqueous layer was extracted by CH2Cl2 (10 mL × 3). The combined organic solution was dried over anhydrous MgSO4, filtered and concentrated in vacuo to afford crude product. Purification by silica gel column chromatography (35 mm × 350 mm column, 4:1 hexanes/CH2Cl2 as eluent, after elution of the first fraction, the eluent was changed to 1:1 hexanes/CH2Cl2) afforded (R)-259 as yellow solid crystals (mp. 191-192 °C) in 71% yield (402 mg, 0.710 mmol). 1 Spectral data for (R)-259: Rf = 0.5 (4:1 hexanes/CH2Cl2); H NMR (CDCl3, 300 MHz) δ 3.39 (s, 6H), 7.05 (d, J = 8.5 Hz, 2H), 7.25 (dt, J = 1.2 Hz, 8.3 Hz, 2H), 7.39 (dt, J = 1.2 Hz, 8.3 Hz, 2H), 7.77 (d, J = 8.3 Hz, 2H), 8.51 (s, 2H); 13 C NMR (CDCl3, 75 MHz) δ 61.10, 92.31, 125.39, 125.64, 125.79, 126.97, 127.07, 132.20, 133.89, 139.92, 154.54; [α ]25 –30.0 (c 1.0, CHCl3). D These spectral data match those previously reported for this compound. 15c (R)-2,2'-dimethoxy-3,3'-bis(2-methoxyphenyl)-1,1'-binaphthalene (R)-261: To a 25 mL flame-dried home-made Schlenk flask (see Figure 2.26) equipped with a stir bar and flushed with argon was added (R)-3,3'-diiodo-2,2'-dimethoxy-1,1'-binaphthalene (R)-259 (1.1 g, 2.0 mmol), 2methoxyphenylboronic acid 260 (760 mg, 5 mmol), and barium hydroxide octahydrate (1.58 g, 5 mmol). Under an argon flow through the side-arm of the Schlenk flask, DME-H2O (6:1, 21 mL) was added through the top of the Teflon valve to dissolve the two reagents. To this mixture was 317 added palladium(II) acetate (22.4 mg, 0.100 mmol) and tris-o-tolylphosphine (60.9 mg, 0.2 mmol). The resulting reaction mixture was degassed three times and charged with argon. The flask was sealed by closing the Teflon valve, and then placed in an 80 ºC oil bath for 2 h. The flask was then allowed to cool to room temperature and opened to argon through the side-arm of the Schlenk flask. Thereafter, the reaction mixture was filtered through a Celite pad and the filtrate was diluted with saturated NH4Cl (aq) and extracted twice with ether. The combined extracts were dried over MgSO4, filtered, and concentrated in vacuo. Purification of the crude product by silica gel chromatography (35 mm × 400 mm column, 9:1 hexanes/EtOAc as eluent, under gravity) afforded pure (R)-261 as a white solid (mp. 97-100 °C) in 95% isolated yield (1.0 g, 1.9 mmol). 1 Spectral data for (R)-261: Rf = 0.39 (9:1 hexanes/EtOAc); H NMR (CDCl3, 600 MHz) δ 3.19 (s, 6H), 3.76 (s, 6H), 6.99 (dd, J = 8.3, 1.0 Hz, 2H), 7.05 (td, J = 7.4, 1.0 Hz, 2H), 7.24-7.28 (m, 2H), 7.33 (d, J = 8.3 Hz, 2H), 7.34-7.39 (m, 4H), 7.46 (dd, J = 7.5, 1.8 Hz, 2H), 7.87 (d, 2H, J = 8.3 Hz), 7.89 (s, 2H); 13 C NMR (CDCl3, 150 MHz) δ 55.71, 60.58, 111.01, 120.41, 124.53, 124.77, 125.85, 125.91, 127.88, 128.48, 128.81, 130.48, 130.81, 131.28, 132.53, 133.82, 154.94, 157.24; [α ]20 +84.0 (c 1.0, CH2Cl2). These spectral data match those previously reported for D this compound. 3e (R)-3,3'-bis(2-hydroxyphenyl)-[1,1'-binaphthalene]-2,2'-diol 89: To a 50 mL flame-dried round bottom flask was added (R)-260 (790 mg, 1.5 mmol) and CH2Cl2 (10 mL). To this solution at –78 °C was added BBr3 (12 mL, 1.0 M in CH2Cl2) drop-wise. The reaction was 318 allowed to warm to 0 °C. The reaction mixture was stirred for 0.5 h at 0 °C and then was allowed to warm to room temperature. After stirring at room temperature for 1 h, the reaction was quenched by the slow addition of the distilled water (15 mL). The aqueous layer was extracted with CH2Cl2 (10 mL × 3). The combined extracts were then washed with water, brine and then dried over MgSO4, filtered, and concentrated in vacuo. Purification of the yellow colored crude product by silica gel chromatography (35 mm × 400 mm column, 3:1 hexanes/EtOAc as eluent, under gravity) afforded pure (R)-89 as a white solid (mp. 144-145 °C) in 85 % isolated yield (600 g, 1.28 mmol). 1 Spectral data for (R)-89: Rf = 0.19 (4:1 hexanes/EtOAc); H NMR (CDCl3, 600 MHz) δ 6.03 (br s, 2H), 6.79 (br s, 2H), 6.90 (t, J = 7.7 Hz, 2H), 7.13-7.18 (m, 2H), 7.25-7.30 (m, 4H), 7.34 (dd, J = 7.7 Hz, 1.7 Hz, 2H), 7.64 (d, J = 7.8 Hz, 2H), 7.75 (s, 2H), (4 protons cannot be located); 13 C NMR (CDCl3, 150 MHz) δ 114.37, 116.40, 121.10, 124.27, 124.39, 124.98, 127.11, 127.74, 128.43, 129.44, 129.83, 131.47, 132.18, 133.48, 149.66, 152.27; [α ]25 –105 (c D 1.0, CHCl3). These spectral data match those previously reported for this compound. 319 3c,3e 4.6.3 NMR analysis of a mixture of BINOL 55, commercial B(OPh)3 and imine 78a or DMAP 216c OH OH B(OPh)3 (0.5 equiv) O O O B O H 55 72 Brønsted acid assisted Lewis acid (BLA) Base + [Base-H] Solvent 25 ºC, 5 min O – O B O O Ph N Ph Ph 74a (Base = imine 78a) 147f (Base = DMAP) Brønsted acid imine 78a Entry 1, Figure 4.4: The NMR of pure BINOL 55 was taken in CD2Cl2. Entry 2, Figure 4.4: To a flame dried 25 mL round bottom flask equipped with a stir bar and flushed with argon was added 4Å Molecular Sieves (150 mg). The sieves were then flame dried in the same flask. To the same flask was added BINOL 55 (28.6 mg, 0.100 mmol), B(OPh)3 (14.5 mg, 0.050 mmol) and CD2Cl2 (3 mL). The resulting mixture was then stirred for 1 h. The 1 sample was then filtered and transferred to a quartz NMR tube and was subjected to H NMR and 11 B NMR analysis. 320 Entry 3, Figure 4.4: Imine 78a (136 mg, 0.05 mmol, 0.5 equiv) was added to the NMR tube containing entry 2. The NMR tube was shaken for 2 min before the analysis. Entry 4 and 5, Figure 4.4: Same as entry 2 and 3 respectively where CDCl3 is used as the NMR solvent. Entry 6, Figure 4.4: Same as entry 4 where DMAP 216c is used as the base. 4.6.4 NMR analysis of a mixture of (R)-3,3ʹ′-(2-OH-C6H4)2-BINOL 89, various boron sources and imine 78a OH OH OH OH 89 boron source (1 equiv) O O O Method I-III H O 91 B Ph O imine 78a O O CD2Cl2 25 ºC 5 min – B O Ph + N H Ph 92a Brønsted acid Entry 1, Figure 4.9: The NMR of pure BINOL derivative 89 was taken in CD2Cl2. Entry 2, Figure 4.4: To a flame dried 25 mL round bottom flask equipped with a stir bar and a 10 mL pressure-equalized addition funnel (containing a cotton plug and ca. 4 g of 4Å Molecular Sieves (pellets) and functioning as a Soxhlet extractor) surmounted by a reflux condenser was added BINOL derivative 89 (23.5 mg, 0.050 mmol), B(OMe)3 (0.5 mL, 0.1 M solution in 321 CD2Cl2, 0.050 mmol) and CD2Cl2 (3 mL). An argon atmosphere was secured and the solution was refluxed at 60 °C for 2 h. The reaction was cooled to room temperature and the addition funnel and condenser were quickly removed and replaced with septum. After cooling to 25 ºC, an additional 1.5 mL of CD2Cl2 was added and then stirred vigorously for 0.5 h. Most of the white precipitate was dissolved and the resulting turbid solution was directly transferred to a 1 quartz NMR tube and was subjected to H NMR and 11 B NMR analysis. Entry 3, Figure 4.9: Imine 78a (136 mg, 0.05 mmol, 1.0 equiv) was added to the NMR tube containing the sample from entry 2. The NMR tube was shaken for 2 min before the analysis. An appearance of yellow color was observed. Entry 4 and 5, Figure 4.9: 1 and 3 equiv of methanol is added to the NMR tube (containing the sample from entry 2) for entries 4 and 5 respectively. Entry 6, Figure 4.4: Same as entry 3 where imine 78a (136 mg, 0.05 mmol, 1.0 equiv) is added to the entry 5. Entry 7, Figure 4.9: To a flame dried 25 mL home made Schlenck flask (see Figure 2.26) equipped with a stir bar and flushed with argon was added BINOL derivative 89 (23.5 mg, 0.050 mmol) and toluene (1 mL). Under an argon flow through the side-arm of the Schlenk flask, BH3•Me2S (25 µL, 2.0 M solution in toluene, 0.05 mmol) was added through the top of the Teflon valve. The flask was sealed by closing the Teflon valve, and then placed in an 100 ºC oil bath for 1 h. After 1 h, a vacuum (0.5 mm Hg) was carefully applied by slightly opening the Teflon valve to remove the volatiles. After the volatiles were removed completely, a full 322 vacuum was applied and maintained for a period of 30 min at a temperature of 100 ºC (oil bath). The flask was then allowed to cool to room temperature and opened to argon through the sidearm of the Schlenk flask. The resulting solid was then dissolved in 1.5 mL of CD2Cl2. The 1 sample was then filtered and transferred to a quartz NMR tube and was subjected to H NMR and 11 B NMR analysis. Entry 8, Figure 4.9: Imine 78a (136 mg, 0.05 mmol, 1.0 equiv) was added to the NMR tube containing the sample from entry 7. The NMR tube was shaken for 2 min before the analysis. An appearance of yellow color was observed. Entry 9, Figure 4.9: To a flame dried 25 mL round bottom flask equipped with a stir bar and flushed with argon was added 4Å Molecular Sieves (150 mg). The sieves were then flame dried in the same flask. To the same flask was added BINOL derivative 89 (23.5 mg, 0.050 mmol), B(OPh)3 (14.5 mg, 0.050 mmol) and CD2Cl2 (1.5 mL). The resulting mixture was then stirred for 1 h. The sample was then filtered and transferred to a quartz NMR tube and was subjected to 1 H NMR and 11 B NMR analysis. Entry 10, Figure 4.9: Imine 78a (136 mg, 0.05 mmol, 1.0 equiv) was added to the NMR tube containing the sample from entry 9. The NMR tube was shaken for 2 min before the analysis. An appearance of yellow color was observed. 323 4.6.5 NMR analysis of a mixture of Phenol 194a, commercial and freshly prepared B(OPh)3 and DMAP 216c N OH B(OPh)3 187a (1 equiv) N H N + (1 equiv) 216c CDCl3 25 ºC, 5 min O O– B O O N 194a 244e Entry 1, Figure 4.13: The NMR of freshly sublimed Phenol 194a was taken in CDCl3. Entry 2, Figure 4.13: The NMR of freshly made B(OPh)3 prepared using the procedure shown in section 4.6.2. Entry 3, Figure 4.13: To the home-made Schlenck flask containing the freshly prepared B(OPh)3 (entry 2) was added freshly sublimed PhOH 194a (9.4 mg, 0.10 mmol, 1.0 equiv). The mixture was dissolved in CDCl3 (1 mL) transferred to a quartz NMR tube and was subjected to 1 H NMR and 11 B NMR analysis. Entry 4, Figure 4.13: DMAP 216c (12.2 mg, 0.100 mmol, 1.00 equiv) was added to the NMR tube containing the sample from entry 3. The NMR tube was shaken for 2 min before the analysis. An appearance of yellow color was observed. 324 Entry 5 and 7, Figure 4.13: The NMR of commercial B(OPh)3 and DMAP was taken in CDCl3 respectively. Entry 6, Figure 4.13: DMAP 216c (12.2 mg, 0.100 mmol, 1.00 equiv) was added to the NMR tube containing the sample from entry 5. The NMR tube was shaken for 2 min before the analysis. An appearance of yellow color was observed. 4.6.6 DFT Calculations 5 All quantum mechanical calculations were performed using the Gaussian ʹ′03. The B3LYP 16 and BHandHLYP 17 density functional were used along with 6-31G* basis sets. The coordinates were provided to Prof. Wulff as a separate file. 325 REFERENCES 326 REFERENCES (1) (a) Zhang, Y.; Desai, A.; Lu, A.; Hu, G.; Ding, Z.; Wulff, W. D. Chem. –Eur. J. 2008, 14, 3785-3803. (b) Zhang, Y.; Lu, Z.; Desai, A.; Wulff, W. D. Org. Lett. 2008, 10, 5429-5432. (c) Mukherjee, M.; Gupta, A. K.; Lu, Z.; Zhang, Y.; Wulff, W. D. J. Org. Chem. 2010, 75, 56435660. (d) Ren, H.; Wulff, W. D. Org. Lett. 2010, 12, 4908-4911. (e) Hu, G.; Huang, L.; Huang, R. H.; Wulff, W. D. J. Am. Chem. Soc. 2009, 131, 15615-15617. (f) Hu, G.; Gupta, A. K.; Huang, R. H.; Mukherjee, M.; Wulff, W. D. J. Am. Chem. Soc. 2010, 132, 14669–14675. (g) Gupta, A. K.; Mukherjee, M.; Wulff, W. D. Org. Lett. 2011, 13, 5866-5869. (h) Desai, A. A.; Wulff, W. D. J. Am. Chem. Soc. 2010, 132, 13100-13103. (i) Vetticatt, M. J.; Desai, A. A.; Wulff, W. D. J. Am. Chem. Soc. 2010, 132, 13104-13107. (j) Desai, A. A.; Morán-Ramallal, R.; Wulff, W. D. Org. Synth. 2011, 88, 224-237. (2) (a) Ishihara, K.; Miyata, M.; Hattori, K.; Tada, T.; Yamamoto, H. J. Am. Chem. Soc. 1994, 116, 10520-10524. (b) Ishihara, K.; Kuroki, Y.; Yamamoto, H. Synlett 1995, 41-42. (c) Kuroki, Y.; Ishihara, K.; Hanaki, N.; Ohara, S.; Yamamoto, H. Bull. Chem. Soc. Jpn. 1998, 71, 12211230. (d) Cros, J. P.; Pérez-Fuertes, Y.; Thatcher, M. J.; Arimori, S.; Bull, S. D.; James, T. D. Tetrahedron: Asymmetry 2003, 14, 1965-1968. (e) Kawate, T.; Yamada, H.; Matsumizu, M.; Nishida, A.; Nakagawa, M. Synlett 1997, 761-762. (f) Yamada, H.; Kawate, T.; Matsumizu, M.; Nishida, A.; Yamaguchi, K.; Nakagawa, M. J. Org. Chem. 1998, 63, 6348-6354. (3) (a) Ishihara, K.; Yamamoto, H. J. Am. Chem. Soc. 1994, 116, 1561-1562. (b) Ishihara, K.; Kurihara, H.; Yamamoto, H. J. Am. Chem. Soc. 1996, 118, 3049-3050. (c) Ishihara, K.; Kurihara, H.; Matsumoto, M.; Yamamoto, H. J. Am. Chem. Soc. 1998, 120, 6920-6930. (d) Ishihara, K.; Kondo, S.; Kurihara, H.; Yamamoto, H.; Ohashi, S.; Inagaki, S. J. Org. Chem. 1997, 62, 30263027. (e) Dai, X.; Davies, H. M. L. Adv. Synth. Catal. 2006, 348, 2449-2456. (4) (a) Cole, T. E.; Quintanilla, R.; Rodewald, S. Synth. React. Inorg. Met.-Org. Chem. 1990, 20, 55-63. (b) Malkowsky, I. M.; Frohlich, R.; Griesbach, U.; Putter, H.; Waldvogel, S. R. Eur. J. Inorg. Chem. 2006, 1690-1697. (c) Cole, T. E.; Bakshi, R. K.; Srebnik, M.; Singaram, B.; Brown, H. C. Organometallics 1986, 5, 2303-2307. (d) Linti, G.; Loderer, D.; Nöth, H.; Polborn, K.; Rattay, W. Chem. Ber. 1994, 127, 1909-1922. (e) Wilson, J. W. J. Chem. Soc., Dalton Trans. 1973, 1628-1630. (f) Nishihara, Y.; Nara, K.; Osakada, K. Inorg. Chem. 2002, 41, 4090-4092. (g) Mannig, D.; Noth, H. J. Chem. Soc., Dalton Trans. 1985, 1689-1692. (h) Knizek, J. r.; N√∂th, H. J. Organomet. Chem. 2000, 614‚Äì615, 168-187. (i) Lawlor, F. J.; Norman, N. C.; Pickett, N. L.; Robins, E. G.; Nguyen, P.; Lesley, G.; Marder, T. B.; Ashmore, J. A.; Green, J. C. Inorg. Chem. 1998, 37, 5282-5288. (j) Carter, C.; Fletcher, S.; Nelson, A. Tetrahedron: Asymmetry 2003, 14, 1995-2004. (k) Raskatov, J. A.; Brown, J. M.; Thompson, A. L. Crystengcomm 2011, 13, 2923-2929. 327 (5) Gaussian 03, Revision D.01 M. J. Frisch, G. W. T., H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman, J. A. Montgomery, Jr., T. Vreven, K. N. Kudin, J. C. Burant, J. M. Millam, S. S. Iyengar, J. Tomasi, V. Barone, B. Mennucci, M. Cossi, G. Scalmani, N. Rega, G. A. Petersson, H. Nakatsuji, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, M. Klene, X. Li, J. E. Knox, H. P. Hratchian, J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R. E. Stratmann, O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli, J. W. Ochterski, P. Y. Ayala, K. Morokuma, G. A. Voth, P. Salvador, J. J. Dannenberg, V. G. Zakrzewski, S. Dapprich, A. D. Daniels, M. C. Strain, O. Farkas, D. K. Malick, A. D. Rabuck, K. Raghavachari, J. B. Foresman, J. V. Ortiz, Q. Cui, A. G. Baboul, S. Clifford, J. Cioslowski, B. B. Stefanov, G. Liu, A. Liashenko, P. Piskorz, I. Komaromi, R. L. Martin, D. J. Fox, T. Keith, M. A. Al-Laham, C. Y. Peng, A. Nanayakkara, M. Challacombe, P. M. W. Gill, B. Johnson, W. Chen, M. W. Wong, C. Gonzalez, and J. A. Pople, Gaussian, Inc., Wallingford CT, 2004 (6) Tu, T.; Maris, T.; Wuest, J. D. Cryst. Growth Des. 2008, 8, 1541-1546. (7) Hu, G. PhD Dissertation, Michigan State University, 2007. (8) Taube, R.; Weckmann, E.; Böhme, P.; Gehrke, J. P. Z. Anorg. Allg. Chem. 1989, 577, 245254. (9) Lang, A.; Knizek, J.; Nöth, H.; Schur, S.; Thomann, M. Z. Anorg. Allg. Chem. 1997, 623, 901-907. (10) (a) Bishop, M.; Shahid, N.; Yang, J.; Barron, A. R. Dalton Trans. 2004, 2621-2634. (b) Pasdeloup, M.; Brisson, C. Org. Magn. Reson. 1981, 16, 164-167. (11) Steinberg, H. Organoboron Chemistry; Wiley Interscience: New York, N.Y., 1964; Vol. 1, ch. 15. (12) Schlesinger, H. I.; Brown, H. C.; Mayfield, D. L.; Gilbreath, J. R. J. Am. Chem. Soc. 1953, 75, 213-215. (13) Hu, G.; Huang, L.; Huang, R. H.; Wulff, W. D. J. Am. Chem. Soc. 2009, 131, 15615-15617. (14) Vetticatt, M.; Wulff, W. D., Unpublished results. 328 (15) (a) Wipf, P.; Jung, J.-K. J. Org. Chem. 2000, 65, 6319-6337. (b) Lingenfelter, D. S.; Helgeson, R. C.; Cram, D. J. J. Org. Chem. 1981, 46, 393-406. (c) Gobbi, L.; Seiler, P.; Diederich, F.; Gramlich, V. Helv. Chim. Acta 2000, 83, 1711-1723. (16) (a) Becke, A. D. Phys. Rev. A 1988, 38, 3098. (b) Lee, C. Y., W.; Parr, R. G. Phys. Rev. B 1988, 37, 785. (17) (a) Becke, A. D. J. Chem. Phys. 1993, 98, 1372-1377. (b) Zhao, Y.; Truhlar, D. G. J. Chem. Theory Comput. 2005, 1, 415-432. (c) Yu, W.; Liang, L.; Lin, Z.; Ling, S.; Haranczyk, M.; Gutowski, M. J. Comput. Chem. 2009, 30, 589-600. 329 CHAPTER 5   AN EXAMINATION OF VARIOUS CHIRAL DIOLS AS LIGANDS FOR ASYMMETRIC AZIRIDINATION REACTION AND THEIR IMPACT ON THE STRUCTURE OF THE BOROX CATALYST I think that we should pursue it a little more! -William D. Wulff 5.1 Introduction Over the past few years, the Wulff group has developed a universal catalytic asymmetric aziridination reaction of imines utilizing a catalyst derived from the vaulted ligands VAPOL 58 or VANOL 59 and commercial B(OPh)3 (Chapter 1, Scheme 1.12). 1 The actual catalyst 190 is a complex consisting of a protonated imine and a chiral counteranion in the form of a boroxinate anion (Chapter 2 and Figure 5.1C). This boroxinate catalyst has been termed as the IMINOBOROX catalyst 190. As discussed in section 2.1.1.3 of chapter 2, these BOROX catalysts can be very diverse in nature. Diversity can be achieved by altering the ligand, the alcohol source and the N-substituent of the imine. Based on these variations, a large pool of catalysts can be generated. These catalysts could be very different in structure and reactivity for a given asymmetric reaction. The aim of the work in this chapter is to explore a novel family of catalysts by employing different ligands and to study the change in the mechanistic behavior of these catalysts. The vaulted biaryl ligand ISOVAPOL 197 and the linear biaryl ligand BINOL 55 and its derivatives of type 56 as well as TADDOL 61a were examined for efficacy in the catalytic asymmetric aziridination reaction. In addition, in order to investigate the structure of the catalyst, NMR experiments were performed on these novel catalysts. 330 5.2 ISOVAPOL: a new entry to the family of vaulted biaryl ligands In 1993, we introduced a new family of chiral diols in the form of the vaulted biaryl ligands. Two of the most studied and prominent members of this family of ligands are VAPOL 58 and VANOL 59 (Figure 5.1A). These vaulted biaryl ligands have been demonstrated to be 2 useful in a variety of important asymmetric reactions including Diels-Alder reactions, Mannich 3 4 5 6 reactions, Baeyer-Villiger reactions, the Petasis reaction, the hydroarylation of alkenes, the 7 hydrogenation of alkenes, 8 asymmetric chlorination and Michael reactions of oxindoles, 9 benzoyloxylation of aryloxindoles, 12 hydroacylation of alkenes. aza-Darzens reaction, 10 propargylation of ketones, 1a-1f,1j 1h,1i 13 imines, multicomponent aziridination of aldehydes, aminoallylation of aldehydes, aldehydes. 15 14 aminals. 18 1g trans-aziridination of heteroatom Diels-Alder reactions of [3+2] cycloaddition of imines, 15 and epoxidation of More recently, chiral phosphoric acids 35 and 36 (Chapter 1) derived from these ligands have been used in the amidation of imines, and Specifically, the BOROX catalyst derived from VAPOL and VANOL ligands have been used in cis-aziridination of imines, imines, 11 19 pinacol rearrangement, 16 and imidation 17 of imines, the asymmetric reduction desymmetrization of aziridines 20 and reduction of 21 In search of more diversity in the BOROX catalyst, in greater mechanistic understanding of its mode of catalysis and in an improvement in aziridination of benzhydryl imines 78, we 331 envisioned the possibility of a new chiral ligand 197 as shown in Figure 5.2 (an isomer of VAPOL, hereafter abbreviated as ISOVAPOL). 5.2.1 Rational design of ISOVAPOL 197 In the past, a series of VAPOL and VANOL derivatives have been prepared 22a examined in the asymmetric aziridination reaction of imines. 2d,22 and Some of these modified ligands 2d were used as chiral Lewis acids in asymmetric Diels-Alder reaction, and Mannich reaction. 22b However, these modifications were made, in most of cases, without any understanding of how the catalyst functions. Now, with the help of the information about the structure of the BOROX catalyst, rational design of new vaulted ligands is possible. One of the most puzzling aspects of the aziridination reaction is that the BOROX catalysts derived from both the VANOL and VAPOL ligands have a nearly identical profile of asymmetric induction over the same range of imine substrates. 1c We were able to rationalize this observation with the help of the knowledge of the structure of the catalyst. The structure of the BOROX catalyst 190a reveals that the π-π stacking interaction of the phenyl group of the imine is primarily over the central ring (B) of the phenanthrene unit of the VAPOL 58 (Figure 5.1C). This corresponds to the B ring of the VANOL boroxinate catalyst 191a (Figure 5.1B). Although, an X-ray structure of the catalyst 1 derived from VANOL has not yet been obtained, H NMR studies suggest that the structure is analogous to the BOROX catalyst 190a (Figure 5.1B). Thus, it appears that the extra benzene ring of VAPOL is not needed, at least in the catalyst for the aziridination reaction. 332 Figure 5.1 (A) Different chiral diols from vaulted biaryl ligands. catalysts derived from VAPOL and VANOL. (B) Different BOROX (C) Diagrammatic representation of X-ray structure of the BOROX catalyst 190a. A B C B OPh O B O– B O O O B OPh A Ph Ph Ph Ph OH OH VAPOL 58 Ph Ph OH OH + [H-imine] B A Ph Ph 104a 190a (imine=111a) VANOL 59 C + [H-imine] OPh O B O– B O O O B OPh 105a 191a (imine=111a) d2 d3 d4 B C – O O B O O B O B O O H H Me MeO d5 d7 d6 d1 CH-π 4.42 Å CH-π 4.14 Å CH-π 3.83 Å π-π 3.44 Å d6 CH-O 2.86 Å d7 Me d2 d5 + N H 2.02 Å d4 Me H-Bond d3 Me A d1 OMe CH-π 4.57 Å IMINO-BOROX 190a As evident from the structure of the catalyst-substrate complex 190a, π-π stacking may be important for asymmetric induction in the case of aromatic aldehydes. However, the case of aliphatic aldehydes is interesting due to the absence of this π-π interaction. Also, as is revealed 333 in the structure of the catalyst; there are numerous CH-π interactions (Figure 5.1C). The mode of the docking of imines generated from aliphatic aldehydes to the catalyst is unknown. As there is no difference in the enantioinduction when either VAPOL or VANOL is used, the orientation of the alkyl group could be indifferent to the presence of ring C. However, it the alkyl group have been orienting in a way such that there are CH-π interactions with the imaginary ring C' (Figure 5.2A). If this were true, moving the C ring to the 9 and 10-positions of VAPOL (or adding another benzene ring at the 5 and 6-positions of VANOL) would lead to the rational design of our new chiral ligand ISOVAPOL 197 (Figure 5.2B). The aim of making ISOVAPOL is multifaceted. One of the reasons to consider ISOVAPOL 197 is its potential lower cost to make than VAPOL. The starting material for the synthesis of ISOVAPOL, 1-naphthyl acetic acid 284 is 10 times cheaper (~$50/Kg) than 2-naphthyl acetic acid 269 (~$540/Kg), which is the starting 23 material for the most convenient synthesis of VAPOL. The former is manufactured on large scale as a plant growth regulator. Recently, we reported a new optimal method for VAPOL and hopefully, a direct application of this method towards the synthesis of ISOVAPOL can be undertaken. 23 Hence, in conjunction with our efforts to probe the mechanistic underpinning of the asymmetric induction observed for BOROX catalysts and to expand the members of the family of vaulted ligands, a project was initiated to synthesize and evaluate ISOVAPOL 197. Figure 5.2 (A) Possible orientation of the imine over the boroxinate core. (B) Rational design of the new vaulted ligand ISOVAPOL 197 334 Figure 5.2 cont’d A C' B + H C N C A Ph Ph R Ar OH OH Ph Ph OPh Ar O B O– B O O O B OPh 58 or 59 B C' B A Ph Ph B C A simplify OH OH remove extra ring B C A rationally Ph Ph OH OH modify Ph Ph OH OH (S)-VAPOL 58 (S)-ISOVAPOL 197 5.2.2 Preparation of ISOVAPOL 197 Recently, we reported a very efficient and convenient large-scale synthesis of VAPOL 23 58. This synthesis of VAPOL involves the preparation of the monomer 263 followed by its oxidative coupling and resolution to get highly optically pure ligand. The key step in the 335 synthesis of the monomer 272 is a cycloaddition/electrocyclic ring-opening (CAEC)/electrocyclic ring- closure/tautomerization cascade (Scheme 5.1). Also, this cascade produces a byproduct that was identified as 2-(2-naphthyl)-3,5-diphenylphenol 273 obtained in <10% yield. The branch point between the two products is the ketene 277 and involves the competition between a [2 + 2] cycloaddition with phenylacetylene 270 giving 281 and an electrocyclic ring closure leading to the formation of 278 (Scheme 5.1B). The cyclobutenone 281 could be expected to begin its own electrocyclization cascade that is initiated with an electrocyclic ring opening to give the dienyl ketene 282 and then an electrocyclic ring closure to give the cyclohexadienone 283 and finally tautomerization to the byproduct 273 (Scheme 5.1B). Scheme 5.1 (A) Preparation of the monomer 272 of VAPOL. (B) Proposed mechanism A 1. SOCl2 (3.6 equiv) 90 ºC, 1h Ph + 2. HO O 269 76.4 mmol (14.2 g) Ph 270 (1.3 equiv) (iPrCO)2O 271(2.0 equiv) Ph 190 ºC, 48 h 3. KOH, H2O, 100 ºC, 1h 336 OH 272 79% Ph OH 273 8% Scheme 5.1 cont’d B SOCl2 HO 90 ºC 1h Cl O 269 KOH 100 ºC, 1h H2O Ph H 190 ºC 272 190 ºC Tauto Ph OCOiPr 280 O 275 276 electrocyclic 4n ring-opening 190 ºC (iPrCO)2O Ph • O O 274 [2+2] Ph 190 ºC Ph OH 279 O 278 4n+2 190 ºC electrocyclic ring-closure Ph • O 277 Ph [2+2] 273 Tautomerize Ph Ph O 4n+2 190 ºC electrocyclic ring-closure Ph • Ph 283 O 282 4n+2 190 ºC electrocyclic ring-opening Ph Ph O 281 In the case of ISOVAPOL, the monomer 285 is expected to result from the acid chloride of 284 with phenyl acetylene in accord with the one-step protocol for the large scale synthesis of 23 VAPOL 58 (Scheme 5.2). First, 1-naphthyl acetyl chloride was prepared by reacting 1- naphthyl acetyl acid 284 with thionyl chloride at 90 °C for 1 h. Second, the procedure involves heating 1-naphthyl acetyl chloride (used without purification) in the presence of phenyl acetylene 270. This initiates the [2+2] cycloaddition of an in-situ generated ketene and then electrocyclic ring opening of the resulting cyclobutenone and then finally, an electrocyclic ring closure of the vinyl ketene. The phenol product is trapped by the iso-butyric anhydride to give an ester. Hydrolysis gave the ISOVAPOL monomer 285 in 26–30% overall yield from acid 284 (Scheme 5.2). The low yield can be partially attributed to the formation of the by-product 286 that is 337 similar to the by-product 273 obtained in the synthesis of the monomer 272 for VAPOL (Scheme 5.2). Interestingly, another by-product 287 (structure not known) was also obtained. Scheme 5.2 Preparation of the ISOVAPOL monomer 285 1. SOCl2 (3.6 equiv) 90 ºC, 1h HO O 284 76.4 mmol (14.2 g) Ph 2. Ph 270 (1.3 equiv) (iPrCO)2O 271 (2.0 equiv) Ph 190 ºC, 48 h + OH 285 5.27g-6.19g (26-30%) 3. KOH, H2O, 100 ºC, 1h + UNK Ph OH 286 1.66g (6%) 287 1.44g The synthesis of the rac-ISOVAPOL was carried out via oxidative coupling by stirring the monomer 285 in mineral oil at 190 °C in the presence of air (Scheme 5.3). This gave the dimer rac-ISOVAPOL in 70% yield. obtained by the deracemization protocol The optically pure ligand (S)-197 was then readily 22c developed in the group in 95% yield and > 99% ee (Scheme 5.3). Scheme 5.3 Preparation of the rac-197 and (S)-ISOVAPOL (S)-197 air flow mineral oil 190 ºC, 36h OH 70% Ph Ph Ph 1. CuCl (1.4 equiv), air (–)-sparteine (3.5 equiv) MeOH, CH2Cl2, 25 ºC OH OH 2. sat. NaHCO (aq) 3 Ph Ph OH OH 95% 285 rac-ISOVAPOL rac-197 5.2.3 (S)-ISOVAPOL (S)-197 Asymmetric aziridination reaction catalyzed by BOROX catalyst derived from ISOVAPOL 338 After the development of a successful synthesis of ISOVAPOL, the stage was set for the examination of its effectiveness in the catalytic aziridination reaction. As a control, we decided to perform each reaction with ISOVAPOL and VANOL to have a better measure of the consequences of the structural differences. One of the first sets of experiments was the examination of ISOVAPOL derived catalyst with various N-protecting groups (Table 5.1) in the aziridination reaction. The new ligand 197 showed results very similar to (R)-VANOL for imines with the four different protecting groups. These results suggested that the binding of the imine with the catalyst prepared from the new ligand 197 might be similar to that from VAPOL or VANOL derived catalysts. Since the aziridination reaction is already well established with MEDAM protecting groups for aryl and alkyl substituents (up to 99% ee), it was decided to choose to the benzhydryl (Bh) protecting group for further study as the model system (lowest asymmetric induction among other N-protecting groups for aryl and alkyl substituents). It must be noted that the benzhydryl amine 126a is commercially available whereas MEDAM amine 126c is not. Table 5.1 Screening of ISOVAPOL 197 with different N-protected imines O Ar Ph N 78a 110a 111a 112a IMINO-BOROX catalyst (5 mol %) Ar + OEt N2 toluene 25 °C, 24 h 85 B(OPh)3 (4 equiv) H2O (1 equiv) Ar Ar Ar N Ph Imine Ar + CO2Et 86a 113a 114a 115a preLigand (5 mol%) tolulene, 80 °C, 1 h catalyst then 05 mm Hg 80 °C, 0.5 h a NH (Ph)H Ph(H) 87a(88a) 116a(117a) 118a(119a) 120a(121a) OPh Ar Ar O B O – N+ B O * H O O B OPh Ph IMINO-BOROX catalyst 339 CO2Et Table 5.1 cont’d # Cat f 1 2 f 3 4 5 6 7 8 Ligand Ar2CH azi 199a 189a (S)-ISOVAPOL (R)-VANOL Bh Bh 86a 288a 289a 290a 191a 291a 292a (S)-ISOVAPOL (R)-VANOL (S)-ISOVAPOL (R)-VANOL (S)-ISOVAPOL (R)-VANOL DAM DAM MEDAM MEDAM BUDAM BUDAM 113a 114a 115a Yield azi b (%) 82 87 ee azi c (%) 92 –89 50:1 >50:1 Yield enamine e (%) 3/7 <1/<1 91 89 96 98 97 98 96 –92 98 –97 96 –96 50:1 >50:1 >50:1 50:1 >50:1 50:1 6/<1 1/<1 2/1 1/1 <1/<1 <1/<1 c:t d a Unless otherwise specified, all reactions were performed with 1 mmol of imine in toluene (0.5 M in imine) with 1.2 equiv of 85 and 5 mol% of the catalyst at 25 °C. The pre-catalyst was prepared by heating 1 equiv of ligand with 4 equiv of commercial B(OPh)3 and 1 equiv of H2O in toluene at 80 °C for 1 h, followed by removing all volatiles under high vacuum (0.1 mm Hg) for 0.5 h at 80 °C. b Isolated Yield. c Determined by Chiral HPLC. d 1 Ratio determined by integration of the methine protons of cis- and trans- aziridine in the H NMR spectrum of the crude reaction mixture. e Determined by integration of the NH signals of 1 enamines relative to the methine proton of cis aziridine in the H NMR spectrum of the crude f reaction mixture. 94% and 96% conversion for entry 1 and 3 respectively. Percent conversion is determined by integration of the methine proton of cis-aziridine relative to the 2 1 sp -CH proton of the unreacted imine in the H NMR spectrum of the crude reaction mixture. Prior to examining the substrate scope, it was thought to screen various solvents to observe any significant change in the yield or ee. While the reaction gave high asymmetric induction with halogenated solvents and with toluene, lower ees, in the range of 80, were obtained in case of oxygenated solvents like ether and EtOAc (Table 5.2). In the end, toluene was selected as the optimum solvent as it gave the highest enantioinduction and less toxic 340 compared to the other solvents. Also, the asymmetric induction was similar with benzhydryl imine 78a for both ligands ISOVAPOL and VANOL in toluene (entries 1 and 2, Table 5.2). Table 5.2 AZ reaction with imines 78 using (S)-ISOVAPOL and various solvents Ph N 78a Ph + Ph IMINO-BOROX catalyst (5 mol %) O Ph OEt N2 Ph Ph Ph N toluene 25 °C, 24 h Ph 85 + CO2Et 86a B(OPh)3 (4 equiv) H2O (1 equiv) preLigand (5 mol%) tolulene, 80 °C, 1 h catalyst then 05 mm Hg 80 °C, 0.5 h a NH CO2Et (Ph)H Ph(H) 87a(88a) OPh Ph Ph O B O – N+ B O * H O O B OPh Ph Imine 78a IMINO-BOROX catalyst # Cat Ligand Solvent % conv e 1 2 199a 189a (S)-ISOVAPOL (R)-VANOL Toluene Toluene 94 100 Yield 86a c (%) 82 87 3 4 199a 189a (S)-ISOVAPOL (R)-VANOL Ether Ether 95 96 83 83 80 –84 >50:1 >50:1 5/6 4/5 5 6 199a 189a (S)-ISOVAPOL Dichloromethane (R)-VANOL Dichloromethane 94 100 79 83 91 –89 25:1 50:1 4/9 4/8 7 8 199a 189a (S)-ISOVAPOL (R)-VANOL Dichloroethane Dichloroethane 94 100 81 83 91 –90 >50:1 >50:1 4/8 4/8 9 10 199a 189a (S)-ISOVAPOL (R)-VANOL EtOAc EtOAc 45 55 36 43 81 –84 20:1 >50:1 5/4 7/4 b ee 86a d (%) 92 –89 50:1 >50:1 Yield 87a/88a f (%) 3/7 <1/<1 c:t a Unless otherwise specified, all reactions were performed with 1 mmol of imine 78a in toluene (0.5 M in imine 78a) with 1.2 equiv of 85 and 5 mol% of the catalyst at 25 °C. The pre-catalyst was prepared by heating 1 equiv of ligand with 4 equiv of commercial B(OPh)3 and 1 equiv of H2O in toluene at 80 °C for 1 h, followed by removing all volatiles under high vacuum (0.1 mm Hg) for 0.5 h at 80 °C. b Percent conversion is determined by integration 341 Table 5.2 cont’d 2 of the methine proton of cis-aziridine relative to the sp -CH proton of the unreacted imine in 1 c the H NMR spectrum of the crude reaction mixture. HPLC. e 1 Isolated Yield. d Determined by Ratio determined by integration of the methine protons of cis- and trans-aziridine in the H NMR spectrum of the crude reaction mixture. f Determined by integration of the NH 1 signals of enamines relative to the methine proton of cis-aziridine in the H NMR spectrum of the crude reaction mixture. After the initial screening of the solvents, we moved on to examine the effect of (S)ISOVAPOL 197 on the reactions of various aryl and alkyl imines 78. Unfortunately, there was no improvement observed in the asymmetric inductions obtained using the ISOVAPOL catalyst for aryl imines as compared to the VANOL catalyst (Table 5.2). The results were quite similar and within the range of experimental error. In fact, both the ligands exhibited similar ees for the reactions of alkyl substituted imines as well (entries 9-12, Table 5.2). a Table 5.3 AZ reaction with imines 78 using (S)-ISOVAPOL AND (R)-VANOL O Ph R N 78 IMINO-BOROX catalyst (5 mol %) Ph + OEt N2 toluene 25 °C, 24 h 85 B(OPh)3 (4 equiv) H2O (1 equiv) preLigand (5 mol%) tolulene, 80 °C, 1 h catalyst then 05 mm Hg 80 °C, 0.5 h Ph Ph Ph N R Imine 78 + CO2Et 86 Ph NH CO2Et (R)H R(H) 87(88) OPh Ph Ph O B O – N+ B O * H O O B OPh R IMINO-BOROX catalyst 342 Table 5.3 cont’d % b conv 199a 189a (S)-ISOVAPOL (R)-VANOL 199b 189b (S)-ISOVAPOL (R)-VANOL 199c 189c (S)-ISOVAPOL (R)-VANOL 199d 189d (S)-ISOVAPOL (R)-VANOL 199e 189e 199f 189f (S)-ISOVAPOL (R)-VANOL (S)-ISOVAPOL (R)-VANOL >50:1 >50:1 3/7 3/6 94 100 62 62 89 –91 9:1 10:1 <1/6 <1/3 80 83 94 –91 >50:1 50:1 2/6 4/6 83 86 72 70 84 –84 79 –77 >50:1 >50:1 >50:1 >50:1 6/<1 <1/8 9/4 5/4 4-Br-C6H4 9 10 11 12 94 –92 4-MeO-C6H4 7 8 82 79 4-Me-C6H4 5 6 3/7 <1/<1 C6H5 3 4 50:1 >50:1 97 100 100 100 1 2 92 –89 94 100 R 82 87 94 100 Ligand ee 86 d (%) 94 100 Cat Yield 86 c (%) # a C6H5 4-Me-C6H4 4-MeO-C6H4 4-Br-C6H4 t-Bu t-Bu Cy Cy c:t Yield 87(88) f (%) e Unless otherwise specified, all reactions were performed with 1 mmol of imine 78 in toluene (0.5 M in imine 78) with 1.2 equiv of 85 and 5 mol% of the catalyst at 25 °C. The pre-catalyst was prepared by heating 1 equiv of ligand with 4 equiv of commercial B(OPh)3 and 1 equiv of H2O in toluene at 80 °C for 1 h, followed by removing all volatiles under high vacuum (0.1 mm Hg) for 0.5 h at 80 °C. b Percent conversion is determined by integration of 2 the methine proton of cis-aziridine relative to the sp -CH proton of the unreacted imine 78 in 1 the H NMR spectrum of the crude reaction mixture. HPLC. 1 e c Isolated Yield. d Determined by Ratio determined by integration of the methine protons of cis- and trans- aziridine in the H NMR spectrum of the crude reaction mixture. f Determined by integration of the 1 NH signals of enamines relative to the methine proton of cis aziridine in the H NMR spectrum of the crude reaction mixture. In conclusion, the new chiral ligand ISOVAPOL 197 was found to be equally good as VANOL and also is potentially less expensive than VAPOL or VANOL. Of course, it may very well behave differently from VAPOL or VANOL in asymmetric reactions other than aziridination. Finally, it adds to the library of the family of vaulted biaryl ligands in our group. 343 Incidentally, more recently, another group member namely Yong Guan was able to increase the stereoinduction (up to 98% ee) of aziridines from benzhydryl imines 78 by synthesizing a derivative of VANOL called to be 7,7ʹ′-tBu2-VANOL 198 (Chapter 2, Table 2.3). 5.2.4 NMR investigation of the BOROX catalysts 191a and 290a In order to gain the evidence for the generation of the BOROX catalysts 191a and 290a from the VANOL and ISOVAPOL ligands, respectively, a series of NMR experiments were performed (Figure 5.3). Various species were identified based on the characteristic peaks i.e. Hx and Hy for VANOL 59 and ISOVAPOL 197 respectively (Figure 5.3A). The study was started with VANOL 59. The chemical shift of the proton Hx for VANOL 59 is at δ = 8.35 ppm (m, CDCl3). The method for precatalyst formation involves heating (S)VANOL with 4 equiv of commercial B(OPh)3 and 1 equiv of H2O of at 80 °C (pre-catalyst method C). This resulted in the generation of a mixture of pyroborate B2 109 (δ Ηx = 8.14 ppm, m, CDCl3), meso-borate B1 107 (δ Ηx = 8.04 ppm, d, CDCl3) and unreacted VANOL 59 in 2.9:1:<0.1 ratio (entry 2, Figure 5.3B). Treatment of this mixture with 1 equiv of the imine 111a at room temperature within a few minutes results in the conversion of the colorless solution of 107 and 109 to a red solution of boroxinate 191a (δ Ηx = 8.55 ppm, d, J = 9.0 Hz, CDCl3) (entry 3, Figure 5.3B). Also, the IMINO-BOROX catalyst 191a has a sharp absorption at δ = 6.09 ppm in 11 B NMR (entry 2, Figure 5.3D). It must be noted that the ratio of B2 109: B1 107: unreacted VANOL 59 are 2.8:1:<0.1, 2.2:1:0.5 and 2.0:1:0.3 with pre-catalyst methods A (ligand:B(OPh)3 344 = 1:3) , B (ligand:B(OPh)3:H2O = 1:3:3) and D (ligand:BH3•Me2S:PhOH:H2O = 1:2:3:1) respectively (not shown here). Figure 5.3 (A) Treatment of (S)-59 and (S)-197 with B(OPh)3 and imine 111a. (B) a 1 H NMR 1 spectra of the reaction mixture in CDCl3. (C) H NMR spectra (methyl and methoxy region) 1 corresponding to the entry 3 and 6 in H NMR spectra in Figure 5.3B. (D) 11 B NMR spectra 1 corresponding to entries 2,3,5 and 6 in the H NMR spectra in Figure 5.3B. A Hy Hy Hx Ph Ph B(OPh)3 (4 equiv) H2O (1 equiv) OH OH Toluene, 80 °C, 1 h then 0.5 mmHg 80 °C. 0.5 h Hy Hx Hx O B OPh + O Ph Ph B1 107 (for (S)-VANOL) 107' (for (S)-ISOVAPOL) 59 ((S)-VANOL) 197 ((S)-ISOVAPOL) Ph Ph OPh O B O B O OPh B2 109 (for (S)-VANOL) 109' (for (S)-ISOVAPOL) CDCl3 imine 111a OMe Hy Ph Ph N OMe [imine-H] + Hx OPh O –O B B O O O B OPh imine 111a B3 191a (for (S)-VANOL) 290a (for (S)-ISOVAPOL) 345 B Figure 5.3 cont’d B3 E-5 + imine 111a Pre-catalyst @ (S)-197 B2 B3 B2 B3 B2 B2 (S)-ISOVAPOL 197 E-2 + imine 111a B3 B3 B2 Pre-catalyst @ (S)-59 B2 B1 (S)-VANOL 59 C Pre-catalyst @ (S)-197 + imine 111a Pre-catalyst @ (S)-59 + imine 111a 346 B1 Figure 5.3 cont’d D B3 Pre-catalyst @ (S)-197 + imine 111a Pre-catalyst @ (S)-197 B3 Pre-catalyst @ (S)-59 + imine 111a Pre-catalyst @ (S)-59 a Note for Figure 5.3B: Entry 1: pure (S)-59. Entry 2: (S)-59 (0.1 mmol) plus 4 equiv B(OPh)3 and 1 equiv H2O were heated at 80 °C in toluene for 1 h followed by removal of volatiles under vacuum for 0.5 h. Entry 3: 1.0 equiv of imine 111a was added to the entry 2 (pre-catalyst) for 10 min at 25 °C. Entry 4: pure (S)-197. Entry 5: (S)-197 (0.1 mmol) plus 4 equiv B(OPh)3 and 1 equiv H2O were heated at 80 °C in toluene for 1 h followed by removal of volatiles under vacuum for 0.5 h. Entry 6: 1.0 equiv of imine 111a was added to the entry 2 (pre-catalyst) for 10 min at 25 °C. 347 Similarly, we were able to identify pyroborate B2 109ʹ′ (δ Ηy = 8.65 ppm, CDCl3) for ISOVAPOL 197 (entry 5, Figure 5.3B) using precatalyst method C (ligand:B(OPh)3:H2O = 1:4:1). A new doublet was observed at δ = 8.58 ppm (J = 8.8 Hz, CDCl3) for proton Ηy for the boroxinate 290a when 1 equiv of imine 111a was added (entry 6, Figure 5.3B). There are many other characteristic peaks in boroxinate 290a and are shown in entry 6 of Figure 5.3B. Additionally, a peak at δ = 5.72 ppm in the 11 B NMR spectrum further supports the formation of 290a (entry 4, Figure 5.3D). The presence of a single doublet in the both boroxinate complexes indicates that the exchange of the iminium ion from the top face of the catalyst to the bottom is fast on the NMR time scale. A striking difference between the two boroxinates 191a and 290a was that the splitting in the methyl and methoxy region of the MEDAM group was missing in the case of VANOL ligand derived catalyst 191a (Figure 5.3C). The splitting of methyl and methoxy into two singlets has been observed for VAPOL derived catalysts (Chapter 2). The chemical shifts of the protons associated with the nitrogen of the protonated imines in the complexes 191a and 290a are δ = 13.74 ppm and δ = 13.67 ppm respectively. 5.2.5 Calculated structure of BOROX catalyst 290a derived from ISOVAPOL (S)-197 The structure of the IMINO-BOROX 290a was explored using DFT calculations. Calculations were performed using Gaussian ʹ′03 at B3LYP/6-31g* level of theory. 24 The predicted structure is shown in Figure 5.4. Several non-covalent interactions (CH-π and π–π) between imine and arene rings of the ISOVAPOL 197 are observed (Figure 5.4). 348 Figure 5.4 Calculated structure of IMINO-BOROX catalyst 290a using Gaussian ʹ′03. Calculated B3LYP/6-31g* structure visualized by the Mercury Program (C, gray; O, red; N, blue; B, pink). Hydrogen atoms omitted for clarity (except N-H). Some secondary interactions are highlighted: d1 = 1.72 Å (H-bonding), d2 = 4.02 Å (CH-π), d3 = 4.10 Å (CH-π or π-π stack), d4 = 4.54 Å (CH-π), d5 = 4.02 Å (CH-π). d2 d5 d4 d3 5.2.6 d1 X-ray crystal structure of ISOVAPOL (S)-197 and VANOL (R)-59 Normally, ISOVAPOL is purified by silica gel chromatography rather than crystallization. In the process of purification of the ISOVAPOL, a few crystals were formed serendipitously. The crystals were then subjected to the X-ray diffraction analysis. The ORTEP diagram of the crystal structure of ISOVAPOL (S)-197 is shown in Figure 5.5A. As was the 25 case in the crystal structure of VAPOL (S)-58, the solid state form of ISOVAPOL (S)-197 lacks intermolecular hydrogen bonding that prevails for BINOL. The dihedral angle between the phenanthrene rings of the (S)-197 is 70.6°. 25 VAPOL. It varies from 80.1° to 88.5° in the case of 26,27 The dihedral angle is <90° corresponds to the cisoid conformation, 349 which alters the preferred packing motif. Also, as in the case of VAPOL, 25 the hydroxyl groups are buried in the pocket created by the phenanthrene rings of the (S)-197. The steric repulsion of these phenanthrene groups inhibits possible hydrogen bonding. Similar observation was made with the X-ray crystal structure of VANOL (R)-59. Three conformations of the unit cell were observed with the dihedral angles 69.6°, 74.6°, 76.9° respectively (Figure 5.5B). This classifies VANOL (R)-59 to be a cisoid conformation and also, like VAPOL and ISOVAPOL, it lacks inter molecular hydrogen bonding. Figure 5.5 (A) ORTEP drawing of X-ray crystal structure of (S)-197 and ORTEP drawing of crystal packing of (S)-197 along b-axis. (B) ORTEP drawing of X-ray crystal structure of all three conformations (in the unit cell) of (R)-59 and ORTEP drawing of crystal packing of (R)-59 along b-axis. A 350 Figure 5.5 cont’d B 351 It must be remembered that in the case of BINOL, hydrogen bonding occurs in both the enantiopure and racemic crystal structures. 28 The dihedral angle between the naphthalenes of all 27 known solid-state forms of BINOL is >90° which is referred to transoid conformation. 5.3 BINOL and its derivatives Up till now, our efforts have revealed the very important role that BOROX catalysts have in chemistry of vaulted biaryl ligands. Thereafter, it was deemed important to examine the role that linear biaryl ligands can play in BOROX catalysis. Prior to the evolution of vaulted biaryl ligands, BINOL 55, a C2-symmetric linear biaryl ligand, has been widely used in a variety of asymmetric reactions. 29 However, one of the major reasons for the ineffectiveness of BINOL in inducing high asymmetric inductions in many reactions is the positioning of the major groove directly opposite to the active site containing the phenol functions (Figure 5.6C). This led us to design a new family of vaulted biaryl ligands where there is a substantially larger pocket around the active site due to the relocation of the major groove (Figure 5.6C). Previous solutions to this limitation of BINOL involved enhancing the chiral pocket around the active site. This approach involves the introduction of the substituents at 3- and 3ʹ′- positions of BINOL thereby generating the new BINOL derivatives 56 (Figure 5.6C). 30 352 Figure 5.6 (A) Vaulted biaryl ligands (B) Linear biaryl ligands (C) Location of major and minor groove in vaulted and linear biaryl ligands. A B R Ph Ph OH OH Ph Ph OH OH OH OH OH OH R (S)-VAPOL (S)-58 (S)-BINOL (S)-55 (S)-VANOL (S)-59 C (S)-56 major groove minor groove Ph OH OH Ph (S)-VAPOL (S)-58 minor groove major groove minor groove major groove R OH OH R OH OH (S)-56 (S)-BINOL (S)-55 A few of the most common structural types reported for borate esters of BINOL and its derivatives are shown in Scheme 5.4. The reaction of BINOL with 1 equiv of B(OPh)3 has been 353 reported to give a compound for which the most probable structure was suggested to be the 31,32 mesoborate 293 but other possible structures could not be excluded (Scheme 5.4A). This compound has been examined as a catalyst for Mannich and heteroatom Diels-Alder reactions of imines, 31,33 the heteroatom Diels-Alder reactions of aldehydes, aldol reactions. 36 34 Diels-Alder reactions 35 and The reaction of BINOL with 0.5 equiv of B(OPh)3 or B(OMe)3 has been reported to give the spiroborate 20-H (Scheme 5.4A). As discussed in Chapter 4, the structure 20-H has been suggested to function as a chiral Lewis acid catalyst for a number of reactions including Mannich reactions, Spengler reaction. 39 33g,37 heteroatom Diels-Alder reactions of imines, 33g,38 and Pictet- The catalytic function of 20-H was proposed to be as a chiral Lewis acid where interaction with a Lewis base disrupts one of the boron-oxygen bonds to give the Lewis 33g,39a acid-Lewis base complex 71 (LB = imine) or 71ʹ′ (LB = nitrone). It must be noted evidence was presented that this complex functions as a Brønsted acid catalyst in reactions with imines and as Lewis acid in reactions of nitrones (Chapter 4). There has been considerable interest in the chiral anion unit in 20-H and the sources of interest include use as a vehicle for the resolution of BINOL, reagent, 42 40 as a structural unit in solution and in the solid state, 41 as a chiral shift and also as a chiral counterion catalyst in aziridination reactions, cyclopropanation reactions, 43 opening of meso aziridiniums. in Friedel-Crafts reactions, 44 354 44 in hydrogenations, 45 43 in and in ring- Scheme 5.4 Common borate esters of (A) BINOL 55 and (B) BINOL derivatives 55 and 89 A O O B OPh 293 + H O –O B O O B(OPh)3 (1 equiv) 4 Å MS, CH2Cl2 25 ºC, 1h )3 55 Ph v) (O e q u i C l 2 B H2 5 (0. S, C 1h M º C, 4 Å 25 20-H BH2Br•SMe2 (1 equiv) CH2Cl2, –20 to 25 ºC OH OH or H BO (2/3 equiv) 3 3 benzene, reflux B TH 3 F, 2 (1 eq uiv 5º C, ) 1h H3BO3 (1.1 equiv) toluene reflux Lewis base O B H O O LB O O BO O B O O 297 O O B several days 295 O O B O B O OO O BOB O O O O 71 (LB = imine) 71' (LB = nitrone) 296 294 B R 1. BH3•THF (1 equiv) AcOH (1 equiv) THF, 20 ºC, 10 min OH OH 2. HOAr R R R O B O O O 56 OH B(OPh)3 OH OH (1 equiv) OH 89 O 298 O O O Lewis – + Base B H O 22-H Brønsted acid 355 O O O H B O LB 90' (LB = aldehydes) Brønsted acid assisted Lewis acid (BLA) The intriguing propeller-like structure 297 was discovered by Kaufmann and Boese when 35 they reacted BINOL with 1 equiv of BH2Br•SMe2 complex (Scheme 5.4A). This bis-triaryl borate was isolated in nearly quantitative yield and contains a [6.6.6]-propellane unit composed of three units of BINOL and two borons and was characterized by X-ray diffraction. This complex has been shown to give high asymmetric inductions in Diels-Alder reactions as a chiral Lewis acid, however, as might be expected, the rates of reaction are quite slow. 35,46 A very similar structure 296 (an isomer of 297) is reported by De-jun and coworkers (Scheme 5.4A). 47 This compound was also found to be composed of three units of BINOL and two borons and was characterized by NMR spectroscopy. It was reported to be formed due to the decomposition of the allyl-boronate 295 on being kept for several days. Another interesting structure that has been reported is the pyroborate 294, which was reported to form upon refluxing BINOL with 1.1 48 equiv of boric acid in toluene (Scheme 5.4A). The pyroborate 294 was characterized by combustion analysis and by IR spectroscopy and was used in the resolution of BINOL. The veracity of the structural assignment of 294 has been called into question as it has been reported that heating BINOL and 0.66 equiv of boric acid in benzene gives rise to the Kaufmann’s 40a propeller 297. There are some examples of the borates derived from BINOL derivatives (Scheme 5.4B). In this case, perhaps the earliest and most widely used class of triaryl borates are those that have internal chelation of the boron to a quinone moiety. Kelly first prepared borates of the type 298 in 1986 for the purpose of effecting an asymmetric Diels-Alder reactions on 49 naphthoquinones (Scheme 5.4B). Also, the reaction between the BINOL derivative 89 and 1 equiv of B(OPh)3 or B(OMe)3 has been reported to give the fused-spiroborate 22-H (Scheme 356 5.4B and Chapter 4). 50 Similar to 20-H, the structure 22-H has been suggested to function as a chiral Lewis acid catalyst for asymmetric Diels-Alder reaction between dienes and enals/alkynals. 50 Gang Hu, one of the former group members, initiated the study of BINOL derived BOROX catalysts and this is summarized in Scheme 5.5B (method C). 51 Analogous to the reaction of the vaulted ligand VAPOL (Scheme 5.5A), he obtained the borate species B2 299a/299b in major quantities (Scheme 5.5B) when BINOL 55 was subjected to the conditions optimized for the generation of B2 borate of VAPOL (ligand:B(OPh)3:H2O = 1:4:1, method C, Chapter 2). Although a single species, NMR and mass spectroscopic analysis could not distinguish between the alternatives structures of 299a and 299b. A mixture of B3 BOROX catalyst 300 (imine = 78) /301 (imine = 111) and spiroborate ion-pair 302 (imine = 78) /303 (imine = 111) was obtained upon the addition of 1 equiv of imine 78/111 to the species B2. It was suggested that, the presence of more than one catalytic species explains the low asymmetric induction (13-20% ee) obtained in the case of the aziridination reaction with imine 78a with BINOL as the ligand (Table 5.4, entries 1-2). 52 When the conditions optimized for B1 (ligand:B(OPh)3 = 1:1 or ligand:BH3•Me2S:PhOH = 1:1:1) were applied, Gang Hu found that a complex mixture of B1 293, B2 299a/299b and Kaufmann’s propeller 297 was formed. A clean generation of B2 299a/299b was obtained on employing B2 conditions (ligand:BH3•Me2S:PhOH:H2O = 1:2:3:1). In the absence of PhOH (ligand:BH3•Me2S = 1:1 or 1:0.5 or 1:0.66), Kaufmann’s propeller 297 is observed as the primary product. Up till this point, 357 all the observations were made by Gang Hu. As the boroxinate involves three boron atoms, we then thought to use 3 equivalents of BH3•Me2S. As a part of this doctoral research, it was found that employing conditions (ligand:BH3•Me2S:PhOH:H2O = 1:3:2:3) optimal for B3 generation also resulted in the formation of B2 as the major species prior to the addition of imine 111a (Figure 5.12A, entry 4). Also, as a part of this doctoral research, the structure of 263/264 was deduced based on the X-ray analysis of similar compound (Chapter 4). Scheme 5.5 BOROX catalysts from (A) (S)-VAPOL 58 and (B) (R)-BINOL 55 A Ph Ph B(OPh)3 (4 equiv) H2O (1 equiv) OH OH Toluene, 80 °C, 1 h then 0.5 mmHg 80 °C. 0.5 h O B OPh + O Ph Ph B1 106 (S)-VAPOL 58 B2 108 imine 78/111 A R OPh O B O B O OPh Ph Ph R + [imine-H] R N A R imine R A 78 H H 111 Me OMe O –O B O O 263 (imine = 78) 264 (imine = 111) 358 + Ph Ph + [imine-H] OPh O B O– B O O O B OPh 188 (imine = 78) 190 (imine = 111) Scheme 5.5 cont’d B B(OPh)3 (4 equiv) H2O (1 equiv) OH OH Toluene, 80 °C, 1 h then 0.5 mmHg 80 °C. 0.5 h O OPh B O B OPh O OPh O B O O B OPh or B2 299a (R)-BINOL 55 B2 299b imine 78/111 [imine-H] O –O B O O 263 (imine = 78) 264 (imine = 111) + + [imine-H] + OPh O B O– + B O O O B OPh 300 (imine = 78) 301 (imine = 111) [imine-H] + O – O B O O 302 (imine = 78) 303 (imine = 111) Later on, another former group member namely Li Huang, was able to obtain the BOROX catalyst in a clean fashion when employing 3,3ʹ′-Ph2-BINOL derivative 56a as the ligand. 53 Also, a significant increase in asymmetric induction (75-76% ee) was observed when 56a was used as the ligand in asymmetric aziridination relative to unsubstituted BINOL 55 (Table 5.5, entries 3-4). However, in 2011, Chen and coworkers reported a huge drop in enantioinduction (34% ee) when they performed the Wulff asymmetric aziridination reaction between EDA and imine 78x derived from p-(methylsulfonyl)benzaldehyde and benzhydryl amine 126a using the BOROX catalyst derived from ligand 56a (Table 5.4, entry 3). 54 In this case, it must be noted that the reaction was performed at –10 °C using B(OH)3 as the boron source. In the search for more diversity in the BOROX catalyst, for increased mechanistic 359 understanding and for improvement in the aziridination with benzhydryl imines 78, we decided to screen several BINOL derivatives of the type 56. The synthesis of these ligands and their effect on the aziridination reaction is discussed below. a Table 5.4 AZ reaction with the catalysts derived from various ligands (Chen’s work) Ph IMINO-BOROX Ph Ph O catalyst Ph Ph NH (10 mol %) N + Ph + CO2Et OEt N (Ar)H toluene Ar N2 Ar CO2Et –10 °C, 18 h Ar(H) 85 78x ent-86x 87x(88x) Ar = 4-SO2Me-C6H4 B(OH)3 + PhOH (40 mol% ) (120 mol%) 4ÅMS toluene reflux, overnight B(OPh)3 preLigand (10 mol%) tolulene, 80 °C, 1 h catalyst then 05 mm Hg 80 °C, 0.5 h Imine 78x B(OPh)3 IMINO-BOROX catalyst # Ligand Cat Yield ent-86x b (%) 1 (R)-VAPOL 58 188x 92 84 >50:1 2 (R)-VANOL 59 189x 93 85 >50:1 3 (R)-3,3ʹ′-Ph2-BINOL 56a 304x 85 34 >50:1 4 (R)- 3,3ʹ′-(9-anthracenyl)2-BINOL 56i 305x 86 0 >50:1 (R)- 3,3ʹ′-(SiPh3)2-BINOL 56g 306x – – – (R,R)- TADDOL 61a 307x – – – 5 6 a e e ee ent-86x c (%) cis:trans d Unless otherwise specified, all reactions were performed with 1 mmol of imine 78x in toluene (0.5 M Isolated yield. in imine 78x) with 1.1 equiv of 85 and 10 mol% of the catalyst at –10 °C. d Determined by HPLC. 1 e c Ratio determined by integration of the methine protons of cis aziridine in the H NMR spectrum of the crude reaction mixture. reaction mixture was stirred at –10 ºC for 18 h and then at 25 ºC for another 18 h. 360 e The 5.3.1 Preparation of BINOL derivatives Based on both steric and electronic factors, we chose the five BINOL derivatives 56a, 56d, 56e, 56f and 56i in our study (Scheme 5.7-5.9). Their syntheses all began with the protection of the hydroxyl units in BINOL by reaction with methyl iodide in the presence of a base. 49b,55 The resulting dimethoxy BINOL 258 was then treated with nBuLi to afford the bis56 ortho-metalated intermediate, which was further reacted with I2 or Br2 to give 259 in high yields. Thereafter, BINOL derivatives 56d 57 58 (R = Br) and 56e 49b,55 or 308 (R = I) were easily obtained by subsequent demethylation using BBr3 (Scheme 5.7). Scheme 5.6 Preparation of dimethoxy-BINOL 258 OH OH MeI, K2CO3 OMe OMe acetone reflux, 36h 90% 55 258 Scheme 5.7 Preparation of BINOL derivatives 56d (R = Br) and 56e (R = I) Br 1. nBuLi, TMEDA Et2O, 3h OMe OMe 2. Br2, 4h 70% Br OMe OMe Br BBr3 OH OH CH2Cl2 rt, 24h 97% 308 Br 56d I 258 1. nBuLi, TMEDA Et2O, 12h OMe OMe 2. I2, 18h 71% I 259 361 I BBr3 OH OH CH2Cl2 rt, 24h 98% I 56e Utilizing Kumada’s coupling in the presence of Ni(PPh3)2Cl2, BINOL derivatives 49b,55 56a (R = Ph) and 56f 59 (R = TRIP) were prepared in good yields after demethylation of the coupled products (Scheme 5.8). Scheme 5.8 Preparation of BINOL derivative (A) 56a (R = Ph) and (B) 56f (R = TRIP) A Br OMe OMe Br 1. Ni(PPh3)2Cl2 PhMgBr 309, Et2O, 20h OH OH 2. BBr3, CH2Cl2, rt, 24h 70% 304 56a B iPr iPr I OMe OMe I 1. Ni(PPh3)2Cl2 ArMgBr 310, Et2O, 24h iPr OH OH iPr 2. BBr3, CH2Cl2, rt, 12h 73% 259 iPr iPr 56f Finally, BINOL derivative 56i (R = 9-phenanthryl) was prepared in 71% yield by Suzuki coupling of 259 with 9-phenanthryl boronic acid 311 in the presence of Pd(PPh3)4 (Scheme 5.9). During the time of this doctoral research, there was no synthesis documented for 56i despite being a well-used ligand. Hence, we used the procedure reported for the analogous ligand 56j (R 60 = 9-anthracenyl). However, very recently, Gong and Hu reported the synthesis of 56i using 362 the same strategy where they employed bis-MOM protected 3,3ʹ′-I2-BINOL derivative instead of 61 (R)-259. Scheme 5.9 Preparation of BINOL derivative 56i (R = 9-phenanthryl) I OMe OMe 1. Pd(PPh3)4, ArB(OH)2 Na2CO3, EtOH, rt, 12h OH OH 2. BBr3, CH2Cl2, rt, 12h 71% I 259 B(OH)2 ArB(OH)2 56i 311 5.3.2 Screening of BINOL and its derivatives on aziridination reaction The success of the BOROX catalyst derived from the 3,3ʹ′-Ph2-BINOL derivative 56a in the aziridination reaction (Table 5.5, entries 3-4) encouraged us to screen other substituted BINOL derivatives of type 56. At the same period, Wipf and co-workers reported a screening of various 3,3ʹ′ di-substituted BINOL derivatives for the Wulff catalytic asymmetric aziridination reaction. 62 In their case, the optimized ligand was BINOL derivative 56b (R = 4-β-Np-C6H4), which gave results (Table 5.5, entry 6) similar to the simple phenyl derivative 56a shown in entries 3 and 4 of Table 5.5. Interestingly, Wipf and coworkers never screened ligand 56a (R = Ph). Since this was a collaborative project, screening of ligands 56d, 56g and 56j was carried out by Li Huang, a former group member. So, we decided to examine the effect of the electronic 363 and steric changes in the BINOL derivatives on the catalytic aziridination reaction. Ligands 56d (R = Br) and 56e (R = I) were used to probe the electronic effect. Both gave asymmetric inductions in the range of 50’s (Table 5.4, entries 8 - 9). Table 5.5 Asymmetric aziridination with the catalysts derived from various BINOL derivatives O Ph Ph N Ph + OEt N2 78a g 3 4 5 6 (R)-55 (R)-56a g (R)-56b R H Ph N Ph + CO2Et NH (Ph)H CO2Et Ph(H) 87a(88a) Imine 78a IMINO-BOROX [pre-catalyst] catalyst Ligand Ligand R R 55 2,4,6-iPr3-C6H3 56f H 56a 56g Ph SiPh3 OH 4-β−Np-C H 56b 2- naphthyl 56h 6 4 OH 4-Ph-C H 9-anthracenyl 56i 6 4 56c 56d 9-phenanthryl 56j Br R 56e I (R)-Ligand R IMINO-BOROX catalyst Ligand Ph ent-86a OPh Ph Ph O –O B B O * N+ OH O O B H * OH OPh Ph 1 2 Ph 85 (R)-Ligand (10 mol%) Method A/A'/C # Ph IMINO-BOROX catalyst (10 mol %) toluene 25 °C, 24 h B(OPh)3 a Cat Pre-cat. b (met) Yield ent86 c (%) 300a + 302a Aʹ′ A 61 66 20 13 17:1 >50:1 13/9 10/7 L. Huang 304a A C 88 90 75 76 >50:1 >50:1 5/4 4/6 L. Huang This work 312a Aʹ′ Aʹ′ 67 76 64 78 >50:1 >50:1 – – P. Wipf 364 ee ent86 d (%) c:t e Yield 87/ 88 f (%) Reference 52 J. Antilla 53 53 P. Wipf 62 62 Table 5.5 cont’d 7 (R)-56c 313a 8 (R)-56d Br 314a 9 (R)-56e I 62 Aʹ′ 68 69 >50:1 – P. Wipf C 89 55 >50:1 4/3 L. Huang 315a C 80 51 >50:1 6/6 This work 316a Aʹ′ C h – 59 78 55 –1.3 –2.0 –0.4 >50:1 >50:1 >50:1 7/9 5/9 8/10 This work This work This work 306a C 80 1 >50:1 2/2 L. Huang P. Wipf 53 10 11 12 (R)-56f 13 (R)-56g 14 (R)-56h 317a Aʹ′ 63 58 >50:1 – 15 (R)-56i 305a C 50 13 15:1 10/11 This work 16 (R)-56j 318a C 75 3 25:1 13/10 L. Huang a Si 53 62 53 Unless otherwise specified, all reactions were performed with 1 mmol of imine 78a in b toluene (0.5 M in imine 78a) with 1.2 equiv of 85 and 10 mol% of the catalyst at 25 °C. Method A: The pre-catalyst was prepared by heating 1 equiv of ligand with 3 equiv of commercial B(OPh)3 in toluene at 80 °C for 1 h, followed by removing all volatiles under high vacuum (0.1 mm Hg) for 0.5 h at 80 °C. Method Aʹ′: The pre-catalyst was prepared by heating 1 equiv of ligand with 3 equiv of commercial B(OPh)3 in CH2Cl2 at 55 °C for 1 h, followed by removing all volatiles under high vacuum (0.1 mm Hg) for 0.5 h at 55 °C. Method C: Same as Method A except 4 equiv of commercial B(OPh)3 and 1 equiv of H2O was used. c Isolated yield. d Determined by chiral HPLC. 1 e Ratio determined by integration of the methine protons of cis aziridine in the H NMR spectrum of the crude reaction 365 Table 5.5 cont’d f mixture. Determined by integration of the NH signals of enamines relative to the methine 1 proton of cis- and trans- aziridine in the H NMR spectrum of the crude reaction mixture. Reaction was performed in CH2Cl2. h g In this case, catalyst is directly generated by heating a mixture of 1 equiv of ligand 56f , 4 equiv of commercial B(OPh)3 and 10 equiv of imine 78a in toluene at 80 °C for 0.5 h. An analysis of the ligands screened by Wipf and co-workers revealed that no ligand was examined bearing an ortho substituted aryl ring at the 3,3ʹ′ positions. 62 Therefore, we decided to screen ligand 56f (R = TRIP). Unfortunately, it gave almost no induction irrespective of the method being used (Table 5.5, entries 10-12). This could be due to an inhibition of the formation of a boroxinate complex resulting for catalyst formation from steric hindrance from the ligand. This was further confirmed as a similar result was obtained when ligand 56g (R = SiPh3) was employed (Table 5.5, entry 13). Chen and coworkers reported no aziridine obtained in the case of the reaction between EDA and the imine 78x derived from p-(methylsulfonyl)benzaldehyde and benzhydryl amine 126a using the BOROX catalyst 306x derived from ligand 56g (Table 5.4, 54 entry 5). Although no ligand with an ortho-substituted aryl ring at the 3,3ʹ′ positions was screened by Wipf and co-workers, they did screen ligand 56h (R = 2-naphthyl) with meta-substitution that gave 58% ee (Table 5.5, entry 14). 62 In order to validate the observation that ortho substitution would have a detrimental effect on asymmetric induction, we decided to screen ligands 56i (R = 9-phenanthryl) and 56j (R = 9-anthracenyl) and as expected, they gave diminished results possibly due to lack of formation of a BOROX catalyst (Table 5.5, entries 15-16). Additionally, 366 Chen and coworkers reported aziridine 86x (Table 5.4, entry 4) in 86% yield and 0% ee obtained from reaction between EDA and the imine derived from p-(methylsulfonyl)benzaldehyde and benzhydryl amine 126a using the BOROX catalyst 305x derived from ligand 56j (R = 9anthracenyl). 54 As discussed earlier (Chapter 2), high asymmetric inductions were obtained in the case of 1 the aziridination reaction mediated by the BOROX catalyst derived from vaulted ligands. Over the years, our aziridination reaction has been further optimized by the fine-tuning of the Nprotecting group of imines. 1a-1c,63 In the past, these protecting groups have been tested with BINOL as the ligand. With BINOL (R)-55, the maximum induction obtained was 67% with the BUDAM phenyl imine 112a (Table 5.6, entry 3). 1b An increase in asymmetric induction was obtained for the imines 78a, 111a and 112a when ligand 56a was used to make the catalyst (Table 5.6, entries 4-6). Surprisingly, an asymmetric induction up to 90% was obtained with the BUDAM phenyl imine 112a when the boron source was switched from B(OPh)3 to BH3•Me2S (Table 5.6, entry 9). However, no significant change was observed for the imines 78a and 111a. Table 5.6 Aziridination with different N-protected Imines using (R)-55 and (R)-56a as ligands O Ar Ph N Ar + OEt N2 toluene 25 °C, 24 h B(OPh)3 or BH3•Me2S Method A'/C/D Ar Ar Ar N Ph 85 78a 111a 112a Ligand (5 mol%) IMINO-BOROX catalyst (5 mol %) Ar + CO2Et ent-86a ent-114a ent-115a Imine [precatalyst] OPh Ar Ar O B O – N+ B O * H O O B OPh Ph 367 a (Ph)H NH CO2Et Ph(H) 87a(88a) 118a(119a) 120a(121a) IMINO-BOROX catalyst Table 5.6 cont’d # 1 2 3 4 5 6 g h i ee azi d (%) Yield enamines f (%) Ligand 300a 301a 319a Ar2CH (R)-BINOL Cat Bh MEDAM BUDAM Aʹ′ j C Aʹ′ 61 72 71 20 38 67 17:1 17:1 nd 13/9 14/10 nd c:t e 304a 320a 321a Bh MEDAM (R)-3,3ʹ′Ph2-BINOL BUDAM C C C 90 89 88 76 79 76 >50:1 >50:1 >50:1 4/6 2/6 4/8 304a 320a 321a 7 8 9 a Yield azi c (%) Pre-cat. b (met) Bh (R)-3,3ʹ′Ph2-BINOL MEDAM BUDAM D D D 89 85 90 76 78 90 50:1 25:1 >50:1 4/7 5/9 1/7 Unless otherwise specified, all reactions were performed with 1 mmol of imine in toluene (0.5 M in imine) with 1.2 equiv of 85 and 5 mol% of the catalyst at 25 °C. b Method Aʹ′: The pre-catalyst was prepared by heating 1 equiv of ligand with 3 equiv of commercial B(OPh)3 in CH2Cl2 at 55 °C for 1 h, followed by removing all volatiles under high vacuum (0.1 mm Hg) for 0.5 h at 55 °C. Method C: The pre-catalyst was prepared by heating 1 equiv of ligand with 4 equiv of commercial B(OPh)3 and 1 equiv of H2O in toluene at 80 °C for 1 h, followed by removing all volatiles under high vacuum (0.1 mm Hg) for 0.5 h at 80 °C. Method D: The pre-catalyst was prepared by heating 1 equiv of (S)-VAPOL, 3 equiv of BH3•Me2S, 2 equiv of PhOH and 3 equiv of H2O in toluene at 100 °C for 1 h, followed by removing all volatiles under high vacuum (0.1 mm Hg) for 0.5 h at 100 °C. nd = not c d e determined. Isolated Yield. Determined by HPLC. Ratio determined by integration of 1 the methine protons of cis- and trans- aziridine in the H NMR spectrum of the crude reaction mixture. f Determined by integration of the NH signals of enamines relative to the methine 1 proton of cis aziridine in the H NMR spectrum of the crude reaction mixture. h i j g Reference 52. Reference 1c. Reference 1b. 5 mol% catalyst. 5.3.3 NMR studies on substrate induced BOROX catalyst formation from BINOL and BINOL derivatives by imine 209h 368 In order to gain an insight into the structures of various species, a detailed NMR study was carried out with imine 111h (derived from p-dimethylamino-benzaldehyde and MEDAM amine 126c). As discussed in Scheme 5.5, Gang Hu found that BINOL (R)-55 formed a mixture of BOROX catalyst 301h (imine = 111h), spiroborate ion-pair 303h (imine = 111h) and an unidentified complex 264h (imine = 111h) following the same protocol, which is employed for our vaulted ligands i.e. VAPOL and VANOL (Figure 5.7B, entry 7). This possibly explains the low asymmetric induction obtained with (R)-55 (Table 5.5, entries 1-3). As a part of this doctoral research, the structure of unidentified complex 264h was found to be a imine-borate complex 264h based on the X-ray analysis of a similar compound 244e in which DMAP is used 11 as the base (Figure 4.14, Chapter 4, δ ( B NMR) = 1.5–2.5 ppm). Although the NMR 1 experiments with BINOL (R)-55 were performed by Gang Hu, the H NMR spectra were neither reported nor analyzed in his dissertation. Hence, after obtaining the spectra from Gang Hu as a personal communication, a detailed critical analysis of these spectra was performed and is presented in Figure 5.7 (entries 1-7). It must be noted that B2 299a/299b is the major species in the presence of excess B(OPh)3 prior to the addition of imine 111h (Figure 5.7B and 5.7C, entry 1 6). Also, the presence of spiroborate 303h was also identified during H NMR analysis (Figure 5.7B and 5.7C, entry 5). Li Huang, a former group member has shown the clean generation of BOROX catalyst 323h when ligand 56a was used. Although the NMR experiments with ligand 1 (R)-56a (Figure 5.7, entries 8-9) were performed by Li Huang, the H NMR spectra were neither reported nor analyzed in her dissertation. Hence, after obtaining the spectra from Li Huang as a personal communication, a detailed critical analysis of these spectra was performed and is 369 1 presented in Figure 5.7 (entries 8-9). A careful H NMR analysis reveal that the conversion of B2 322a/322b derived from 56a to BOROX catalyst 323h is small (Figure 5.7C, entries 8 and 9). This was further confirmed from the 11 B NMR where the ratio of tetra-coordinate boron: tri- coordinate boron is 1:6 instead of 1:2 (Figure 5.7B, entry 9). However, the chiral pocket of 323h might be good enough to provide increased enantioselectivity compared to catalysts derived from other BINOL derivatives. Figure 5.7 (A) Treatment of (R)-55 and (R)-56a with commercial B(OPh)3 and imine 111h. (B) a 11 1 B NMR spectra of the reaction mixture in CDCl3. (C) H NMR spectra (aromatic region) corresponding to the 11 1 B NMR spectra in Figure 5.7B and entry 11 is pure (R)-56a. (D) H NMR spectra (methyl and methoxy) corresponding to entries 2,5,7,9 and 10 in the 11 spectra in Figure 5.7B. A [imine-H] R imine 111h OH B(OPh)3 OH CDCl 3 R 55 (R=H) 56a (R=Ph) rt, 5 min + + [imine-H] R OPh O B O– B O + O O B OPh R 301h (R=H) 323h (R=Ph) + [imine-H] MEDAM N 111h Ar = 4-NMe2-C6H4 Ar Ph O – O Ph + B Ph O O Ph 264h 370 R R O – O B O O R R 303h (R=H) 324h (R=Ph) B NMR Figure 5.7 cont’d B 323h 56 (R=Ph) + B(OPh)3 + imine 111h (1:3:1) 323h 56a (R=Ph) + B(OPh)3 + H2O + imine 111h (1:4:1:1) 264h 264h 56a (R=Ph) + B(OPh)3 + H2O (1:4:1) 55 (R=H) + B(OPh)3 + H2O + imine 111h (1:4:1:1) 304h 302h 264h 55 (R=H) + B(OPh)3 + H2O (1:4:1) 304h 55 (R=H) + B(OPh)3 + imine 111h (2:1:1) 55 (R=H) + B(OPh)3 (2:1) 55 (R=H) 264h B(OPh)3 + imine 111h (1:1) B(OPh)3 C 56a 56a 322a/b 323h 322a/b 323h 322a/b 299a/b 322a/b 299a/b 303h 299a/b 299a/b 303h 55 55 371 Figure 5.7 cont’d D a Note for Figure 5.7B: Entry 1: neat B(OPh)3. Entry 2: commercial B(OPh)3 plus imine 111h (1 equiv) for 5 min at 25 °C. Entry 3: pure BINOL (R)-55. Entry 4: (R)-55 (0.2 mmol) plus 0.5 equiv commercial B(OPh)3 for 5 min at 25 °C. Entry 5: (R)-55 (0.2 mmol) plus 0.5 equiv commercial B(OPh)3 plus imine 111h (0.5 equiv) for 5 min at 25 °C. Entry 6: (R)-55 (0.1 mmol) plus 4 equiv commercial B(OPh)3 and 1 equiv H2O were heated at 80 °C in toluene for 1 h followed by removal of volatiles under vacuum for 0.5 h. Entry 7: 1.0 equiv of imine 111h was added to the entry 6 (pre-catalyst) for 10 min at 25 °C. Entry 8: same as entry 6 except (R)56a is used instead of (R)-55. Entry 9: 1.0 equiv of imine 111h was added to the entry 8 (pre- 372 catalyst) for 10 min at 25 °C. Entry 10: (R)-56a (0.1 mmol) plus 3 equiv commercial B(OPh)3 plus imine 111h (1 equiv) for 10 min at 25 °C. As a result of work in this thesis (Chapter 2), it was envisioned that the direct generation of the boroxinate catalyst 323h could be achieved without the generation of any pre-catalyst. Indeed, it was delightful to observe the generation of the boroxinate catalyst 323h in greater amounts by simple mixing 56a, commercial B(OPh)3 and imine 111h at room temperature 1 (Figure 5.7B and 5.7C, entry10). The H NMR spectrum shows that there is no formation of B2 322a/322b under these conditions similar to that observed for VAPOL. Additionally, the splitting in the methyl and methoxy regions (Figure 5.7D, entry10) is also observed similar to cases involving vaulted ligand, VAPOL (Chapter 2). 1f Also, we have been able to perform the aziridination reaction with the BOROX catalyst 323h generated by simple mixing of the components. The result is comparable to that obtained by employing the BOROX catalyst generated via pre-catalyst (75% ee, Scheme 5.10 vs. 76% ee, Table 5.6, entries 4 and 7). While good inductions were observed in the aziridination reaction of imine 78a with the BOROX catalysts derived from the BINOL derivative 56a, lower enantioselectivities were obtained when 51 B1 catalysts of type 74a and 92a (this work) were utilized (Scheme 5.10B). 373 Scheme 5.10 (A) One-pot aziridination with imine 78a using (R)-55 and (R)-56a as the ligands. (B) aziridination with B1 catalysts. A O Ph Ph N Ph Ph OEt Ligand (10 mol%) B(OPh)3 (30 mol%) N2 Ph 85 toluene 25 °C, 24 h toluene, 25 °C Ph Ph N Ph 78a + CO2Et (R)-55 (R)-56a 63 84 13 75 CO2Et (Ph)H Ph(H) 87a(88a) ent-86a Yield ee Ligand ent-86a (%) ent-86a (%) c:t NH Yield 87a(88a) (%) 18:1 50:1 3(4) 7(8) B Ph O Ph Ph N Ph + OEt N2 78a Ligand catalyst Ph catalyst (10 mol %) solvent 25 °C, 24 h Ph N Ph 85 Ph + CO2Et ent-86a NH (Ph)H CO2Et Ph(H) 87a(88a) Yield ee solvent ent-86a (%) ent-86a (%) cis:trans Yield 87a(88a) (%) (S)-55 (S,S)-74a CH2Cl2 (R)-89 (R)-92a Toluene Ph + N H 47 80 40 48 2:1 >100:1 24(23) 6(8) Ph Ph Ph Ph O + N – O H B O Ph O O – O B O O (R)-92a B1 (FSB) (S,S)-74a B1 (SB) 374 The focus was then shifted towards NMR studies of BOROX catalysts from BINOL derivatives of type 56 other than 56a. A detailed NMR study was carried out for ligands 56e, 56f, 56i and 56j (Scheme 5.11). The results with ligands 56e and 56i are presented in Figure 5.5. Scheme 5.11 NMR study of the BOROX catalysts using (R)-56 as the ligand R R MEDAM N 111h Ar = 4-NMe2-C6H4 Ar + [imine-H] OPh Ph O B O Ph O– O– + B O B O O B O Ph O OPh Ph R 1. B(OPh)3 (4 equiv) H2O (1 equiv) OH OH Toluene, 80 °C, 1 h then 0.5 mmHg 80 °C. 0.5 h R 2. imine 111h (1 equiv) 56e (R = I) 56f (R = TRIP) 56i (R = 9-phenanthryl) 56j (R = 9-anthracenyl) [imine-H] 325h (R = I) 326h (R = TRIP) 327h (R = 9-phenanthryl) 328h (R = 9-anthracenyl) + 264h A careful NMR study shows that the boroxinate catalyst 325h was generated from ligand 56e (R = I) (Figure 5.8, entries 1-3). A very interesting observation was made in the case of BINOL derivative 56i. It must be remembered that only 13% ee was observed in the aziridination with a catalyst generated from 56i (Table 5.4, entry 15). A small amount of BOROX catalyst 327h was observed along with some amount of achiral borate imine complex 264h (Figure 5.8, entry 4). It seems like the formation of the catalyst 327h is slow as the 11 absorption at δ ( B NMR) ≅ 5 ppm increases with longer time periods (Figure 5.8, entries 4-7). Additionally, the splitting of the methyl and methoxy absorptions is also observed similar to 1 observations involving vaulted ligands (Figure 5.8B). Further, the characteristic peak (δ, H NMR = 8.75-8.83 ppm, multiplet) of the ligand 56i was found to be shifted upfield to δ = 8.40 ppm, doublet (Figure 5.8C, entries 4-7). No spiroborate catalyst of the type 74a was observed in 375 11 these cases due to the absence of an absorption at δ ( B NMR) ≅ 10 ppm. In most cases, a peak at δ ≅ 11.7 ppm was observed for the proton attached to the nitrogen of the iminium ion (Figure 5.8C). All observations made for ligand 56i were also made for ligand 56e. In the case of ligand 1 56e, the characteristic peak (δ, H NMR = 8.52 ppm, singlet) of the ligand 56i was found to be shifted upfield to δ = 8.12 ppm, singlet (Figure 5.8C, entries 1-3). Figure 5.8 Treatment of (R)-56e and (R)-56i with commercial B(OPh)3 and imine 111h. (A) 11 11 a 1 B NMR spectra of the reaction mixture in CDCl3. (B) H NMR spectra corresponding to the 1 + B NMR spectra in Figure 5.8A. (C) H NMR spectra showing the NH region corresponding to the 11 B NMR in Figure 5.8A. A E-4 (after 3.5 d) E-4 (after 3 d) E-4 (after 24 h) 327h 264h Pre-catalyst @ (R)-56i (R = 9-phenanthryl) + imine 111h E-1 (after 3 d) E-1 (after 24 h) 325h Pre-catalyst @ (R)-56e (R = I) + imine 111h 376 264h B Figure 5.8 cont’d C NH NH NH NH + + + + NH NH NH + + + 377 a Note for Figure 5.8A: Entry 1: (R)-56e (0.1 mmol) plus 4 equiv commercial B(OPh)3 and 1 equiv H2O were heated at 80 °C in toluene for 1 h followed by removal of volatiles under vacuum for 0.5 h. Thereafter, 1.0 equiv of imine 111h was added at 25 °C. Entry 2 and 3: entry 1 after 24 h and 3 days respectively. Entry 4: (R)-56i (0.1 mmol) plus 4 equiv commercial B(OPh)3 and 1 equiv H2O were heated at 80 °C in toluene for 1 h followed by removal of volatiles under vacuum for 0.5 h. Thereafter, 1.0 equiv of imine 111h was added at 25 °C. Entry 5: entry 4 after 24 h. Entry 6: entry 1 after 3 days. Entry 7: entry 1 after 3.5 days. A small amount of BOROX catalyst 328h and a large amount of the achiral borate-imine complex 264h was observed when ligand 56j (R = anthracenyl) was subjected to NMR analysis (Figure 5.9, entries 1-4). This could explain the low asymmetric induction in this case. In fact, a 78% yield of aziridine 86a is obtained when imine 78a is reacted with EDA in the presence of 40 mol% B(OPh)3 only suggesting that the reaction is catalyzed by an achiral Brønsted acid of type + – 264a [imine-H] [B(OPh)4] . In the case of ligand 56f (R = TRIP), there was no sign of boroxinate catalyst. Instead, a lot of the achiral borate-imine complex 264h was obtained which increased with time (Figure 5.9, entries 5-7). The NMR study of the boroxinate catalysts generated from BINOL derivatives 56 supports the results obtained in the Wulff catalytic asymmetric aziridination reaction (Figure 5.7-5.9 and Table 5.5). 378 Figure 5.9 Treatment of (R)-56f and (R)-56j with commercial B(OPh)3 and imine 111h. (A) 11 11 a 1 B NMR spectra of the reaction mixture in CDCl3. (B) H NMR spectra corresponding to the 1 + B NMR spectra in Figure 5.9A. (C) H NMR spectra showing the NH region corresponding to the 11 B NMR spectra in Figure 5.9A. A E-5 (after 3 d) E-5 (after 24 h) 264h Pre-catalyst @ (R)-56f (R = TRIP) + imine 111h E-1 (after 3.5 d) E-1 (after 3 d) E-1 (after 24 h) Pre-catalyst @ (R)-56j (R = 9-anthracenyl) + imine 111h 328h 379 264h B Figure 5.9 cont’d C NH NH NH NH + + + + 380 a Note for Figure 5.9A: Entry 1: (R)-56j (0.1 mmol) plus 4 equiv commercial B(OPh)3 and 1 equiv H2O were heated at 80 °C in toluene for 1 h followed by removal of volatiles under vacuum for 0.5 h. Thereafter, 1.0 equiv of imine 111h was added at 25 °C. Entry 2: entry 1 after 24 h. Entry 3: entry 1 after 3 days. Entry 4: entry 1 after 3.5 days. Entry 5: (R)-56f (0.1 mmol) plus 4 equiv commercial B(OPh)3 and 1 equiv H2O were heated at 80 °C in toluene for 1 h followed by removal of volatiles under vacuum for 0.5 h. Thereafter, 1.0 equiv of imine 111h was added at 25 °C. Entry 6: entry 4 after 24 h. Entry 7: entry 4 after 3 days. We have observed that BINOL (R)-55 formed a mixture of BOROX catalyst 301h, spiroborate ion-par 303h, and achiral imine-borate complex 264h following the same protocol, which was employed for our vaulted ligands i.e. VAPOL and VANOL (Figure 5.7B, entry 7). The interesting question then arises as to whether H8-BINOL (R)-53 would give clean formation of boroxinate or not? Unfortunately, only the achiral borate-imine complex 264h was observed when the reaction of H8-BINOL (R)-53 with B(OPh)3 and imine 111h was subjected to NMR analysis (Figure 5.10, entries 1-3). The achiral complex 264h increased with time and a very small amount of boroxinate catalyst was observed in the 11 B NMR spectrum after 3 days (Figure 5.10A, entry 3). It is interesting to notice the completely different behavior of H8-BINOL (R)-53 compared to BINOL (R)-55. 381 Figure 5.10 Treatment of (R)-53 and commercial B(OPh)3 and imine 111h. (A) 11 B NMR spectra of the reaction mixture in CDCl3. Entry 1: (R)-53 (0.1 mmol) plus 4 equiv commercial B(OPh)3 and 1 equiv H2O were heated at 80 °C in toluene for 1 h followed by removal of volatiles under vacuum for 0.5 h. Thereafter, 1.0 equiv of imine 111h was added at 25 °C. 1 Entry 2: entry 1 after 24 h. Entry 3: entry 1 after 3 days. (B) H NMR spectra corresponding to the 11 1 B NMR spectra in Figure 5.10A. (C) H NMR spectra showing the methyl and methoxy region corresponding to the 11 B NMR spectra in Figure 5.10A. A E-1 (after 3 d) E-1 (after 24 h) 264h Pre-catalyst @ (R)-53 + imine 111h 382 B Figure 5.10 cont’d E-1 (after 3 d) E-1 (after 24 h) Pre-catalyst @ (R)-53 + imine 111h C E-1 (after 3 d) E-1 (after 24 h) Pre-catalyst @ (R)-53 + imine 111h 383 5.3.4 Calculated structure of BOROX catalyst 323a derived from 3,3ʹ′-Ph2-BINOL 56a We have observed many non-covalent interactions between the iminium ion and arene rings of the vaulted ligands with the aid of an X-ray crystal structure of the BOROX catalyst 190a generated from (S)-VAPOL and imine 111a (Figure 5.1C). 1f We were not able to obtain single crystals of 323a (imine = 111a and ligand = (S)-56a) suitable for X-ray analysis. In an attempt to gain an insight into the nature of any non-covalent interactions in the IMINO-BOROX 323a, computational methods were undertaken to explore its structure. performed using Gaussian ʹ′03 at B3LYP/6-31g* level of theory. 24 Calculations were The calculated lowest energy structure is shown in Figure 5.11. Similar to the structure of 190a, there are many non-covalent interactions suggested by the calculated structure of 323a. In addition to the hydrogen bond (d1 = 1.70 Å), there are several CH-π interactions: one is between one of the MEDAM methyl groups and one of the naphthalene rings (d2 = 4.42 Å) and another is between a methyl group on the other MEDAM ring and a phenyl ring from the phenol component (d4 = 4.30 Å). There are several other CH-π interactions including those between the ortho hydrogen on one aryl ring and the π-system of another aryl ring (d3 = 4.28 Å, d5 = 3.97 Å and d6 = 4.58 Å). Another important interaction between the catalyst and the substrate is a π−π stacking interaction between the protonated iminium moiety and one of the phenyl rings at the 3,3ʹ′ positions of the ligand (d7 = 3.75 Å). In addition, another π−π stacking interaction was found between one of the phenyl rings from the phenol component and the other phenyl ring at the 3,3ʹ′ positions of the ligand (d8 = 4.44 Å). These possible interactions suggest that the iminium is tightly bound in the chiral 384 pocket and this might be responsible for higher asymmetric induction observed for the ligand 56a (Table 5.5). However, it must be remembered that this is only a prediction for the catalyst substrate complex and does not represent a transition state for the aziridination reaction since the diazo compound is not involved. a Figure 5.11 Calculated structure of IMINO-BOROX catalyst 323a using Gaussian ʹ′03. (A) Calculated B3LYP/6-31g* structure visualized by the Mercury Program (C, gray; O, red; N, blue; B, yellow; H, white). Hydrogen atoms omitted for clarity (except N-H). (B) Space-filling rendition of 323a with the same orientation and showing hydrogens. The boroxinate anion is given in green and the iminium cation is in traditional colors. A B d4 d2 d6 d3 d5 d1 d7 d8 385 a Note for Figure 5.11A: Some secondary interactions are highlighted: d1 = 1.70 Å (H-bonding), d2 = 4.42 Å (CH-π), d3 = 4.28 Å (CH-π), d4 = 4.30 Å (CH-π), d5 = 3.97 Å (CH-π), d6 = 4.58 Å (CH-π), d7 = 3.75 Å (CH-π or π-π stack), d8 = 4.44 Å (CH-π or π-π stack). 5.4 Generation of BOROX catalyst 329 with BINOL 55 using DMSO as the base. We have seen that DMSO is capable of generating the boroxinate catalyst in the case of vaulted ligands (Chapter 2). Hence, the thought was entertained as to whether or not DMSO would behave in a same manner with linear biaryl ligands. Meanwhile, another group member namely, Wynter Osminski found that a mixture of BINOL and commercial B(OPh)3 in the ratio of 2:1 in d6-DMSO would generate the spiroborate 330 (Figure 5.12, entry 2). As a part of this work, we mixed one equiv of BINOL 55 with 3 equiv of commercial B(OPh)3 in d6-DMSO. Surprisingly, boroxinate 329 was observed as the major species with only a small amount of the spiroborate 330 (Figure 5.12, entry 3). This is in stark contrast to the use of imine as the base, which gives a mixture of spiroborate and boroxinate catalyst (Figure 5.7). An appreciable + – amount of the achiral [DMSOH] [B(OPh)4] complex 244f was also observed (Figure 5.12, entry 3). Thereafter, we performed these experiments in CDCl3 with 1-5 equivalents of DMSO. This was done to quantify the amount needed to generate the boroxinate catalyst using DMSO. It seems that atleast 5 equivalents of DMSO is needed to drive the reaction in the forward direction towards the generation of boroxinate catalyst 329 (Figure 5.12, entries 5 and 6). It must be noted that spiroborate 330 appears not to have been formed due to the lack of an 11 absorption at δ ( B NMR) ≅ 10 ppm (Figure 5.12B, entry 6). 386 Figure 5.12 (A) Treatment of BINOL (R)-55 and DMSO with different boron sources. (B) 1 NMR spectra of the reaction mixture. (C) H NMR spectra corresponding to the 11 a 11 B B NMR spectra in Figure 5.12B except that the entry 1 is pure (R)-55 in d6-DMSO. A OH OH Me2SO B(OPh)3 + [Me2SO-H] NMR solvent rt, 5 min 55 OPh O –O B B O + O OB OPh + [Me2SO-H] O –O B O O + [Me2SO-H] + Ph O –O Ph B Ph O O Ph 330 329 244f B 329 244f Pre-catalyst @ (S)-55 + DMSO (1:5, in CDCl3) 244f Pre-catalyst @ (S)-55 + DMSO (1:1, in CDCl3) Pre-catalyst @ (S)-55 (in CDCl3) 329 244f (S)-55 + B(OPh)3 (1:3, in d6-DMSO) 330 (S)-55 + B(OPh)3 (2:1, in d6-DMSO) 244f B(OPh)3 (in d6-DMSO) 387 Figure 5.12 cont’d C 329 Pre-catalyst @ (S)-55 + DMSO (1:5, in CDCl3) Pre-catalyst @ (S)-55 + DMSO (1:1, in CDCl3) 299a/b 329 299a/b 299a/b Pre-catalyst @ (S)-55 (in CDCl3) 299a/b 297 297 329 329 (S)-55 + B(OPh)3 (1:3, in d6-DMSO) 330 (S)-55 + B(OPh)3 (2:1, in d6-DMSO) 330 55 55 B(OPh)3 (in d6-DMSO) a Note for Figure 5.12B: Entry 1: commercial B(OPh)3 in d6-DMSO. Entry 2: (R)-55 (0.1 mmol) plus 0.5 equiv commercial B(OPh)3 stirred in d6-DMSO (1 mL) for 1 h in presence of 150 mg 4Å Molecular Sieves. Entry 3: (R)-55 (0.1 mmol) plus 3 equiv commercial B(OPh)3 stirred in d6-DMSO (1 mL) for 1 h. Entry 4: (R)-55 (0.1 mmol) plus 3 equiv BH3•Me2S, 2 equiv of PhOH and 3 equiv H2O were heated at 100 °C in toluene for 1 h followed by removal of volatiles under vacuum for 0.5 h. The NMR was taken in CDCl3. Entry 5: 1.0 equiv of DMSO was added to entry 4 at 25 °C. Entry 5: 5.0 equiv of DMSO was added to entry 4 at 25 °C. 388 5.5 TADDOL and its effect on the Wulff catalytic asymmetric aziridination reaction TADDOL is one of the most common chiral diols used in the field of asymmetric catalysis. 64 Hence, we decided to screen TADDOL (R,R)-61a as a ligand substitute for VANOL or VAPOL for our aziridination reaction. Unfortunately, while aziridine 86a was obtained in 73% yield, no asymmetric induction was observed (Scheme 5.12). Scheme 5.12 Aziridination with imine 78a using (R,R)-61a as the ligand. O Ph Ph Ph + N OEt N2 78a IMINO-BOROX catalyst (10 mol %) toluene 25 °C, 24 h O OH O OH Ph Ph B(OPh)3 (4 equiv) H2O (1 equiv) Ph N Ph 85 Ph Ph Ph Ph + CO2Et ent-86a 73% y, <1% ee cis:trans = 20:1 [pre-catalyst] Toluene, 80 °C, 1 h then 0.5 mmHg 80 °C. 0.5 h Ph Imine 78a NH (Ph)H CO2Et Ph(H) 78a(88a) 9% (13%) IMINO-BOROX catalyst (R,R)-61a (10 mol%) It is assumed that this result is due to the background reaction. A 78% yield of aziridine 86a is obtained when imine 78a is reacted with EDA in the presence of 40 mol% B(OPh)3 only + suggesting that the reaction is catalyzed by an achiral Brønsted acid of type 264a [imine-H] – [B(OPh)4] . The result with TADDOL (R,R)-61a was further supported by NMR analysis that failed to detect any boroxinate with TADDOL (R,R)-61a when imine 111h was added (Figure 389 5.13, entry 3). No change was observed even after 12 h (Figure 5.13, entry 4). The only tetra+ – coordinate species observed is the achiral [imine-H] [B(OPh)4] 264h. Figure 5.13 Treatment of (R,R)-61a and commercial B(OPh)3 with imine 111h. (A) 11 B NMR spectra of the reaction mixture in CDCl3. Entry 1: pure B(OPh)3. Entry 2: (R,R)-61a (0.1 mmol) plus 4 equiv commercial B(OPh)3 and 1 equiv H2O were heated at 80 °C in toluene for 1 h followed by removal of volatiles under vacuum for 0.5 h. Entry 3: 1.0 equiv of imine 111h 1 was added to the entry 3 (pre-catalyst) for 10 min at 25 °C. Entry 4: entry 3 after 12 h. (B) H NMR spectra corresponding to the 11 B NMR spectra in Figure 5.13A expect that the entry 1 is pure (R,R)-61a. A 264h E-3 (after 12 h) 264h Pre-catalyst @ (R,R)-61a + imine 111h Pre-catalyst @ (R,R)-61a B(OPh)3 390 Figure 5.13 cont’d B E-3 (after 12 h) Pre-catalyst @ (R,R)-61a + imine 111h Pre-catalyst @ (R,R)-61a (R,R)-61a It must be noted that Chen and coworkers reported no aziridine 86x (not shown) from reaction between EDA and imine derived from p-(methylsulfonyl)benzaldehyde and benzhydryl 54 amine 126a using the catalyst 307x derived from TADDOL (R,R)-61a, B(OH)3 and PhOH. this case, they performed the reaction at –10 °C (see Table 5.4, entry 6). 391 In 5.6 Conclusions The diversity of the novel BOROX catalysts was explored by altering the chiral diol component in the boroxinate catalyst. In the process, a potentially inexpensive ligand ISOVAPOL 197 was developed and was found to be equally efficient as the other vaulted ligands that have been evaluated for the Wulff aziridination reaction. Also, linear biaryl ligands were screened for the first time. BINOL 55 and BINOL derivatives 56 generated boroxinate catalysts in various amounts depending on the sterics and electronics of the substituents at the 3,3ʹ′ positions. A detailed NMR study helped to reveal the favorable and unfavorable conditions for generation of the BOROX catalyst. Hopefully, the information gained from the experiments described in this chapter will help in designing new catalytic systems for other asymmetric reactions. 392 APPENDIX 393 5.7 Experimental 5.7.1   General information ........................................................................................................ 395   5.7.2   Synthesis of imines 78, 110a, 111a, 111h and 112a ...................................................... 395   5.7.3   Synthesis of ISOVAPOL (S)-197 (Scheme 5.2 and 5.3) ................................................ 400   5.7.4   Synthesis of aziridines 86, 113a, 114a and 115a using (S)-ISOVAPOL and (R)-VANOL (Table 5.1, 5.2 and 5.3) ............................................................................................................... 406   5.7.5   NMR analysis of a mixture of VANOL, B(OPh)3 , and imine 111a (Figure 5.3) ......... 415   5.7.6   NMR analysis of a mixture of ISOVAPOL, B(OPh)3 , and imine 111a (Figure 5.3) ... 417   5.7.7   Synthesis of BINOL derivatives 258, 259, 308, 56a, 56d-f and 56i (Scheme 5.6-5.9) .. 417   5.7.8   Asymmetric aziridination with BINOL 55, BINOL derivatives 56 and TADDOL 61a (Table 5.4-5.6 and Scheme 5.12) ................................................................................................ 428   5.7.9   One-Pot asymmetric aziridination with 3,3ʹ′-Ph2-BINOL (R)-56a and aziridination with B1 catalyst (R)-92a (Scheme 5.10) ............................................................................................. 431   5.7.10   NMR analysis of a mixture of B(OPh)3, imine 111h and BINOL 56a (Figure 5.7).... 433   5.7.11   NMR analysis of a mixture of B(OPh)3, imine 111h with BINOL derivatives (R)-56 or H8-BINOL (R)-53 or TADDOL (R,R)-61a (Figure 5.8-5.10 and 5.13) ................................... 434   5.7.12   NMR analysis of a mixture of B(OPh)3, DMSO and BINOL (R)-55 (Figure 5.12) .... 435   5.7.13   DFT calculations ........................................................................................................... 437   394 5.7.1 General Information Same as Chapter 2. 5.7.2 Synthesis of imines 78, 110a, 111a, 111h and 112a General Procedure for the synthesis of aldimines – Illustrated for the synthesis of Nbenzylidene-1,1-diphenylmethanamine 78a. O MgSO4 + CH2Cl2 25 °C, 24 h H2N 127a N 78a 126a N-benzylidene-1,1-diphenylmethanamine 78a: To a 50 mL flame-dried round bottom flask filled with argon was added benzhydryl amine 126a (0.92 g, 5.00 mmol), MgSO4 (1.0 g, 8.4 mmol, freshly flame-dried) and dry CH2Cl2 (15 mL). After stirring for 10 min, benzaldehyde 127a (0.54 g, 5.05 mmol, 1.01 equiv) was added. The reaction mixture was stirred at room temperature for 24 h. The reaction mixture was filtered through Celite and the Celite bed was washed with CH2Cl2 (10 mL × 3) and then the filtrate was concentrated by rotary evaporation to give the crude imine as an off-white solid. Crystallization (1:5 ethyl acetate/hexanes) and collection of the first crop afforded 78a as white solid crystals (mp. 99-101 °C) in 80% isolated yield (1.09 g, 4 mmol). 395 1 Spectral data for 78a: H NMR (CDCl3, 300 MHz) δ 5.64 (s, 1H), 7.20-7.90 (m, 15H), 8.46 (s, 1H); 13 C NMR (CDCl3, 75 Hz) δ 77.62, 126.69, 127.40, 128.15, 128.19, 128.24, 130.47, 136.07, 143.64, 160.48. These spectral data match those previously reported for this 1a compound. N-(4-methylbenzylidene)-1,1-diphenylmethanamine 78d: Imine 78d was prepared according to the procedure described N above for imine 78a. Crystallization (1:5 ethyl acetate/hexanes) Me and collection of the first crop afforded 78d as white solid 78d crystals (mp. 73-74 °C) in 80% isolated yield (1.14 g, 4 mmol). 1 Spectral data for 78d: H NMR (CDCl3, 300 MHz) δ 2.44 (s, 3H), 5.64 (s, 1H), 7.26-7.48 (m, 12H), 7.80 (d, J = 8 Hz, 2H), 8.45 (s, 1H); 13 C NMR (CDCl3, 75 Hz) δ 21.50, 76.57, 126.89, 127.66, 128.38, 128.41, 129.21, 133.88, 141.01, 143.98, 160.67. These spectral data match those previously reported for this compound. 1a N-(4-methoxybenzylidene)-1,1-diphenylmethanamine 78e: Imine 78e was prepared according to the procedure described N MeO above for imine 78a. Crystallization (1:5 ethyl acetate/hexanes) and collection of the first crop afforded 78e as white solid 78e crystals (mp. 108-109 °C) in 80% isolated yield (1.21 g, 4 mmol). 396 1 Spectral data for 78e: H NMR (CDCl3, 300 MHz) δ 3.82 (s, 3H), 5.55 (s, 1H), 6.91 (d, J = 8.8 Hz, 2H), 7.28-7.40 (m, 10H), 7.78 (d, J = 8.8 Hz, 2H), 8.34 (s, 1H); 13 C NMR (CDCl3, 75 Hz) δ 55.32, 77.77, 113.88, 126.85, 127.67, 128.37, 129.99, 144.11, 160.01. These spectral data match those previously reported for this compound. 1a N-(4-bromobenzylidene)-1,1-diphenylmethanamine 78g: Imine 78g was prepared according to the procedure described N above for imine 78a. Crystallization (1:5 ethyl acetate/hexanes) Br and collection of the first crop afforded 78g as white solid crystals 78g (mp. 96-97 °C) in 75% isolated yield (1.31 g, 3.75 mmol). 1 Spectral data for 78g: H NMR (CDCl3, 300 MHz) δ 5.23 (s, 1H), 7.15-7.35 (m, 10H), 7.47 (d, J = 7 Hz, 2H), 7.64 (d, J = 7 Hz, 2H), 8.28 (s, 1H); 13 C NMR (CDCl3, 75 Hz) δ 77.85, 127.05, 127.60, 128.46, 129.84, 131.75, 143.62, 159.51. These spectral data match those previously reported for this compound. 1a N-(cyclohexylmethylene)-1,1-diphenylmethanamine 78v: Imine 78v was prepared according to the procedure described above for N imine 78a. Crystallization (1:5 ethyl acetate/hexanes) and collection of the first crop afforded 78v as white solid crystals (mp. 49-51 °C) in 78v 70% isolated yield (0.97 g, 3.5 mmol). 397 1 Spectral data for 78v: H NMR (CDCl3, 300 MHz) δ 1.10-1.90 (m, 10H), 2.20 (bs, 1H), 5.21 (s, 1H), 7.00-7.60 (m, 10H), 7.59 (d, J = 5.5 Hz, 1H); 13 C NMR (CDCl3, 75 Hz) δ 25.82, 26.41, 30.13, 43.91, 78.35, 127.20, 127.97, 128.73, 144.41, 169.51. These spectral data match those previously reported for this compound. 1a N-(2,2-dimethylpropylidene)-1,1-diphenylmethanamine 78w: Imine 78w was prepared according to the procedure described above for imine N 78a. Crystallization (1:9 ethyl acetate/hexanes) and collection of the first crop afforded 78w as white solid crystals (mp. 51-52 °C) in 50% isolated 78w yield (0.63 g, 0.25 mmol). 1 Spectral data for 78w: H NMR (CDCl3, 300 MHz) δ 1.27 (s, 9H), 5.50 (s, 1H), 7.34 (t, J = 7 Hz, 2H), 7.44 (t, J = 7 Hz, 4H), 7.49 (d, J = 7 Hz, 4H), 7.85 (s, 1H); 13 C NMR (CDCl3, 75 Hz) δ 26.94, 36.38, 77.36, 126.68, 127.44, 128.25, 144.23, 171.48. These spectral data match those previously reported for this compound. 1a N-benzylidene-bis(4-methoxyphenyl)methylamine 110a: See Chapter 2 N-phenylmethylidene-bis(4-methoxy-3,5-dimethylphenyl)methylamine 111a: See Chapter 2 N-benzylidene-1,1-bis(3,5-di-tert-butyl-4-methoxyphenyl)methanamine 112a: See Chapter 2 398 N-(4-dimethylaminobenzylidene)-bis(4-methoxy-3,5- OMe dimethylphenyl)methylamine 111h: Imine 111h was prepared according to the procedure described above for N imine 78a except following differences: (1) the scale of Me2N OMe the reaction was 10 mmol; (2) 4 Å molecular sieves (6 111h g, freshly dried) were used instead of MgSO4; (3) 1.03 equiv of aldehyde was used; (4) the 1 reaction time was 1 week (the reaction was followed by H NMR). Crystallization (1:3 EtOAc/hexanes) and collection of the first crop afforded 111h as yellow solid crystals (mp 167169 ºC) in 51% isolated yield (2.20 g, 5.10 mmol). 1 Spectral data for 111h: H NMR (CDCl3, 300 MHz) δ 2.25 (s, 12H), 3.00 (s, 6H), 3.68 (s, 6H), 5.30 (s, 1H), 6.69 (d, J = 9.0 Hz, 2H), 7.00 (s, 4H), 7.70 (d, J = 9.0 Hz, 2H), 8.24 (s, 1H); 13 C NMR (CDCl3, 75 MHz) δ 16.21, 40.26, 59.59, 77.30, 111.83, 125.37, 128.16, 129.93, 130.44, -1 134.00, 152.36, 155.96, 160.09; IR (thin film) 2926w, 2824w, 1636w, 1606s, 1526 m cm ; + Mass spectrum (NPOE, +FAB): m/z (% rel intensity) 430 M (52), 283 (100). Anal calcd for C28H34N2O2: C, 78.10; H, 7.96; N, 6.51; Found: C, 77.98; H, 8.17; N, 6.90. These spectral data match those previously reported for this compound. 399 1f 5.7.3 Synthesis of ISOVAPOL (S)-197 (Scheme 5.2 and 5.3) 5.7.3.1 Preparation of ISOVAPOL monomer 285: 1. SOCl2 (3.6 equiv) 90 ºC, 1h HO O 284 76.4 mmol (14.2 g) Ph 2. Ph 270 (1.3 equiv) (iPrCO)2O 271 (2.0 equiv) Ph 190 ºC, 48 h + OH 285 5.27g-6.19g (26-30%) 3. KOH, H2O, 100 ºC, 1h + UNK Ph OH 286 1.66g (6%) 287 1.44g 3-phenylphenanthren-1-ol 284: To a 250 mL flame-dried round bottom flask equipped with a large stirrer bar and a condenser filled with argon was added 1-naphthylacetic acid 284 (14.23 g, 76.42 mmol) and thionyl chloride (20 mL, 274 mmol). The mixture was heated to reflux for 1 h (oil bath temperature: 90 °C), and then all of the volatiles were carefully removed by high vacuum (0.5 mmHg) with 2 nd trap to protect the pump. To the flask containing the resulted brown oil was added phenylacetylene 270 (11.00 mL, 100.2 mmol) and isobutyric anhydride 271 (25.00 mL, 146.2 mmol) under argon, and the resulting mixture was heated and stirred at 190 °C for 48 h with gentle nitrogen flow across top of the condenser. The brown reaction mixture was cooled down to below 100 °C (about 80 °C, oil bath temperature), and then 4.5 N KOH (100 mL) was added. The reaction was then allowed to stir at 100 °C (oil bath temperature) for 15 h. The brown solution was then cooled to room temperature and ether (100 mL) was added and stirred for 10 min. The organic layer was separated. The aqueous layer was extracted twice with ether (100 mL × 2) and the combined organic layer was washed with brine (100 mL) and dried over MgSO4, filtered. The dark-colored solution (crude product) was then combined with silica 400 gel (100 mL). A piece of cotton was inserted into the neck of the trap of the rotary evaporator before removing the solvents. Both the flask and trap was then put on high vacuum (0.5 mm Hg) for 30 min. A silica gel chromatography column (60 × 350 mm) was prepared by filling the column with hexanes followed by the addition of the silica gel slurry in hexanes. The dried silica gel with the pre-adsorbed crude product was then loaded onto the column carefully. The column was then eluted with a 1:2 mixture of CH2Cl2/hexanes under gravity for approximately 6 h. A void volume of about 700 mL was collected and discarded. A second fraction was collected containing the first byproduct 286 (1.66 g, Rf = 0.71 in 1:3 EtOAc: hexane, orange, mp. 82-84 °C) indicated by TLC. It was followed by second byproduct 287 (1.44 g, Rf =0.68 in 1:3 EtOAc: hexane, red, the structure is not known). When the byproducts had finished eluting, elution was continued under N2 pressure (1:1 CH2Cl2/hexanes) to afford the pure monomer 285 as a yellow solid (mp. 177-178 °C) in 26-30 % yield (5.47-6.19 g, 19.9-22.9 mmol) 1 Spectral data for 285: Rf = 0.65 (1:3 EtOAc/hexanes); H NMR (CDCl3, 300 MHz) δ 5.37 (s, 1 H), 7.2 (s, 1 H), 7.41-7.38 (m, 1 H), 7.49 (t, 2 H, J = 7.3 Hz), 7.66-7.58 (m, 2 H), 7.75-7.73 (m, 3 H), 7.89 (d, 1 H, J = 7.8 Hz), 8.13 (d, 1 H, J = 9.0 Hz), 8.72 (d, 1 H, J = 8.1 Hz). 13 C NMR (CDCl3, 75 MHz) δ 110.12, 114.144, 119.76, 121.06, 123.15, 126.26, 126.62, 126.84, 127.49, 127.54, 128.70, 128.89, 130.20, 132.08, 132.48, 139.74, 141.32, 152.23; IR (KBr disc) 3521 s, 3059 w, 1619 w, 1601 m, 1569 w, 1405 w, 1277 w, 1227 w, 1152 w, 1138 m, 1076 m, 821 m, -1 + 749 s cm ; Mass spectrum m/z (% rel intensity) 270 (100) M , 241 (27), 165 (11), 135 (19), 120 (22), 77(10); Anal calcd for C20H14O: C, 88.86; H, 5.22; Found: C, 88.84; H, 5.21. 401 1 Spectral data for 286: Rf = 0.71 in 1:3 EtOAc: hexane; H NMR (CDCl3, 600 MHz) δ 7.00-7.03 (m, 2H), 7.05-7.07 (m, 2H), 7.31 (dd, J = 7.0, 1.0 Hz, 1H), 7.36 (dd, J = 12.4, 1.8 Hz, 2H), 7.397.43 (m, 2H), 7.45 (td, J = 7.6, 1.3 Hz, 1H), 7.47-7.50 (m, 4H), 7.70-7.74 (m, 3H), 7.83 (d, J = 8.2 Hz, 1H), 7.86 (d, J = 7.8 Hz, 1H); 13 C NMR (CDCl3, 151 MHz) δ 112.89, 121.32, 123.76, 125.54, 125.68, 126.30, 126.56, 126.87, 127.12, 127.53, 127.63, 128.50, 128.75, 128.83, 128.86, 129.86, 132.05, 132.36, 133.75, 140.47, 141.12, 142.26, 143.66, 153.88; IR (thin film) 3532 br, -1 3059 w, 1614 w, 1599 m, 1569 w, 1496 w, 1390 m, 1298 m, 1172 m cm ; HRMS (ESI-TOF) + m/z 395.1405 [(M+Na ); calcd. for C28H20ONa : 395.1412] 5.7.3.2 Preparation of racemic ISOVAPOL rac-197 and (S)-ISOVAPOL (S)-197: air flow mineral oil 190 ºC, 36h OH 70% Ph Ph Ph 1. CuCl (1.4 equiv), air (–)-sparteine (3.5 equiv) MeOH, CH2Cl2, 25 ºC OH OH 2. sat. NaHCO (aq) 3 Ph Ph OH OH 95% 285 rac-ISOVAPOL rac-197 (S)-ISOVAPOL (S)-197 3,3'-diphenyl-2,2'-biphenanthrene-1,1'-diol rac-197: To a 500 mL three-neck round bottom flask equipped with a stir bar and a 400 mm Allihn water cooled condenser was added 3phenylphenanthren-1-ol 285 (4.02 g, 14.9 mmol) and light mineral oil (25 mL). The flask was 402 transferred to oil bath at 190 °C. The stir bar in the oil bath was stopped before the flask was put into it to warm up for about 30 min till solid melted without any disturbance. A thick needle was introduced into the flask via the second neck to about 5 cm above the surface of reaction mixture and was used to provide a stream of house air, which was maintained at a flow rate of 0.15 – 0.20 L/min. The third neck was sealed with a rubber septum. Air f low was then introduced into the flask with a vigorous stirring of the reaction mixture. The reaction was kept at same temperature for 36 h. The flask was then cooled down to ambient temperature followed by the addition of hexanes (250 mL). The mixture was then stirred for 30 min. It was then kept at –20 °C for 12 h followed by suction filtration. It was then dried on high vacuum (0.5 mm Hg) for 2 h to afford the crude product as a yellow powder. Purification by Crystallization: The crude product was then transferred to a 500 mL round bottom flask equipped with a condenser. The residue was rinsed with toluene (50 mL × 2) and transferred to the 500 mL round bottom flask. The resulted mixture was stirred and heated to boil while more toluene was added in 50 mL fraction till solid dissolved. The dark-brown solution was then cooled down to room temperature and kept at –20 °C overnight. The top solution was filtered without disturbing the precipitate over vacuum. A piece of new filter paper was then used to collect the brown crystal via suction filtration, washed by hexanes (20 mL × 2) and dried over vacuum to afford the first crop product rac-197 as an off- white solid (mp. 312313 °C) in 50% yield (2.00 g, 3.73 mmol). The mother liquor was dried and the residue was crystallized in toluene (150mL) and cooled down to room temperature for 12 h followed by –20 °C overnight to afford second crop product rac-197 as an off-white solid (mp. 312-313 °C) in 20% yield (0.8 g, 1.49 mmol). The combined yield was 70% (2.80 g, 5.22 mmol). 403 1 Spectral data for rac-197: Rf = 0.33 (1:9 EtOAc/hexanes) H NMR (CDCl3, 300 MHz) δ 5.85 (s, 2 H), 6.73 (d, J = 7.1 Hz, 4H), 6.99 (t, J = 7.4 Hz, 4H), 7.06-7.11 (m, 2H), 7.59-7.65 (m, 4H), 7.83 (d, J = 9.1 Hz, 2H), 7.92-7.97 (m, 2H), 8.17 (s, 2H), 8.30 (d, J = 9.1 Hz, 2H), 8.58-8.62 (m, 2H); 13 C NMR (DMSO, 125 MHz) δ 114.98, 119.37, 121.15, 121.25, 123.15, 125.12, 126.16, 126.61, 126.64, 126.96, 128.31, 128.90, 129.63, 130.27, 131.70, 141.48, 141.68, 152.38; IR (KBr disc) 3521 vs, 3468 vs, 3059 w, 1616 w, 1594 m, 1566 w, 1509 w, 1482 w, 1393 m, 1362 -1 m, 1253 m, 1224 s, 1195 w, 1141 m, 1076 w, 931 w, 866 w, 823 s, 752 s, 700 s cm ; Mass spectrum m/z (% rel intensity) 538 (44) M+, 537 (23), 370 (15), 269 (76), 241 (78), 231 (100), 215 (44), 77(2). Anal calcd for C40H26O2: C, 89.19; H, 4.87; Found: C, 89.17; H, 4.89. (S)-3,3'-diphenyl-2,2'-biphenanthrene-1,1'-diol (S)-197: To a 50 mL round bottomed flask was added CuCl (155 mg, 1.60 mmol), (–)-sparteine (760 mg, 3.20 mmol) and MeOH (30 mL). The reaction mixture was open to air and sonicated in an ultrasonic water bath for 0.5 h to afford a deep green solution. The flask was then sealed with a rubber septum and deoxygenated by purging with argon for 1 h (30 min in the solution and 30 min above the solution). To another 500 mL round bottomed flask equipped with a stir bar was added rac-197 (500 mg, 1.14 mmol) and CH2Cl2 (120 mL). The solution was purged with argon for 1 h as well (30 min in the solution and 30 min above the solution). The prepared Cu-sparteine complex solution was then transferred through a cannula to the solution of rac-197. The mixed solution was then sonicated for 10 min and the flask was then covered with aluminum foil and allowed to stir at room temperature under slow constant flow of argon for 3 h. To the reaction mixture was added saturated NaHCO3 solution (10 mL) and the resulting mixture was stirred for 5 min. The 404 mixture was then poured into a 500 mL separatory funnel with water (50 mL). The aqueous layer was then extracted with CH2Cl2 (50 mL × 3). The combined organic layer was dried over anhydrous Na2SO4. The solution was then filtered through a short plug of dry silica gel (40 × 50 mm column) which was flushed with CH2Cl2 (100 mL) to give a light yellow solution with the Cu residue remaining on the top. The resulting solution was then concentrated in vacuo followed by exposure to high vacuum (0.05 mm Hg) for 30 min to afford the crude product as a dark yellow solid. Purification of the crude product by silica gel chromatography (40 mm × 300 mm column, 9:1 hexanes / EtOAc as eluent, dry loading) afforded pure (S)-ISOVAPOL 197 as an orange solid (mp. 315-316 ºC) in 95% yield (474 mg, 1.08 mmol). The optical purity of 197 was determined to be greater than 99% ee by HPLC analysis (Pirkle D-phenylglycine column, 75:25 hexane/iPrOH at 260nm, flow-rate: 2.0 mL/min). Retention times; Rt = 20.01 min ((S)- ISOVAPOL 197) and Rt = 22.05 min ((R)-ISOVAPOL 197). 1 Spectral data for (S)-197: Rf = 0.33 (1:9 EtOAc/hexanes) H NMR (CDCl3, 300 MHz) δ 5.85 (s, 2 H), 6.73 (d, J = 7.1 Hz, 4H), 6.99 (t, J = 7.4 Hz, 4H), 7.06-7.11 (m, 2H), 7.59-7.65 (m, 4H), 7.83 (d, J = 9.1 Hz, 2H), 7.92-7.97 (m, 2H), 8.17 (s, 2H), 8.30 (d, J = 9.1 Hz, 2H), 8.58-8.62 (m, 2H); 13 C NMR (DMSO, 125 MHz) δ 114.98, 119.37, 121.15, 121.25, 123.15, 125.12, 126.16, 126.61, 126.64, 126.96, 128.31, 128.90, 129.63, 130.27, 131.70, 141.48, 141.68, 152.38; IR (KBr disc) 3521 vs, 3468 vs, 3059 w, 1616 w, 1594 m, 1566 w, 1509 w, 1482 w, 1393 m, 1362 -1 m, 1253 m, 1224 s, 1195 w, 1141 m, 1076 w, 931 w, 866 w, 823 s, 752 s, 700 s cm ; Mass + spectrum m/z (% rel intensity) 538 (44) M , 537 (23), 370 (15), 269 (76), 241 (78), 231 (100), 405 215 (44), 77(2); Anal calcd for C40H26O2: C, 89.19; H, 4.87; Found: C, 89.22; H, 4.86; [α ]20 – D 200.5 (c 1.0, EtOAc) on 99% ee material (HPLC). 5.7.4 Synthesis of aziridines 86, 113a, 114a and 115a using (S)-ISOVAPOL and (R)VANOL (Table 5.1, 5.2 and 5.3) General Procedure for performing aziridination – Illustrated for the synthesis of (2R,3R)ethyl 1-benzhydryl-3-phenylaziridine-2-carboxylate 86a using pre-catalyst method C. O Ph Ph N 78a IMINO-BOROX catalyst 199a (5 mol %) Ph + OEt N2 toluene 25 °C, 24 h Ph Ph Ph N + Ph 85 CO2Et 86a B(OPh)3 (4 equiv) H2O (1 equiv) pre(S)-ISOVAPOL catalyst (5 mol%) tolulene, 80 °C, 1 h (Method C) then 05 mm Hg 80 °C, 0.5 h Imine 78a Ph NH CO2Et (Ph)H Ph(H) 87a(88a) OPh Ph Ph O B O – N+ B O * H O O B OPh Ph IMINO-BOROX catalyst 199a (2R,3R)- ethyl 1-benzhydryl-3-phenylaziridine-2-carboxylate 86a: To a 25 mL flame-dried home-made Schlenk flask (see Figure 2.26) equipped with a stir bar and flushed with argon was added (S)-ISOVAPOL (27 mg, 0.05 mmol), commercial B(OPh)3 (58 mg, 0.2 mmol) and water (0.9 µL, 0.05 mmol). Under an argon flow through the side-arm of the Schlenk flask, dry toluene (2 mL) was added through the top of the Teflon valve to dissolve the two reagents. The flask was sealed by closing the Teflon valve, and then placed in an 80 ºC oil bath for 1 h. After 1 h, a vacuum (0.5 mm Hg) was carefully applied by slightly opening the Teflon valve to remove 406 the volatiles. After the volatiles were removed completely, a full vacuum was applied and maintained for a period of 30 min at a temperature of 80 ºC (oil bath). The flask was then allowed to cool to room temperature and opened to argon through the side-arm of the Schlenk flask. To the flask containing the pre-catalyst (made from method C) was first added the aldimine 78a (271 mg, 1 mmol) and then dry toluene (2 mL) under an argon flow through sidearm of the Schlenk flask. The reaction mixture was stirred for 5 min to give a light orange solution. To this solution was rapidly added ethyl diazoacetate (EDA) 85 (124 µL, 1.2 mmol) followed by closing the Teflon valve. The resulting mixture was stirred for 24 h at room temperature. Immediately upon addition of ethyl diazoacetate the reaction mixture became an intense yellow, which changed to light yellow towards the end of the reaction. The reaction was dilluted by addition of hexane (6 mL). The reaction mixture was then transferred to a 100 mL round bottom flask. The reaction flask was rinsed with dichloromethane (5 mL × 2) and the rinse was added to the 100 mL round bottom flask. The resulting solution was then concentrated in vacuo followed by exposure to high vacuum (0.05 mm Hg) for 1 h to afford the crude aziridine as an off-white solid. A measure of the extent to which the reaction went to completion was estimated from the 1 H NMR spectrum of the crude reaction mixture by integration of the aziridine ring methine protons relative to either the imine methine proton or the proton on the imine carbon. The 1 cis/trans ratio was determined by comparing the H NMR integration of the ring methine protons for each aziridine in the crude reaction mixture. The cis (J = 7-8 Hz) and the trans (J = 2-3 Hz) coupling constants were used to differentiate the two isomers. The yields of the acyclic enamine 1 side products 87a and 88a were determined by H NMR analysis of the crude reaction mixture 407 by integration of the N-H proton relative to the that of the cis-aziridine methine protons with the aid of the isolated yield of the cis-aziridine. Purification of the crude aziridine by silica gel chromatography (35 mm × 400 mm column, 19:1 hexanes/EtOAc as eluent, under gravity) afforded pure cis-aziridine 86a as a white solid (mp. 127.5-128.5 °C on 92% ee material) in 82% isolated yield (293 mg, 0.820 mmol); cis/trans: 50:1. Enamine side products: 3% yield of 87a and 7% yield of 88a. The optical purity of 86a was determined to be 92% ee by HPLC analysis ((CHIRALCEL OD-H column, 90:10 hexanes/iPrOH at 222 nm, flow-rate: 0.7 mL/min): retention times; Rt = 9.01 min (major enantiomer, 86a) and Rt = 4.67 min (minor enantiomer, ent-86a). The same reaction afforded aziridine 86a in 87% yield and 89% ee using the (R)VANOL boroxinate catalyst 189a. 1 Spectral data for 86a: Rf = 0.3 (1:9 EtOAc/hexanes); H NMR (CDCl3, 500 MHz) δ 0.95 (t, 3H, J = 7.3 Hz), 2.64 (d, J = 6.8 Hz, 1H), 3.19 (d, J = 6.8 Hz, 1H), 3.91 (q, J = 7.1 Hz, 2H), 3.93 (s, 1H), 7.16-7.38 (m, 11H), 7.47 (d, J = 7.1 Hz, 2H), 7.58 (d, J = 7.6 Hz, 2H); 13 C NMR (CDCl3, 75 Hz) δ 13.93, 46.36, 48.01, 60.57, 77.68, 127.18, 127.31, 127.39, 127.52, 127.76, 127.78, 128.48, 135.00, 142.37, 142.49, 167.75; [α ]20 + 33.4 (c 1.0, CH2Cl2) on 91% ee material D (HPLC). These spectral data match those previously reported for this compound. 1a (2R,3R)-ethyl 1-benzhydryl-3-p-tolylaziridine-2- carboxylate 86d: Imine 78d (286 mg, 1.00 mmol) was reacted according to the N general procedure described above with (S)-ISOVAPOL as the CO2Et Me ligand. Purification of the crude aziridine by silica gel 86d 408 chromatography (35 mm × 350 mm column, 9:1 hexanes / EtOAc as eluent) afforded pure aziridine 86d as a white solid (mp. 148-149 °C) in 82% isolated yield (304 mg, 0.820 mmol). cis/trans: ≥ 50:1. Enamine side products: 3% yield of 87d and 7% yield of 88d. The optical purity of 86d was determined to be 94% ee by HPLC analysis (CHIRALCEL OD-H column, 90:10 hexanes/iPrOH at 222 nm, flow-rate: 0.7 mL/min). Retention times, Rt = 8.54 min (major enaniomer, 86d) and Rt = 4.46 min (minor enantiomer, ent-86d). 1 Spectral data for 86d: Rf = 0.30 (1:9 EtOAc/hexanes). H NMR (CDCl3, 300 MHz) δ 0.99 (t, J = 7.3 Hz, 3H), 2.27 (s, 3H), 2.62 (d, J = 6.8 Hz, 1H), 3.16 (d, J = 6.6 Hz, 1H), 3.91 (s, 1H), 3.93 (q, J = 7.3 Hz, 2H), 7.03 (d, J = 8.0 Hz, 2H), 7.15-7.34 (m, 8H), 7.46 (d, J = 6.8 Hz, 2H), 7.57 (d, J = 6.8 Hz, 2H); 13 C NMR (CDCl3, 75 Hz) δ 13.97, 21.12, 46.32, 48.00, 60.53, 77.72, 127.15, 127.20, 127.34, 127.51, 127.64, 128.45, 131.94, 136.88, 142.42, 142.53, 167.82; [α ]20 D +24.6 (c 1.0, CH2Cl2) on 94% ee material. These spectral data match those previously reported for this compound. 1a (2R,3R)-ethyl 1-benzhydryl-3-(4-methoxyphenyl)aziridine-2carboxylate 86e2: Imine 78e (302 mg, 1.00 mmol) was reacted N according to the general procedure described above with (S)CO2Et MeO 86e ISOVAPOL as ligand. The silica gel for column chromatography was pre-conditioned by preparing a slurry in a 1:9 mixture of Et3N:CH2Cl2 which was loaded into a column (35 mm × 350 mm), the solvent was drained and then the silica gel was dried by flushing with nitrogen for one hour. The silica gel column was 409 then saturated with a 1:9 mixture of ethyl acetate:hexanes, the crude aziridine was loaded onto the column and then elution with the same solvent afforded pure aziridine 86e as a white solid (mp. 136-137 °C) in 62% isolated yield (240 mg, 0.620 mmol). cis/trans: 9:1. Enamine side products: <1% yield of 87e and 6% yield of 88e. The optical purity of 86e was determined to be 89 % ee by HPLC analysis (CHIRALCEL OD-H column, 95:5 hexanes/iPrOH at 222 nm, flowrate: 0.7 mL/min). Retention times, Rt = 15.52 min (major enantiomer, 86e) and Rt = 7.14 min (minor enantiomer, ent-86e). 1 Spectral data for 86e: Rf = 0.2 (1:9 EtOAc/hexanes). H NMR (CDCl3, 300 MHz) δ 1.00 (t, J = 7.3 Hz, 3H), 2.60 (d, J = 6.8 Hz, 1H), 3.14 (d, J = 6.9 Hz, 1H), 3.74 (s, 3H), 3.91 (s, 1H), 3.93 (q, J = 7.1 Hz, 2H), 6.77 (d, J = 8.8 Hz, 2H), 7.14-7.32 (m, 8H), 7.45 (d, J = 6.9 Hz, 2H), 7.57 (d, J = 7.2 Hz, 2H); 13 C NMR (CDCl3, 75 MHz) δ 13.99, 46.29, 47.70, 55.13, 60.52, 77.66, 113.18, 20 127.06, 127.15, 127.18, 127.34, 127.49, 128.44, 128.86, 142.39, 142.54, 158.85, 167.85; [α ]D +24.0 (c 1.0, CH2Cl2) on 89% ee material. These spectral data match those previously reported for this compound. (2R,3R)-ethyl 1a 1-benzhydryl-3-(4-bromophenyl)aziridine-2- carboxylate 86g: Imine 78g (350 mg, 1.00 mmol) was reacted N CO2Et Br according to the general procedure described above with (S)ISOVAPOL as ligand. Purification of the crude aziridine by silica 86g gel chromatography (35 mm × 350 mm column, 9:1 hexanes/EtOAc as eluent) afforded pure aziridine 86g as a white solid (mp. 150-151 °C) in 80% isolated yield 410 (175 mg, 0.4 mmol). cis/trans: ≥ 50:1. Enamine side products: 2% yield of 87g and 6% yield of 88g. The optical purity of 86g was determined to be 94% ee by HPLC analysis (CHIRALCEL OD-H column, 98:2 hexanes/iPrOH at 222 nm, flow-rate: 1.0 mL/min). Retention times, Rt = 14.31 min (major enaniomer, 86g) and Rt = 5.56 min (minor enantiomer, ent-86g). 1 Spectral data for 86g: Rf = 0.33 (1:9 EtOAc/hexanes). H NMR (CDCl3, 500 MHz) δ 1.00 (t, J = 7.1 Hz, 3H), 2.66 (d, J = 6.8 Hz, 1H), 3.12 (d, J = 6.6 Hz, 1H), 3.92 (s, 1H), 3.93 (q, J = 7.1 Hz, 2H), 7.16-7.37 (m, 10H), 7.43 (d, J = 6.8 Hz, 2H), 7.56 (d, J = 6.9 Hz, 2H); 13 C NMR (CDCl3, 125 MHz) δ 13.98, 46.46, 47.33, 60.73, 77.58, 121.33, 127.12, 127.28, 127.41, 127.50, 128.52, 128.54, 129.54, 130.89, 134.03, 142.13, 142.30, 167.43; [α ]20 +9.1 (c 1.0, CH2Cl2) on 94% ee D material. These spectral data match those previously reported for this compound. (2R,3R)-ethyl 1a 1-benzhydryl-3-cyclohexylaziridine-2-carboxylate 86v: Imine 78v (278 mg, 1.00 mmol) was reacted according to the N CO2Et 86v general procedure described above with (S)-ISOVAPOL as ligand. Purification of the crude aziridine by silica gel chromatography (35 mm × 350 mm column, 15:1 hexanes /EtOAc as eluent) afforded pure aziridine 86v as a white solid (mp. 162.5-163 °C) in 72% isolated yield (262 mg, 0.72 mmol). cis/trans: ≥ 50:1. Enamine side products: 9% yield of 87v and 4% yield of 88v. The optical purity of 86v was determined to be 79 % ee by HPLC analysis (CHIRALCEL OD-H column, 99:1 hexanes/iPrOH at 222 nm, flowrate: 1.0 mL/min). Retention times, Rt = 6.88 min (major enaniomer, 86v) and Rt = 3.41 min (minor enantiomer, ent-86v). 411 1 Spectral data for 86v: Rf = 0.2 (1:15 EtOAc/hexanes). H NMR (CDCl3, 500 MHz) δ 0.49 (dq, J = 10 Hz, 3 Hz, 1H), 0.90-1.66 (m, 10H), 1.23 (t, J = 7.1 Hz, 3H), 1.78 (dd, J = 7.1 Hz, 3.0 Hz, 1H), 2.24 (d, J = 6.8 Hz, 1H), 3.59 (s, 1H), 4.13-4.26 (m, 2H), 7.18-7.34 (m, 8H), 7.47 (d, J = 7.5 Hz, 2H); 13 C NMR (CDCl3, 75 MHz) δ 14.28, 25.35, 25.53,26.12, 30.10, 30.70, 36.26, 43.40, 52.12, 60.70, 78.17, 126.89, 127.05, 127.49, 128.27, 128.30, 128.36, 142.31, 142.71, 169.65; [α ]20 +112.6 (c 1.0, CH2Cl2) on 79% ee material. These spectral data match those previously D reported for this compound. 1a (2R,3R)-ethyl 1-benzhydryl-3-tert-butylaziridine-2-carboxylate 86w: Imine 78w (252 mg, 1.00 mmol) was reacted according to the general N CO2Et 86w procedure described above with (S)-ISOVAPOL as ligand. Purification of the crude aziridine by silica gel chromatography (35 mm × 350 mm column, 9:1 hexanes / EtOAc as eluent) afforded pure aziridine 86w as a white solid (mp. 149150 °C) in 83% isolated yield (280 mg, 0.83 mmol). cis/trans: ≥ 50:1. Enamine side products: 6% yield of 87w and <1% yield of 88w. The optical purity of 86w was determined to be 84 % ee by HPLC analysis (CHIRALCEL OD-H column, 99:1 hexanes/iPrOH at 222 nm, flow-rate: 1.0 mL/min). Retention times, Rt = 10.64 min (major enaniomer, 86w) and Rt = 3.74 min (minor enantiomer, ent-86w). 1 Spectral data for 86w: Rf = 0.33 (1:9 EtOAc/hexanes). H NMR (CDCl3, 300 MHz) δ 0.73 (s, 9H), 1.33 (t, J = 7.1 Hz, 3H), 1.79 (d, J = 7.3 Hz, 1H), 2.10 (d, J = 7.1 Hz, 1H), 3.63 (s, 1H), 4.07-4.18 (m, 1H), 4.22-4.33 (m, 1H), 7.21-7.37 (m, 6H), 7.43 (d, J = 6.8 Hz, 2H), 7.70 (d, J = 412 7.0 Hz, 2H); 13 C NMR (CDCl3, 75 MHz) δ 14.09, 27.39, 31.60, 43.37, 56.05, 60.59, 79.19, 126.84, 127.24, 127.37, 128.17, 128.20, 128.27, 142.60, 143.44, 169.74; [α ]20 +133.0 (c 1.0, D CH2Cl2) on 84% ee material. These spectral data match those previously reported for this compound. 1a MeO OMe (2R,3R)-Cis-1-(N-1-bis(4-methoxyphenyl)methyl) -2- carboxyethyl-3-phenylaziridine 113a. Imine 110a (332 mg, N 1.00 mmol) was reacted according to the general procedure CO2Et 113a described above with (S)-ISOVAPOL as ligand. Purification of the crude aziridine by silica gel chromatography (35 mm × 350 mm column, 9:1 hexanes / EtOAc as eluent, after elution of the first fraction, which contains EDA and / or enamine side products 116a and 117a, the eluent was changed to 5:1 hexanes / EtOAc) afforded pure aziridine 113a as a white solid (mp 89.5-90.5 ºC) in 90% isolated yield (376 mg, 0.900 mmol); cis/trans: 50:1. Enamine side products: 6% yield of 116a and <1% yield of 117a. The optical purity of 113a was determined to be 96% ee by HPLC analysis (CHIRALPAK AD column, 90:10 hexanes/iPrOH at 226nm, flow-rate: 1.0 mL/min): retention times; Rt = 8.78 min (major enantiomer, 113a) and Rt = 15.49 min (minor enantiomer, ent113a). Spectral data for 113a: See experimental of Chapter 2 413 MeO OMe (2R,3R)-Cis-1-(N-1-bis(4-methoxy-3,5-dimethylphenyl) methyl)-2-carboxyethyl-3-phenylaziridine 114a: Imine 111a (388 mg, 1.00 mmol) was reacted according to the N CO2Et general procedure described above with (S)-ISOVAPOL as ligand. 114a Purification of the crude aziridine by silica gel chromatography (35 mm × 350 mm column, 9:1 hexanes / EtOAc as eluent, after elution of the first fraction, which contains EDA and / or enamine side products 118a and 119a, the eluent was changed to 5:1 hexanes / EtOAc) afforded pure aziridine 114a as a white solid (mp 107-108 ºC) in 96 % isolated yield (454 mg, 0.96 mmol).; cis/trans: ≥ 50:1. Enamine side products: 2% yield of 118a and 1% yield of 119a. The optical purity of 114a was determined to be 98% ee by HPLC (CHIRALCEL OD-H column, 99:1 hexanes/iPrOH at 226 nm, flow-rate: 0.7 mL/min). Retention times; Rt = 8.96 min (major enantiomer, 114a) and Rt = 12.85 min (minor enantiomer, ent114a). 1 Spectral data for 114a: Rf = 0.42 (1:9 EtOAc/hexane). H NMR (CDCl3, 500 MHz) δ 0.98 (t, J = 7.1 Hz, 3H), 2.18 (s, 6H), 2.24 (s, 6H), 2.55 (d, J = 6.8 Hz, 1H), 3.10 (d, J = 6.6 Hz, 1H), 3.62 (s, 3H), 3.66 (s, 1H), 3.68 (s, 3H) 3.87-3.97 (m, 2H), 7.09 (s, 2H), 7.18 (s, 2H), 7.21 (d, J = 7.6 Hz, 2H), 7.35-7.37 (m, 3H); 13 C (CDCl3, 125 MHz) δ 14.01, 16.16, 16.22, 46.26, 48.20, 59.52, 59.58, 60.47, 77.04, 127.21, 127.41, 127.70, 127.80,127.85, 130.59, 130.60, 135.33, 137.79, 137.96, 155.95, 156.10, 168.01. [α ]20 +41.3 (c 1.0, EtOAc) on 99% ee material (HPLC). These D spectral data match those previously reported for this compound. 414 1c tBu (2R,3R)-ethyl-1-(bis(3,5-di-tert-butyl-4-methoxyphenyl) tBu MeO OMe tBu tBu N CO2Et 115a methyl)-3-phenylaziridine-2-carboxylate 115a: Imine 112a (278 mg, 0.5 mmol) was reacted according to the general procedure described above with (S)-ISOVAPOL as ligand. Purification of the crude aziridine by silica gel chromatography (35 mm × 350 mm column, 20:1 hexanes/EtOAc as eluent) afforded pure aziridine 115a as a white solid (mp. 156-158 ºC) in 97% isolated yield (652 mg, 0.97 mmol).; cis/trans: ≥ 50:1. Enamine side products: <1% yield of 120a and <1% yield of 121a. The optical purity of 115a was determined to be 96% ee by HPLC (Pirkle covalent (R,R) Whelk-O 1 column, 99:1 hexanes/iPrOH at 225 nm, flow-rate: 1.0 mL/min). Retention times; Rt = 9.72 min (major enantiomer, 115a) and Rt = 5.38 min (minor enantiomer, ent-115a). 1 Spectral data for 115a: Rf = 0.26 (20:1 hexanes/EtOAc); H NMR (CDCl3, 300 MHz) δ = 0.97 (t, J = 7.1 Hz, 3H), 1.31 (s, 18H), 1.39 (s, 18H), 2.64 (d, J = 6.8 Hz, 1H), 3.15 (d, J = 6.8 Hz, 1H), 3.59 (s, 3H), 3.65 (s, 3H), 3.82 (s, 1H), 3.84-3.96 (m, 2H), 7.16-7.19 (m, 1H), 7.22-7.25 (m, 2H), 7.31 (s, 2H), 7.41 (s, 2H), 7.46 (d, J = 7.1 Hz, 2H); 13 C NMR (CDCl3, 75 MHz) δ 13.95, 32.04, 32.13, 35.71, 35.78, 46.35, 48.78, 60.50, 63.93, 64.01, 125.37, 125.49, 127.23, 127.58, 3 128.15, 135.35, 136.69, 136.85, 143.00, 143.08, 158.23, 158.25, 168.27 (one sp carbon not located). [α ]20 +5.5 (c 1.0, EtOAc) on 96% ee material (HPLC). These spectral data match D those previously reported for this compound. 5.7.5 1b NMR analysis of a mixture of VANOL, B(OPh)3 , and imine 111a (Figure 5.3) 415 As shown in Figure 5.3 of this chapter, a mixture of (S)-VANOL 59 and B(OPh)3 187a results in mesoborate B1 107 and pyroborate B2 109 and unreacted VANOL 59 when subjected 1 to the pre-catalyst method C. Also, it was evident from the H NMR and 11 B NMR that no boroxinate B3 191a was formed unless imine 111a was added (characteristic peaks i.e. δ 8.551 8.56 ppm and δ 5.5-5.7 were missing in H NMR and 11 B NMR respectively). Unless otherwise noted, commercial B(OPh)3 is used in all the experiments. Also, Ph3CH is used as the internal standard. Experimental: * OH B(OPh)3 (4 equiv) H2O (1 equiv) OH tolulene, 80 °C, 1 h then 0.5 mm Hg 59 80 °C, 0.5 h pre-catalyst method C OPh + B O B * O OPh 109 O B2 O * O B OPh + 107 B1 CDCl3 25 °C, 10 min 0.1 M imine 111a (1 equiv) + [imine-H] OPh O –O B B O * O O B 191a OPh B3 1 Entry 1, Figure 5.3: The H NMR of pure (S)-VANOL taken in CDCl3. 416 OH * OH 59 (unreacted) Entry 2, Figure 5.3: The pre-catalyst was made using method C employing (S)-VANOL (44 mg, 0.1 mmol), commercial B(OPh)3 (116 mg, 0.4 mmol) water (1.8 µL, 0.1 mmol). To the flask containing the pre-catalyst was first added the Ph3CH (12.22 mg, 0.05 mmol) and then CDCl3 (1 mL) under an argon flow through side-arm of the Schlenk flask. The reaction mixture was then stirred for 10 min. The off-white colored solution was then directly transferred to a 1 quartz NMR tube and was subjected to H NMR and 11 B NMR analysis. Entry 3, Figure 5.3: The pre-catalyst was made using method C employing (S)-VANOL (44 mg, 0.1 mmol), commercial B(OPh)3 (116 mg, 0.4 mmol) water (1.8 µL, 0.1 mmol). To the flask containing the pre-catalyst was first added the imine 111a (39 mg, 0.1 mmol), Ph3CH (12.22 mg, 0.05 mmol) and then CDCl3 (1 mL) under an argon flow through side-arm of the Schlenk flask. The reaction mixture was then stirred for 10 min. The red colored solution was then directly transferred to a 1 quartz NMR tube and was subjected to H NMR and 5.7.6 11 B NMR analysis. NMR analysis of a mixture of ISOVAPOL, B(OPh)3 , and imine 111a (Figure 5.3) Same as section 5.7.5 using (S)-ISOVAPOL instead of (S)-VANOL. 5.7.7 Synthesis of BINOL derivatives 258, 259, 308, 56a, 56d, 56e, 56f and 56i (Scheme 5.6-5.9) 5.7.7.1 Synthesis of BINOL derivative 258: See experimental of Chapter 4 417 5.7.7.2 Synthesis of BINOL derivative 259: See experimental of Chapter 4 5.7.7.3 Synthesis of BINOL derivative 308: Br 1) nBuLi, TMEDA Et2O, 3 h OMe OMe 2) Br , 4 h 2 OMe OMe Br 70% (R)-258 (R)-308 (R)-3,3'-dibromo-2,2'-dimethoxy-1,1'-binaphthalene (R)-308: In a 50 mL flame-dried threenecked round bottomed flask equipped with a N2-inlet were placed dry Et2O (20 mL) and n TMEDA (256 mg, 0.330 mL, 2.20 mmol). To this solution was added BuLi (1.2 mL, 3.0 mmol, 2.5 M in hexanes). The solution was stirred for 30 min at room temperature. To this solution was added solid (R)-258 (314 mg, 1.00 mmol) in one portion and the reaction mixture was stirred for 3 h. The resulting light brown suspension was cooled to –78 °C, and Br2 (1.9 g, 0.62 mL, 12 mmol) was added via syringe over a period of 10 min. The solution was then allowed to warm to room temperature and was left stirring for 4 h. The reaction was quenched with saturated Na2S2O3 solution (10 mL) and stirred for 30 min. The organic layer was separated, and the aqueous layer was extracted by CH2Cl2 (10 mL × 3). The combined organic solution was dried over anhydrous MgSO4, filtered and concentrated in vacuo to afford crude product. Purification by silica gel column chromatography (35 mm × 350 mm column, 8:1 hexanes/EtOAc as eluent) afforded (R)-308 as yellow solid (mp. 174-175 °C) in 70% yield (331 mg, 0.700 mmol). 418 1 Spectral data for (R)-308: Rf = 0.55 (4:1 hexanes/CH2Cl2); H NMR (CDCl3, 500 MHz) δ 3.51 (s, 6H), 7.09 (d, J = 8.5 Hz, 2H), 7.27 (ddd, J = 8.4, 6.9, 1.3 Hz, 2H), 7.41-7.44 (m, 2H), 7.82 (d, J = 8.2 Hz, 2H), 8.27 (s, 2H); 13 C NMR (CDCl3, 125 MHz) δ 61.08, 117.48, 125.75, 125.84, 126.52, 126.83, 127.11, 131.43, 132.97, 133.07, 152.53; [α ]20 +71.4 (c 1.4, THF). These D spectral data match those previously reported for this compound. 49b,55 5.7.7.4 Synthesis of BINOL derivative (R)-56a: Br OMe OMe Br 1. Ni(PPh3)2Cl2 PhMgBr 309, Et2O, 20h OH OH 2. BBr3, CH2Cl2, rt, 24h 70% 304 56a (R)-3,3'-diphenyl-[1,1'-binaphthalene]-2,2'-diol (R)-56a: In a 50 mL flame-dried round bottomed flask equipped with a N2-inlet were placed (R)-308 (236 mg, 0.500 mmol) and Ni(PPh3)2Cl2 (26 mg, 0.04 mmol) and dry Et2O (10 mL). To this suspension was added PhMgBr 309 (1.0 mL, 3.0 mmol, 3.0 M in ether) over a period of 10 min. The reaction mixture was heated at reflux for 20 h, cooled to 0 °C, and quenched with water (1 mL). After addition of 1 N HCl solution (20 mL), the mixture was stirred for 10 min and extracted with ether. The 419 ether layer was washed with brine, dried (Na2SO4), and concentrated in vacuo. Purification by silica gel column chromatography (35 mm × 350 mm column, 10:1 hexanes/EtOAc as eluent) afforded the coupling product as colorless solid in 75% yield (175 mg, 0.375 mmol). To a solution of this coupling product (175 mg, 0.375 mmol) in CH2Cl2 (10 mL) was added BBr3 (1.5 mL, 1.5 mmol, 1.0 M in CH2Cl2) drop-wise at –78 °C. The reaction was allowed to warm to 0 °C. The reaction mixture was stirred for 0.5 h at 0 °C and then was allowed to warm to room temperature. After stirring at room temperature for 24 h, the reaction was quenched by the slow addition of the distilled water (1.5 mL) in an ice bath. The aqueous layer was extracted with CH2Cl2 (5 mL × 3). The combined extracts were then washed with water, brine and then dried over MgSO4, filtered, and concentrated in vacuo. Purification of the yellow colored crude product by silica gel chromatography (20 mm × 200 mm column, 8:1 hexanes/EtOAc as eluent, under gravity) afforded pure (R)-56a as a white solid (mp. 202-203 °C) in 70% isolated yield (154 mg, 0.350 mmol, over two steps). 1 Spectral data for (R)-56a: Rf = 0.36 (8:1 hexanes/CH2Cl2); H NMR (CDCl3, 500 MHz) δ 5.30 (s, 2H), 7.16-7.54 (m, 12H), 7.82 (d, J = 7.5 Hz, 4H), 7.90 (d, J = 8.0 Hz, 2H), 8.00 (s, 2H); 13 C NMR (CDCl3, 75 MHz) δ 112.30, 124.23, 124.30, 127.32, 127.74, 128.42, 128.46, 129.40, 129.57, 130.61, 131.38, 132.86, 137.40, 150.08; [α ]20 +106.2 (c 1.0, THF). These spectral data D match those previously reported for this compound. 420 49b,55 5.7.7.5 Synthesis of BINOL derivative 56d: Br OMe OMe Br Br BBr3 OH OH CH2Cl2 rt, 24h 97% Br (R)-308 (R)-56d (R)-3,3'-dibromo-[1,1'-binaphthalene]-2,2'-diol (R)-56d: In a 50 mL flame-dried round bottomed flask equipped with a N2-inlet were placed (R)-308 (472 mg, 1.0 mmol) and dry CH2Cl2 (10 mL). To this solution was added BBr3 (6.0 mL, 6.0 mmol, 1.0 M in CH2Cl2) dropwise at 0 °C. The reaction was allowed to warm to room temperature. After stirring at room temperature for 12 h, the reaction was quenched by the slow addition of the distilled water (10 mL) in an ice bath. The aqueous layer was extracted with CH2Cl2 (10 mL × 3). The combined extracts were then washed with water, brine and then dried over MgSO4, filtered, and concentrated in vacuo. Purification of the crude product by silica gel chromatography (35 mm × 400 mm column, 15:1 hexanes/EtOAc as eluent) afforded pure (R)-56d as a white solid (mp. 245-246 °C) in 97 % isolated yield (431 mg, 0.970 mmol). 1 Spectral data for (R)-56d: Rf = 0.31 (9:1 hexanes/ EtOAc); H NMR (CDCl3, 500 MHz) δ 5.54 (s, 2H), 7.12 (d, J = 8.5 Hz, 2H), 7.24-7.42 (m, 4H), 7.82 (d, J = 8.0 Hz, 6H), 8.25 (s, 2H); 13 C NMR (CDCl3, 75 MHz) δ 112.22, 114.57, 124.60, 124.86, 127.39, 127.58, 129.70, 132.73, 421 132.75, 147.98; [α ]20 + 98.6 (c 1.0, THF). These spectral data match those previously reported D for this compound. 57 5.7.7.6 Synthesis of BINOL derivative 56e: I OMe OMe I I BBr3 OH OH CH2Cl2 rt, 24h 98% I (R)-56e (R)-259 (R)-3,3'-diiodo-[1,1'-binaphthalene]-2,2'-diol (R)-56e: In a 50 mL flame-dried round bottomed flask equipped with a N2-inlet were placed (R)-259 (567 mg, 1.0 mmol) and dry CH2Cl2 (10 mL). To this solution was added BBr3 (6.0 mL, 6.0 mmol, 1.0 M in CH2Cl2) drop-wise at 0 °C. The reaction was allowed to warm to room temperature. After stirring at room temperature for 12 h, the reaction was quenched by the slow addition of the distilled water (10 mL) in an ice bath. The aqueous layer was extracted with CH2Cl2 (10 mL × 3). The combined extracts were then washed with water, brine and then dried over MgSO4, filtered, and concentrated in vacuo. Purification of the crude product by silica gel chromatography (35 mm × 400 mm column, 1:1 hexanes/CH2Cl2 as eluent) afforded pure (R)-56e as a yellow solid (mp. 312-315 °C) in 97 % isolated yield (527 mg, 0.980 mmol). 1 Spectral data for (R)-56d: Rf = 0.54 (1:1 hexanes/ CH2Cl2); H NMR (CDCl3, 300 MHz) δ 5.42 422 (brs, 2H), 7.07 (d, J = 8.2 Hz, 2H), 7.31 (ddd, J = 8.2, 6.9, 1.3 Hz, 2H), 7.38 (ddd, J = 8.2, 6.9, 1.3 Hz, 2H), 7.79 (d, J = 7.7 Hz, 2H), 8.52 (s, 2H); 13 C NMR (CDCl3, 75 MHz) δ 86.51, 112.52, 124.34, 124.61, 127.11, 127.78, 130.63, 133.09, 140.20, 150.01; [α ]20 +101.0 (c 1.0, THF). D These spectral data match those previously reported for this compound. 58 5.7.7.7 Synthesis of BINOL derivative 56f: iPr iPr I OMe OMe 1. Ni(PPh3)2Cl2 ArMgBr , Et2O, 24h iPr OH OH iPr 2. BBr3, CH2Cl2, rt, 12h 73% I (R)-259 iPr ArMgBr iPr MgBr 310 iPr iPr (R)-56f iPr 2-bromo-1,3,5-triisopropylbenzene 310ʹ′ : In a flame-dried 25 mL three-neck flask equipped with a condenser, was placed 1,3,5-triisopropylbenzene (3.07 g, 3.6 mL, 15 mmol), carbon tetrachloride (2 mL) and iron powder (0.12 g). The reaction vessel was cooled in an ice-salt bath and light was excluded by wrapping the flask in tin foil and covering it with a towel. Bromine (2.4 g, 0.77 mL, 15 mmol) in carbon tetrachloride (2 mL) was added dropwise over a 10-min period. Hydrogen Bromide evolved was led off through the condenser and absorbed in water. The reaction mixture was allowed to stand overnight. The mixture was then washed with water (10 mL × 2), 20% sodium hydroxide (5 mL × 2), and water (10 mL). The resulting solution was 423 then dried over anhydrous CaC12 and concentrated in vacuo to afford the crude product. Benzylic halide impurities in the product were destroyed by adding the crude concentrate to a solution obtained by dissolving sodium (0.5 g) in absolute ethanol (15 mL). The reaction mixture was then allowed to stand overnight followed by the dilution with water (50 mL). The organic layer was separated, and the aqueous layer was extracted with CCl4 (10 mL × 3). The combined organic layers were washed with water (10 mL × 2), brine (10 mL) and then dried over anhydrous CaCl2. It was then filtered and concentrated in vacuo to give crude product. Purification by distillation furnished 310ʹ′ (bp. 96 – 97 °C at 0.1 mm Hg) as a colorless oil in 70 % yield (2.97 g, 10.54 mmol). 1 Spectral data for 310ʹ′: H NMR (CDCl3, 300 MHz) δ 1.29-1.32 (m, 18 H), 2.87 (sept, J = 6.8 Hz, 1H), 3.48 (sept, J = 6.8 Hz, 2H), 6.98 (s, 2H); 13 C NMR (CDCl3, 75 MHz) δ 23.1, 24.03, 33.54, 34.05, 122.26, 147.36, 147.79. (2,4,6-triisopropylphenyl)magnesium Bromide 310: A three-neck round-bottom flask containing Mg (301 mg, 12.4 mmol, 20 mesh ) was equipped with a condenser and an addition funnel. A 1.0 mL portion of a 1.4 M solution of 2,4,6-triisopropylphenyl bromide 310ʹ′ (1.98 g in 5 mL of Et2O, 7 mmol) was added to the flask through the addition funnel. After 5 min, 0.02 mL (0.0002 mmol) of 1,2-dibromoethane was added to the mixture. Once the solution began to reflux, the remaining 2,4,6-triisopropylphenyl-bromide solution was slowly added over 1 h. After the addition was complete, the reaction was allowed to reflux for 12 h. The resulting Grignard reagent was directly in the next step. (R)-3,3'-Bis(2,4,6-triisopropylphenyl)-2,2'-dihydroxy-1,1'-dinaphthyl 56f: In a 50 mL flame- 424 dried round bottomed flask equipped with a N2-inlet were placed (R)-259 (567 mg, 1.0 mmol) and Ni(PPh3)2Cl2 (106 mg, 0.15 mmol) and dry Et2O (12 mL). To this suspension was added freshly prepared Grignard reagent 310 (7.0 mmol) over a period of 10 min. The reaction mixture was stirred for 10 min at room temperature and then heated at reflux for 24 h. The reaction mixture was then cooled to 0 °C, and quenched slowly by the addition of HCl (6 mL, 1 M). After addition of 1 N HCl solution (6 mL), the mixture was stirred for 10 min and extracted with ether (10 mL × 3). The ether layer was washed with brine, dried (Na2SO4), and concentrated in vacuo. Purification by silica gel column chromatography (35 mm × 350 mm column, 9:1 hexanes/ CH2Cl2 as eluent) afforded the coupling product as colorless solid in 76% yield (547 mg, 0.76 mmol). To a solution of this coupling product (547 mg, 0.76 mmol) in CH2Cl2 (20 mL) was added BBr3 (5.3 mL, 5.3 mmol, 1.0 M in CH2Cl2) drop-wise at 0 °C. The reaction was allowed to room temperature. After stirring at room temperature for 12 h, the reaction was quenched by the slow addition of the distilled water (7 mL) in an ice bath. The aqueous layer was extracted with CH2Cl2 (10 mL × 3). The combined extracts were then washed with water, brine and then dried over MgSO4, filtered, and concentrated in vacuo. Purification of the brown colored crude product by silica gel chromatography (35 mm × 400 mm column, 5:1 hexanes/ CH2Cl2 as eluent) afforded pure (R)-56f as a white solid (mp. 134-135 °C) in 73% isolated yield (504 mg, 0.73 mmol, over two steps). Sometimes, (R)-56f has been obtained as yellow solid. In that case, it was washed with hexanes and white compound was obtained after the washings. 425 1 Spectral data for (R)-56f: Rf = 0.25 (5:1 hexanes/ CH2Cl2); H NMR (CDCl3, 300 MHz) δ 1.01(d, J = 6.8 Hz, 6H), 1.08 (t, J = 6.8 Hz, 12H), 1.17 (d, J = 6.8 Hz, 6H), 1.29 (d, J = 6.8 Hz, 12H), 2.66 (sept, J = 6.8 Hz, 2H), 2.82 (sept, J = 6.8 Hz, 2H), 2.94 (sept, J = 6.8 Hz, 2H), 4.90 (s, 2H), 7.10 (s, 2H), 7.12 (s, 2H), 7.25-7.38 (m, 6H), 7.74 (s, 2H), 7.84 (d, J = 7.6 Hz, 2H); 13 C NMR (CDCl3, 75 MHz) δ 23.71, 23.91,23.96, 24.04, 24.27, 24.30, 30.85, 30.90, 34.34, 113.18, 121.17, 121.22, 123.75, 124.53, 126.53, 126.60, 128.23, 129.07, 129.14, 130.39, 130.65, 133.49, 147.77, 147.84, 149.15, 150.64; [α ]20 + 79.0 (c 2.0, THF). These spectral data match those D previously reported for this compound. 59 5.7.7.8 Synthesis of BINOL derivative 56i: I OMe OMe 1. Pd(PPh3)4, ArB(OH)2 Na2CO3, EtOH, rt, 12h OH OH 2. BBr3, CH2Cl2, rt, 12h 71% I (R)-259 B(OH)2 ArB(OH)2 (R)-56i 311 (R)-3,3'-di(phenanthren-9-yl)-[1,1'-binaphthalene]-2,2'-diol (R)-56i: In a 50 mL flame-dried home-made Schlenk (see Figure 2.26) flask equipped with a N2-inlet were placed (R)-259 (567 mg, 1.00 mmol) and 9-phenanthranylboronic acid 311 (922 mg, 4.15 mmol), dry toluene (8 mL), 426 ethanol (4 mL) and aqueous Na2CO3 (4 mL, 2M). The suspension was purged with nitrogen for 30 min. Under the flow of nitrogen, Pd(PPh3)4 (116 mg, 0.100 mmol) was added. The flask was sealed by closing the Teflon valve and then placed in an 90 ºC oil bath for 14 h. The reaction mixture was cooled to room temperature and was filtered followed by the addition of CH2Cl2 (10 mL) and water (5 mL). The aqueous layer was extracted with CH2Cl2 (10 mL × 3). The combined extracts were then washed with brine and then dried over MgSO4, filtered, and concentrated in vacuo. The resulting crude coupling product was dissolved in CH2Cl2 (15 mL). To this solution was added BBr3 (2.7 mL, 2.7 mmol, 1.0 M in CH2Cl2) drop-wise at 0 °C. The reaction was allowed to warm to room temperature. After stirring at room temperature for 12 h, the reaction was quenched by the slow addition of the distilled water (5 mL) in an ice bath. The aqueous layer was extracted with CH2Cl2 (5 mL × 3). The combined extracts were then washed with water, brine and then dried over MgSO4, filtered, and concentrated in vacuo. Purification of the yellow colored crude product by silica gel chromatography (35 mm × 400 mm column, 4:1 hexanes/ CH2Cl2 as eluent, under gravity) afforded pure (R)-56i as a yellow solid (mp. 148-150 ºC, decomposition) in 71 % isolated yield (454 mg, 0.710 mmol, over two steps). 1 Spectral data for (R)-56i: Rf = 0.57 (4:1 hexanes/CH2Cl2); H NMR (CDCl3, 600 MHz) δ 5.22, 5.23, 5.28, 5.33, (4 singlets, combined integration: 2H), 7.42-7.80 (m, 15H), 7.88-7.92 (m, 2H), 7.95-8.00 (m, 5H), 8.10-8.12 (m, 2H), 8.75-8.83 (m, 4H); 13 C NMR (CDCl3, 150 MHz) δ 113.07, 113.17, 113.48, 122.82, 122.85, 123.10, 123.14, 123.21, 123.24, 124.50, 124.53, 124.71, 427 124.74, 124.93, 125.00, 126.94, 127.01, 127.05, 127.13, 127.16, 127.22, 127.28, 127.53, 127.59, 128.60, 128.71, 129.01, 129.07, 129.19, 129.41, 129.52, 129.54, 129.66, 129.67, 129.77, 130.63, 130.66, 130.69, 130.76, 130.78, 130.81, 131.29, 131.34, 131.35, 131.39, 131.66, 131.68, 131.70, 131.71, 132.26, 132.32, 133.79, 133.82, 133.92, 133.94, 133.99, 134.20, 150.80, 150.85, 150.87; [α ]20 +45.5.0 (c 1.0, CHCl3). These spectral data match those previously reported for this D compound. 5.7.8 61 Asymmetric aziridination with BINOL 55, BINOL derivatives 56 and TADDOL 61a (Table 5.4-5.5 and Scheme 5.12) General Procedure for performing aziridination – Illustrated for the synthesis of (2S,3S)ethyl 1-benzhydryl-3-phenylaziridine-2-carboxylate 86a using pre-catalyst method C and 3,3ʹ′-Ph2-BINOL (R)-56a as the ligand. O Ph Ph N 78a IMINO-BOROX catalyst 304a (10 mol %) Ph + OEt N2 toluene 25 °C, 24 h Ph Ph Ph N + Ph 85 CO2Et 86a B(OPh)3 (4 equiv) H2O (1 equiv) pre(R)-56a catalyst (10 mol%) tolulene, 80 °C, 1 h (Method C) then 05 mm Hg 80 °C, 0.5 h (R)-56a = 3,3'-Ph2-BINOL Imine 78a Ph NH CO2Et (Ph)H Ph(H) 87a(88a) OPh Ph Ph O B O – N+ B O * H O O B OPh Ph IMINO-BOROX catalyst 304a (2S,3S)- ethyl 1-benzhydryl-3-phenylaziridine-2-carboxylate ent-86a: To a 25 mL flamedried home-made Schlenk flask (see Figure 2.26) equipped with a stir bar and flushed with argon 428 was added (R)-56a (44 mg, 0.1 mmol), commercial B(OPh)3 (116 mg, 0.4 mmol) and water (1.8 µL, 0.1 mmol). Under an argon flow through the side-arm of the Schlenk flask, dry toluene (2 mL) was added through the top of the Teflon valve to dissolve the two reagents. The flask was sealed by closing the Teflon valve, and then placed in an 80 ºC oil bath for 1 h. After 1 h, a vacuum (0.5 mm Hg) was carefully applied by slightly opening the Teflon valve to remove the volatiles. After the volatiles were removed completely, a full vacuum was applied and maintained for a period of 30 min at a temperature of 80 ºC (oil bath). The flask was then allowed to cool to room temperature and opened to argon through the side-arm of the Schlenk flask. To the flask containing the pre-catalyst (made from method C) was first added the aldimine 78a (271 mg, 1 mmol) and then dry toluene (2 mL) under an argon flow through sidearm of the Schlenk flask. The reaction mixture was stirred for 5 min to give a light orange solution. To this solution was rapidly added ethyl diazoacetate (EDA) 85 (124 µL, 1.2 mmol) followed by closing the Teflon valve. The resulting mixture was stirred for 24 h at room temperature. Immediately upon addition of ethyl diazoacetate the reaction mixture became an intense yellow, which changed to light yellow towards the end of the reaction. The reaction was dilluted by addition of hexane (6 mL). The reaction mixture was then transferred to a 100 mL round bottom flask. The reaction flask was rinsed with dichloromethane (5 mL × 2) and the rinse was added to the 100 mL round bottom flask. The resulting solution was then concentrated in vacuo followed by exposure to high vacuum (0.05 mm Hg) for 1 h to afford the crude aziridine as an off-white solid. A measure of the extent to which the reaction went to completion was estimated from the 1 H NMR spectrum of the crude reaction mixture by integration of the aziridine ring methine 429 protons relative to either the imine methine proton or the proton on the imine carbon. The 1 cis/trans ratio was determined by comparing the H NMR integration of the ring methine protons for each aziridine in the crude reaction mixture. The cis (J = 7-8 Hz) and the trans (J = 2-3 Hz) coupling constants were used to differentiate the two isomers. The yields of the acyclic enamine 1 side products 87a and 88a were determined by H NMR analysis of the crude reaction mixture by integration of the N-H proton relative to the that of the cis-aziridine methine protons with the aid of the isolated yield of the cis-aziridine. Purification of the crude aziridine by silica gel chromatography (35 mm × 400 mm column, 19:1 hexanes/EtOAc as eluent, under gravity) afforded pure cis-aziridine ent-86a as a white solid (mp. 127.5-128.5 °C) in 90% isolated yield (322 mg, 0.900 mmol); cis/trans: >50:1. Enamine side products: 4% yield of 87a and 6% yield of 88a. The optical purity of ent-86a was determined to be 76% ee by HPLC analysis ((CHIRALCEL OD-H column, 90:10 hexanes/iPrOH at 222 nm, flow-rate: 0.7 mL/min): retention times; Rt = 9.01 min (minor enantiomer, 86a) and Rt = 4.67 min (major enantiomer, ent-86a). 1 Spectral data for ent-86a: Rf = 0.3 (1:9 EtOAc/hexanes); H NMR (CDCl3, 500 MHz) δ 0.95 (t, 3H, J = 7.3 Hz), 2.64 (d, J = 6.8 Hz, 1H), 3.19 (d, J = 6.8 Hz, 1H), 3.91 (q, J = 7.1 Hz, 2H), 3.93 (s, 1H), 7.16-7.38 (m, 11H), 7.47 (d, J = 7.1 Hz, 2H), 7.58 (d, J = 7.6 Hz, 2H); 13 C NMR (CDCl3, 75 Hz) δ 13.93, 46.36, 48.01, 60.57, 77.68, 127.18, 127.31, 127.39, 127.52, 127.76, 127.78, 128.48, 135.00, 142.37, 142.49, 167.75; [α ]20 –29.6 (c 1.0, CH2Cl2) on 76% ee D material (HPLC). These spectral data match those previously reported for this compound. 430 1a The Wulff asymmetric aziridination reaction was performed following the above described procedure (precatalyst method C) using ligands (R)-56a, 56e, 56f, 56i and (R,R)-61a. Also imines 111a and 112a were subjected to the asymmetric aziridination reaction using pre-catalyst methods C and D (see chapter 2 for details for pre-catalyst methods) and 10 mol% of liagand (R)-56a. The purification details and spectral data for resulting aziridines 114a and 115a has been described in section 5.7.4. 5.7.9 One-pot asymmetric aziridination with 3,3ʹ′-Ph2-BINOL (R)-56a and aziridination with B1 catalyst (R)-92a (Scheme 5.10) a) One-pot aziridination: O Ph Ph N 78a Ph (R)-3,3'-Ph2-BINOL (10 mol%) B(OPh)3 (30 mol%) toluene, 25 °C, 5 min OEt N2 Ph 85 toluene 25 °C, 24 h Ph N Ph CO2Et ent-86a (2S,3S)- ethyl 1-benzhydryl-3-phenylaziridine-2-carboxylate ent-86a: To a 25 mL flamedried round bottom flask filled with argon was added (R)-56a (44 mg, 0.1 mmol), commercial B(OPh)3 (87 mg, 0.3 mmol) and aldimine 78a (271 mg, 1.00 mmol). The mixture was dissolved in toluene (1 mL) at room temperature. The reaction mixture was stirred for 5 min to give a light orange solution. To this solution was rapidly added EDA 85 (124 µL, 1.20 mmol) and the resulting mixture was stirred for 24 h at room temperature. The reaction was diluted by the addition of 6 mL hexane. The reaction mixture was then transferred to a 100 mL round bottom 431 flask. The reaction flask was rinsed with dichloromethane (5 mL × 2) and the rinse was added to the 100 mL round bottom flask. The resulting solution was then concentrated in vacuo followed by exposure to high vacuum (0.05 mm Hg) for 1 h to afford the crude aziridine as an off-white solid. Purification of the crude aziridine by silica gel chromatography (as discussed above) afforded pure aziridine 86a as a white solid in 84% yield and 75% ee. b) Aziridination with B1 catalyst (R)-92a: Ph N 78a B1 catalyst 92a (10 mol %) O Ph Ph + OEt Ph N toluene 25 °C, 24 h N2 Ph CO2Et ent-86a 85 BH3•Me2S (1 equiv) (R)-89 (10 mol%) tolulene, 100 °C, 1 h then 0.5 mm Hg 100 °C, 0.5 h Imine 78a precatalyst Ph O – B O O O Ph B1 catalyst 92a Ph N+ H Ph (R)-92a B1 (FSB) (2S,3S)- ethyl 1-benzhydryl-3-phenylaziridine-2-carboxylate ent-86a: To a 25 mL flamedried home-made Schlenk flask (see Figure 2.26) equipped with a stir bar and flushed with argon was added (R)-89 (47 mg, 0.1 mmol) and BH3•Me2S (50 µL, 0.2 mmol, 2.0 M in toluene). 432 Under an argon flow through the side-arm of the Schlenk flask, dry toluene (2 mL) was added through the top of the Teflon valve to dissolve the two reagents. The flask was sealed by closing the Teflon valve, and then placed in an 100 ºC oil bath for 1 h. After 1 h, a vacuum (0.5 mm Hg) was carefully applied by slightly opening the Teflon valve to remove the volatiles. After the volatiles were removed completely, a full vacuum was applied and maintained for a period of 30 min at a temperature of 100 ºC (oil bath). The flask was then allowed to cool to room temperature and opened to argon through the side-arm of the Schlenk flask. To the flask containing the pre-catalyst was first added the aldimine 78a (271 mg, 1 mmol) and then dry toluene (2 mL) under an argon flow through side-arm of the Schlenk flask. The reaction mixture was stirred for 5 min to give a light orange solution. To this solution was rapidly added ethyl diazoacetate (EDA) 85 (124 µL, 1.2 mmol) followed by closing the Teflon valve. The resulting mixture was stirred for 24 h at room temperature. The reaction was diluted by the addition of 6 mL hexane. The reaction mixture was then transferred to a 100 mL round bottom flask. The reaction flask was rinsed with dichloromethane (5 mL × 2) and the rinse was added to the 100 mL round bottom flask. The resulting solution was then concentrated in vacuo followed by exposure to high vacuum (0.05 mm Hg) for 1 h to afford the crude aziridine as an off-white solid. Purification of the crude aziridine by silica gel chromatography (as discussed above) afforded pure aziridine 86a as a white solid in 80% yield and 48% ee. 5.7.10 NMR analysis of a mixture of B(OPh)3, imine 111h and BINOL 56a (Figure 5.7) The details for entries 1-9 of Figure 5.7 can be found in the theses of Gang Hu and Li Huang. The entry 10 of Figure 5.7 is part of this doctoral research and is described below. 433 B(OPh)3 (3 equiv) * OH imine 111h (1 equiv) OH CDCl3, 25 °C, 10 min 0.1 M (R)-56a + [imine-H] OPh O –O B B O * O O B 304a OPh N Me2N MEDAM 111h B3 To a 10 mL flame-dried round bottom flask, equipped with a stir bar, filled with argon was added 3,3ʹ′-Ph2-BINOL (R)-56a (44 mg, 0.1 mmol, 1 equiv.), commercial B(OPh)3 (87 mg, 0.3 mmol, 3 equiv.), imine 111h (43 mg, 0.1 mmol, 1 equiv.), Ph3CH (12.22 mg, 0.05 mmol) and CDCl3(1 mL). The resultant mixture was stirred for 10 min at room temperature. The red 1 colored solution was then directly transferred to a quartz NMR tube and was subjected to H NMR and 11 B NMR analysis. 5.7.11 NMR analysis of a mixture of B(OPh)3, imine 111h with BINOL derivatives (R)-56 or H8-BINOL (R)-53 or TADDOL (R,R)-61a (Figure 5.8-5.10 and 5.13) * OH OH Ligand 1) B(OPh)3 (4 equiv) H2O (1 equiv) tolulene, 80 °C, 1 h then 0.5 mm Hg 80 °C, 0.5 h 2) imine 111h (1 equiv) CDCl3, 25 °C, 10 min 0.1 M + [imine-H] OPh O –O B B O * O O B OPh B3 434 N Me2N MEDAM 111h To a 25 mL flame-dried home-made Schlenk flask (see Figure 2.26) equipped with a stir bar and flushed with argon was added (R)-56e (54 mg, 0.1 mmol), commercial B(OPh)3 (116 mg, 0.4 mmol) and water (1.8 µL, 0.1 mmol). Under an argon flow through the side-arm of the Schlenk flask, dry toluene (2 mL) was added through the top of the Teflon valve to dissolve the two reagents. The flask was sealed by closing the Teflon valve, and then placed in an 80 ºC oil bath for 1 h. After 1 h, a vacuum (0.5 mm Hg) was carefully applied by slightly opening the Teflon valve to remove the volatiles. After the volatiles were removed completely, a full vacuum was applied and maintained for a period of 30 min at a temperature of 80 ºC (oil bath). The flask was then allowed to cool to room temperature and opened to argon through the side-arm of the Schlenk flask. To the flask containing the pre-catalyst (made from method C) was first added the imine 111h (43 mg, 0.1 mmol) and then and CDCl3(1 mL) under an argon flow through side-arm of the Schlenk flask. The resultant mixture was stirred for 10 min at room temperature. The red 1 colored solution was then directly transferred to a quartz NMR tube and was subjected to H NMR and 11 B NMR analysis. The NMR tube was covered with aluminum foil and the cap was taped with Teflon for storage for longer time periods. Ligands 56f, 56i, 56j, 53 and 61a were subjected to NMR analysis following the above-described procedure. 5.7.12 NMR analysis of a mixture of B(OPh)3, DMSO and BINOL (R)-55 (Figure 5.12) B(OPh)3 (3 equiv) DMSO (1-5 equiv) * OH conditions OH NMR solvent 25 °C, 10-60 min 0.1 M (R)-55 + [DMSO-H] OPh O –O B B O * O O B 329 OPh B3 435 1 Entry 1, Figure 5.12: The H NMR of commercial B(OPh)3 has been taken in d6-DMSO. Entry 2, Figure 5.12: To a 10 mL flame-dried round bottom flask, equipped with a stir bar, filled with argon was added BINOL (R)-55 (29 mg, 0.1 mmol, 1 equiv.), commercial B(OPh)3 (14.5 mg, 0.050 mmol, 0.5 equiv), 4Å MS (150 mg, freshly flame dried) and d6-DMSO (1 mL). The resultant mixture was stirred for 1 h at room temperature. The resulting solution was then 1 filtered and then transferred to a quartz NMR tube and was subjected to H NMR and 11 B NMR analysis. Entry 3, Figure 5.12: To a 10 mL flame-dried round bottom flask, equipped with a stir bar, filled with argon was added BINOL (R)-55 (29 mg, 0.1 mmol, 1 equiv), commercial B(OPh)3 (87 mg, 0.3 mmol, 3 equiv) and d6-DMSO (1 mL). The resultant mixture was stirred for 1 h at room temperature. The resulting solution was then directly transferred to a quartz NMR tube and 1 was subjected to H NMR and 11 B NMR analysis. Entry 4, Figure 5.12: To a 25 mL flame-dried home-made Schlenk flask (see Figure 2.26) equipped with a stir bar and flushed with argon was added BINOL (R)-55 (29 mg, 0.1 mmol, 1 equiv), and BH3•Me2S (150 µL, 0.3 mmol, 2.0 M in toluene), PhOH (18.8, 0.2 mmol) and H2O (5.4 µL, 0.3 mmol). Under an argon flow through the side-arm of the Schlenk flask, dry toluene (2 mL) was added through the top of the Teflon valve to dissolve the two reagents. The flask was sealed by closing the Teflon valve, and then placed in an 100 ºC oil bath for 1 h. After 1 h, a vacuum (0.5 mm Hg) was carefully applied by slightly opening the Teflon valve to remove the 436 volatiles. After the volatiles were removed completely, a full vacuum was applied and maintained for a period of 30 min at a temperature of 100 ºC (oil bath). The flask was then allowed to cool to room temperature and opened to argon through the side-arm of the Schlenk flask. To the flask containing the pre-catalyst was added CDCl3 (1 mL) under an argon flow through side-arm of the Schlenk flask. The reaction mixture was then stirred for 10 min. The off-white colored solution was then directly transferred to a quartz NMR tube and was subjected 1 to H NMR and 11 B NMR analysis. Entry 5, Figure 5.12: Same as entry 4 except that DMSO (7 µL, 0.1 mmol, 1 equiv) was added prior to that analysis. Entry 6, Figure 5.12: Same as entry 4 except that DMSO (35 µL, 0.5 mmol, 5 equiv) was added prior to that analysis. 5.7.13 DFT Calculations 24 All quantum mechanical calculations were performed using the Gaussian ʹ′03. coordinates were provided to Prof. Wulff as a separate file. 437 The REFERENCES 438 REFERENCES (1) (a) Zhang, Y.; Desai, A.; Lu, A.; Hu, G.; Ding, Z.; Wulff, W. D. Chem. –Eur. J. 2008, 14, 3785-3803. (b) Zhang, Y.; Lu, Z.; Desai, A.; Wulff, W. D. Org. Lett. 2008, 10, 5429-5432. (c) Mukherjee, M.; Gupta, A. K.; Lu, Z.; Zhang, Y.; Wulff, W. D. J. Org. Chem. 2010, 75, 56435660. (d) Ren, H.; Wulff, W. D. Org. Lett. 2010, 12, 4908-4911. (e) Hu, G.; Huang, L.; Huang, R. H.; Wulff, W. D. J. Am. Chem. Soc. 2009, 131, 15615-15617. (f) Hu, G.; Gupta, A. K.; Huang, R. H.; Mukherjee, M.; Wulff, W. D. J. Am. Chem. Soc. 2010, 132, 14669–14675. (g) Gupta, A. K.; Mukherjee, M.; Wulff, W. D. Org. Lett. 2011, 13, 5866-5869. (h) Desai, A. A.; Wulff, W. D. J. Am. Chem. Soc. 2010, 132, 13100-13103. (i) Vetticatt, M. J.; Desai, A. A.; Wulff, W. D. J. Am. Chem. Soc. 2010, 132, 13104-13107. (j) Desai, A. A.; Morán-Ramallal, R.; Wulff, W. D. Org. Synth. 2011, 88, 224-237. (k) Desai, A. A.; Ren, H.; Mukherjee, M.; Wulff, W. D. Org. Process Res. Dev. 2011, 15, 1108-1115. (2) (a) Bao, J. M.; Wulff, W. D.; Rheingold, A. L. J. Am. Chem. Soc. 1993, 115, 3814-3815. (b) Bao, J. M.; Wulff, W. D. Tetrahedron Lett. 1995, 36, 3321-3324. (c) Heller, D. P.; Goldberg, D. R.; Wulff, W. D. J. Am. Chem. Soc. 1997, 119, 10551-10552. (d) Heller, D. P.; Goldberg, D. R.; Wu, H. Q.; Wulff, W. D. Can. J. Chem. 2006, 84, 1487-1503. (3) Xue, S.; Yu, S.; Deng, Y.; Wulff, W. D. Angew. Chem., Int. Ed. 2001, 40, 2271-2274. (4) Bolm, C.; Frison, J. C.; Zhang, Y.; Wulff, W. D. Synlett 2004, 1619-1621. (5) Lou, S.; Schaus, S. E. J. Am. Chem. Soc. 2008, 130, 6922-6923. (6) Harada, H.; Thalji, R. K.; Bergman, R. G.; Ellman, J. A. J. Org. Chem. 2008, 73, 6772-6779. (7) van Leeuwen, P. W. N. M.; Rivillo, D.; Raynal, M.; Freixa, Z. J. Am. Chem. Soc. 2011, 133, 18562-18565. (8) Zheng, W.; Zhang, Z.; Kaplan, M. J.; Antilla, J. C. J. Am. Chem. Soc. 2011, 133, 3339-3341. (9) Zhang, Z.; Zheng, W.; Antilla, J. C. Angew. Chem., Int. Ed. 2011, 50, 1135-1138. (10) Larson, S. E.; Li, G.; Rowland, G. B.; Junge, D.; Huang, R.; Woodcock, H. L.; Antilla, J. C. Org. Lett. 2011, 13, 2188-2191. 439 (11) Barnett, D. S.; Schaus, S. E. Org. Lett. 2011, 13, 4020-4023. (12) Hoffman, T. J.; Carreira, E. M. Angew. Chem., Int. Ed. 2011, 50, 10670-10674. (13) Newman, C. A.; Antilla, J. C.; Chen, P.; Predeus, A. V.; Fielding, L.; Wulff, W. D. J. Am. Chem. Soc. 2007, 129, 7216-7217. (14) Ren, H.; Wulff, W. D. J. Am. Chem. Soc. 2011, 133, 5656-5659. (15) Gupta, A. K.; Wulff, W. D., Unpublished results. (16) Rowland, G. B.; Zhang, H.; Rowland, E. B.; Chennamadhavuni, S.; Wang, Y.; Antilla, J. C. J. Am. Chem. Soc. 2005, 127, 15696-15697. (17) Liang, Y.; Rowland, E. B.; Rowland, G. B.; Perman, J. A.; Antilla, J. C. Chem. Commun. 2007, 4477-4479. (18) Li, G.; Liang, Y.; Antilla, J. C. J. Am. Chem. Soc. 2007, 129, 5830-5831. (19) Snyder, S. A.; Thomas, S. B.; Mayer, A. C.; Breazzano, S. P. Angew. Chem., Int. Ed. 2012, 51, 4080-4084. (20) (a) Rowland, E. B.; Rowland, G. B.; Rivera-Otero, E.; Antilla, J. C. J. Am. Chem. Soc. 2007, 129, 12084-12085. (b) Larson, S. E.; Baso, J. C.; Li, G. L.; Antilla, J. C. Org. Lett. 2009, 11, 5186-5189. (c) Della, S. G.; Lattanzi, A. Org. Lett. 2009, 11, 3330-3333. (21) Chen, M.-W.; Chen, Q.-A.; Duan, Y.; Ye, Z.-S.; Zhou, Y.-G. Chem. Commun. 2012, 48, 1698-1700. (22) (a) Loncaric, C.; Wulff, W. D. Org. Lett. 2001, 3, 3675-3678. (b) Rampalakos, K. PhD Thesis, Michigan State University, 2008. (c) Hu, G.; Holmes, D.; Gendhar, B. F.; Wulff, W. D. J. Am. Chem. Soc. 2009, 131, 14355-14364. (23) Ding, Z.; Osminski, W. E. G.; Ren, H.; Wulff, W. D. Org. Process Res. Dev. 2011, 15, 1089-1107 and references therein. 440 (24) Gaussian 03, Revision D.01 M. J. Frisch, G. W. T., H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman, J. A. Montgomery, Jr., T. Vreven, K. N. Kudin, J. C. Burant, J. M. Millam, S. S. Iyengar, J. Tomasi, V. Barone, B. Mennucci, M. Cossi, G. Scalmani, N. Rega, G. A. Petersson, H. Nakatsuji, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, M. Klene, X. Li, J. E. Knox, H. P. Hratchian, J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R. E. Stratmann, O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli, J. W. Ochterski, P. Y. Ayala, K. Morokuma, G. A. Voth, P. Salvador, J. J. Dannenberg, V. G. Zakrzewski, S. Dapprich, A. D. Daniels, M. C. Strain, O. Farkas, D. K. Malick, A. D. Rabuck, K. Raghavachari, J. B. Foresman, J. V. Ortiz, Q. Cui, A. G. Baboul, S. Clifford, J. Cioslowski, B. B. Stefanov, G. Liu, A. Liashenko, P. Piskorz, I. Komaromi, R. L. Martin, D. J. Fox, T. Keith, M. A. Al-Laham, C. Y. Peng, A. Nanayakkara, M. Challacombe, P. M. W. Gill, B. Johnson, W. Chen, M. W. Wong, C. Gonzalez, and J. A. Pople, Gaussian, Inc., Wallingford CT, 2004 (25) Price, C. P.; Matzger, A. J. J. Org. Chem. 2005, 70, 1-6. (26) The terms cisoid and transoid describe biaryl dihedral angles of <90° and >90°, respectively.   (27) (a) Kerr, K. A.; Robertso, J. M. J Chem Soc B 1969, 1146-1149. (b) Kress, R. B.; Duesler, E. N.; Etter, M. C.; Paul, I. C.; Curtin, D. Y. J. Am. Chem. Soc. 1980, 102, 7709-7714. (28) (a) Mori, K.; Masuda, Y.; Kashino, S. Acta Crystallogr., Sect. C: Cryst. Struct. Commun. 1993, 49, 1224-1227. (b) Toda, F.; Tanaka, K.; Miyamoto, H.; Koshima, H.; Miyahara, I.; Hirotsu, K. J. Chem. Soc., Perkin Trans. 2 1997, 1877-1885. (29) (a) Brunel, J. M. Chem. Rev. 2005, 105, 857-897. (b) Brunel, J. M. Chem. Rev. 2007, 107, PR1-PR45. (30) Chen, Y.; Yekta, S.; Yudin, A. K. Chem. Rev. 2003, 103, 3155-3211. (31) Hattori, K.; Yamamoto, H. J. Org. Chem. 1992, 57, 3264-3265. (32) The preparation of 294 has been called into doubt due to failure at the preparation of related compounds, see: Chong, J. M.; Shen, L.; J. Am. Chem. Soc. 2009, 131, 12882-12883 (33) (a) Hattori, K.; Miyata, M.; Yamamoto, H. J. Am. Chem. Soc. 1993, 115, 1151-1152. (b) Hattori, K.; Yamamoto, H. Tetrahedron 1993, 49, 1749-1760. (c) Hattori, K.; Yamamoto, H. 441 Synlett 1993, 129-130. (d) Hattori, K.; Yamamoto, H. Synlett 1993, 239-240. (e) Hattori, K.; Yamamoto, H. Bioorg. Med. Chem. Lett. 1993, 3, 2337-2342. (f) Hattori, K.; Yamamoto, H. Tetrahedron 1994, 50, 2785-2792. (g) Ishihara, K.; Miyata, M.; Hattori, K.; Tada, T.; Yamamoto, H. J. Am. Chem. Soc. 1994, 116, 10520-10524. (h) Lock, R.; Waldmann, H. Tetrahedron Lett. 1996, 37, 2753-2756. (i) Lock, R.; Waldmann, H. Chem.–Eur. J. 1997, 3, 143151. (j) Banerjee, A.; Schepmann, D.; Kohler, J.; Wurthwein, E. U.; Wunsch, B. Bioorg. Med. Chem. 2010, 18, 7855-7867. (34) Momiyama, N.; Tabuse, H.; Terada, M. J. Am. Chem. Soc. 2009, 131, 12882-12883. (35) Thormeier, S.; Carboni, B.; Kaufmann, D. E. J. Organomet. Chem. 2002, 657, 136-145. (36) Zimmer, R.; Peritz, A.; Czerwonka, R.; Schefzig, L.; Reissig, H. U. Eur. J. Org. Chem. 2002, 3419-3428. (37) (a) Ishihara, K.; Kuroki, Y.; Yamamoto, H. Synlett 1995, 41-42. (b) Kuroki, Y.; Ishihara, K.; Hanaki, N.; Ohara, S.; Yamamoto, H. Bull. Chem. Soc. Jpn. 1998, 71, 1221-1230. (38) Cros, J. P.; Pérez-Fuertes, Y.; Thatcher, M. J.; Arimori, S.; Bull, S. D.; James, T. D. Tetrahedron: Asymmetry 2003, 14, 1965-1968. (39) (a) Kawate, T.; Yamada, H.; Matsumizu, M.; Nishida, A.; Nakagawa, M. Synlett 1997, 761762. (b) Yamada, H.; Kawate, T.; Matsumizu, M.; Nishida, A.; Yamaguchi, K.; Nakagawa, M. J. Org. Chem. 1998, 63, 6348-6354. (40) (a) Periasamy, M.; Venkatraman, L.; Sivakumar, S.; Sampathkumar, N.; Ramanathan, C. R. J. Org. Chem. 1999, 64, 7643-7645. (b) Periasamy, M.; Ramanathan, C. R.; Kumar, N. S. Tetrahedron: Asymmetry 1999, 10, 2307-2310. (c) Periasamy, M.; Kumar, N. S.; Sivakumar, S.; Rao, V. D.; Ramanathan, C. R.; Venkatraman, L. J. Org. Chem. 2001, 66, 3828-3833. (d) Liu, D.; Shan, Z.; Liu, F.; Xiao, C.; Lu, G.; Qin, J. Helv. Chim. Acta 2003, 86, 157-163. (41) (a) Green, S.; Nelson, A.; Warriner, S.; Whittaker, B. J. Chem. Soc., Perkin Trans. 1 2000, 4403-4408. (b) Tu, T.; Maris, T.; Wuest, J. D. Cryst. Growth Des. 2008, 8, 1541-1546. (c) Raskatov, J. A.; Brown, J. M.; Thompson, A. L. Crystengcomm 2011, 13, 2923-2929. (42) Llewellyn, D. B.; Arndtsen, B. A. Can. J. Chem. 2003, 81, 1280-1284. (43) Llewellyn, D. B.; Adamson, D.; Arndtsen, B. A. Org. Lett. 2000, 2, 4165-4168. 442 (44) Carter, C.; Fletcher, S.; Nelson, A. Tetrahedron: Asymmetry 2003, 14, 1995-2004. (45) Chen, D.; Sundararaju, B.; Krause, R.; Klankermayer, J.; Dixneuf, P. H.; Leitner, W. ChemCatChem 2010, 2, 55-57. (46) Kaufmann, D.; Boese, R. Angew. Chem., Int. Ed. 1990, 29, 545-546. (47) De-jun, L.; Zi-xing, S.; Guo-ping, W.; Jin-gui, Q. Wuhan University Journal of Natural Sciences 2003, 8, 1138-1142. (48) Shan, Z. X.; Xiong, Y.; Li, W. Z.; Zhao, D. J. Tetrahedron: Asymmetry 1998, 9, 3985-3989. (49) (a) Kelly, T. R.; Whiting, A.; Chandrakumar, N. S. J. Am. Chem. Soc. 1986, 108, 35103512. (b) Wipf, P.; Jung, J.-K. J. Org. Chem. 2000, 65, 6319-6337. (c) Landells, J. S.; Larsen, D. S.; Simpson, J. Tetrahedron Lett. 2003, 44, 5193-5196. (d) Snyder, S. A.; Tang, Z. Y.; Gupta, R. J. Am. Chem. Soc. 2009, 131, 5744-5745. (50) (a) Ishihara, K.; Yamamoto, H. J. Am. Chem. Soc. 1994, 116, 1561-1562. (b) Ishihara, K.; Kurihara, H.; Yamamoto, H. J. Am. Chem. Soc. 1996, 118, 3049-3050. (c) Ishihara, K.; Kurihara, H.; Matsumoto, M.; Yamamoto, H. J. Am. Chem. Soc. 1998, 120, 6920-6930. (d) Ishihara, K.; Kondo, S.; Kurihara, H.; Yamamoto, H.; Ohashi, S.; Inagaki, S. J. Org. Chem. 1997, 62, 30263027. (51) Hu, G. PhD Dissertation, Michigan State University, 2007. (52) Antilla, J. C.; Wulff, W. D. Angew. Chem., Int. Ed. 2000, 39, 4518-4521. (53) Huang, L. PhD Dissertation, Michigan State University, 2011. (54) Wang, Z. H.; Li, F.; Zhao, L.; He, Q. Q.; Chen, F. E.; Zheng, C. Tetrahedron 2011, 67, 9199-9203. (55) Lingenfelter, D. S.; Helgeson, R. C.; Cram, D. J. J. Org. Chem. 1981, 46, 393-406. (56) (a) Tsang, W. C. P.; Schrock, R. R.; Hoveyda, A. H. Organometallics 2001, 20, 5658-5669. (b) Gobbi, L.; Seiler, P.; Diederich, F.; Gramlich, V. Helv. Chim. Acta 2000, 83, 1711-1723. 443 (57) O'Dell, R.; McConville, D. H.; Hofmeister, G. E.; Schrock, R. R. J. Am. Chem. Soc. 1994, 116, 3414-3423. (58) Kickova, A.; Donovalova, J.; Kasak, P.; Putala, M. New J. Chem. 2010, 34, 1109-1115. (59) Zhu, S. S.; Cefalo, D. R.; La, D. S.; Jamieson, J. Y.; Davis, W. M.; Hoveyda, A. H.; Schrock, R. R. J. Am. Chem. Soc. 1999, 121, 8251-8259. (60) Singh, R.; Czekelius, C.; Schrock, R. R.; Mueller, P.; Hoveyda, A. H. Organometallics 2007, 26, 2528-2539. (61) Hu, W.; Zhou, J.; Xu, X.; Liu, W.; Gong, L. Org. Synth. 2011, 88, 406-417. (62) Wipf, P.; Lyon, M. A. ARKIVOC 2007, xii, 91-98. (63) Lu, Z.; Zhang, Y.; Wulff, W. D. J. Am. Chem. Soc. 2007, 129, 7185-7194. (64) (a) Pellissier, H. Tetrahedron 2008, 64, 10279-10317. (b) Seebach, D.; Beck, A. K.; Heckel, A. Angew. Chem., Int. Ed. 2001, 40, 92-138. 444 CHAPTER 6     DIRECT IMINO-BOROX CATALYSIS ASYMMETRIC AZIRIDINATION, [3+2] CYCLOADDITION, UGI REACTION AND KINETIC RESOLUTION OF IMINES You should never ignore the crude weight and the crude NMR especially if the reaction fails to give the desired product. -William D. Wulff 6.1 Catalytic asymmetric one-pot aziridination In the present section of this chapter, the asymmetric catalytic aziridination reaction (AZ reaction) of imines derived from dianisylmethyl (DAM) amine was examined with the IMINO BOROX catalysts. As a result, a new one-pot procedure was developed for the aziridination reaction. 1 Apart from asymmetric aziridination reactions using chiral auxiliaries, considerable advances have been made in the field of catalytic asymmetric aziridination over the past few years. 2 Primarily, there are two main approaches that have been taken towards catalytic asymmetric aziridination: 3 a) addition of nitrogen to olefins via nitrene transfer with 4 organometallic catalysts or organocatalysis b) addition of carbon to imines via metal-carbene 5 transfer (carbene generated from diazo compound or sulfur ylides) or the reaction of a diazo 6 7 compound with an imine activated by either Lewis acid or Brønsted acid. It must noted that the asymmetric aziridination reaction between the imines and diazo compounds in the presence 445 of an acid catalyst must not be mistaken for Aza-Darzens reaction as both are mechanistically 2a distinct. auxiliaries. In fact, an asymmetric Aza-Darzens reaction has only been reported with chiral 2a As discussed in previous chapters, our aziridination protocol is a Brønsted acid catalyzed reaction. 8 Over the last several years we have developed a general method for the catalytic asymmetric synthesis of aziridines that is based on the reaction of diazo compounds with imines and which is mediated by asymmetric catalysts generated from the VANOL and VAPOL ligands and various boron compounds. 8-9 Early on it was determined that with imines derived from benzhydryl (Bh) amine 126a and catalysts derived from triphenylborate, aziridines could be obtained in high yields and asymmetric inductions from the reaction of ethyl 10 diazoacetate and other diazo compounds. The reactions are also highly diastereoselective giving cis-2,3-disubstituted aziridines and in most cases only trace amounts of the trans-aziridine can be detected. The scope of the reaction is broad and includes imines derived from a variety of aldehydes including electron-rich and electron-poor aromatic aldehydes and 1°, 2° and 3° aliphatic aldehydes. 9a The imines from aromatic aldehydes gave aziridines with 90-95% ee and imines from aliphatic aldehydes gave aziridines with 77-87% ee. 9a Interestingly, both VANOL and VAPOL derived catalysts are equally effective and give nearly the same asymmetric inductions for each substrate across the entire range of 12 substrates examined. 9a During the studies directed toward mapping the active site of the chemzyme in this reaction, it was revealed that while the use of a diphenylmethyl group on the imine is essential to the success of this reaction, it does not represent the optimal substituent since it was found that 446 various diarylmethyl groups were far more effective. 9b A collection of 14 different diarylmethyl substituents was screened for the reaction of imines derived from benzaldehyde and the optimal 9b selectivity (99% ee) was found for the tetra-t-butyldianisylmethyl (BUDAM) group. With the identification of the BUDAM substituent as optimal for the imine from benzaldehyde, this substituent was in turn screened with imines prepared from BUDAM amine 126d and eleven different aldehydes. The reactions of BUDAM imines from aromatic aldehydes were definitely superior to their benzhydryl analogs giving 98-99% ee for most substrates with VAPOL derived catalysts; however, the reactions of BUDAM imines from aliphatic aldehydes were not significantly different from their benzhydryl analogs giving ee’s generally in the 80’s. Thus, the goal of the present work is to identify the optimal diarylmethyl substituent that will provide universal access to optically pure aziridines from the AZ reaction irrespective of the substrate. One of the great advantages of the BUDAM substituent is that it can be easily cleaved under acidic conditions without opening the aziridine ring when the aziridine is treated with 4 9b equivalents of triflic acid in anisole at room temperature. The corresponding benzhydryl aziridines leads to ring opening under all acidic conditions that were screened. 11 The facile cleavage of the BUDAM group under acidic conditions can be attributed to the fact that a significantly more stable diarylmethyl cation is formed during the cleavage. Thus, in seeking the ideal diarylmethyl substituent for the imine, one of the characteristics that would be most desired would be its ability to be removed from the aziridine without causing any deleterious effects to the aziridine. One of the other diarylmethyl groups that was identified in our previous work as superior to the unsubstituted diphenylmethyl (benzhydryl or Bh) group in the AZ reaction is the 447 11 dianisylmethyl (DAM) group. The presence of the methoxyl substituents in the DAM group is 11 sufficient to provide for the clean cleavage of the DAM group under acidic conditions. We have previously examined the scope of the aziridination of DAM imines from a variety of aldehydes and found that these imines tend to give slightly improved yields and asymmetric inductions than the corresponding benzhydryl imines. 11 However, this survey was conducted with methylene chloride and carbon tetrachloride as solvent. Since we have subsequently found that toluene is in many respects superior to either methylene chloride and carbon tetrachloride for 9a the AZ reaction, we decided to revisit the scope of the AZ reaction of DAM imines. Meanwhile, a lot of mechanistic studies were carried out in our group regarding the identification of the active catalyst structures. Prior to these studies, it was believed that the active catalyst is B1 106/107 (Scheme 2.1, Chapter 2) that was generated from VAPOL or VANOL when reacted with triphenyl borate. This proposed structure was based on studies by Yamamoto, 12 however no spectroscopic evidence existed for such catalyst structures. Further, Dr. Yu Zhang, one of the previous group members, found out that there are two boron species B2 9a 108/109 and B1 106/107 on the basis of NMR and MS studies (Scheme 2.1, Chapter 2). Additionally, it was found that the catalyst enriched with B2 108/109 gives higher asymmetric induction and higher rates in the aziridination reaction compared to a catalyst mixture enriched 9a with B1 106/107. In the continuing effort to probe the mechanistic rationale for the asymmetric induction observed for catalysts generated from VAPOL and VANOL, a major breakthrough was the identification of the active boroxinate catalyst 188/189 (imine = 448 8 benzhydryl imines 78) which contains three boron atoms (Scheme 2.1, Chapter 2). Surprisingly, the catalyst proved to be a Brønsted acid catalysis in operation contrary to the common belief of that the aziridination reaction involved Lewis-acid catalysis. Furthermore, it was found that the boroxinate 188/189 is formed by the reaction of the pyroborate 108 with the imine 78, with or without the presence of an additional equivalent of B(OPh)3. Hence, the catalytic mixture obtained by mixing ligand (1 equiv), B(OPh)3 (4 equiv) and H2O (1 equiv) is actually a “pre-catalyst” (Method C, Table 2.1, entry 4, Chapter 2 and Scheme 6.2B). The protocol for the aziridination reaction using pre-catalyst made by method C is termed as procedure IV (Table 2.1, entry 4, Chapter 2 and Scheme 6.2B). The shortcoming of the optimized protocol for the aziridination of imines include the need to generate a pre-catalyst (mixture of B1 106/107 and B2 108/109) from the VAPOL or VANOL ligand and B(OPh)3. In the pre-catalyst protocol, the exposure to high vacuum at 80 °C is not sufficient to remove the third equivalent of B(OPh)3 after the pyroborate 108/109 is formed, although the phenol produced in the alkoxy exchange between the ligand and B(OPh)3 is removed. However, the major difficulty of the protocol is the removal of the volatiles during the preparation of the pre-catalyst. Removing the solvent and other volatiles at 80 °C under high vacuum often occurs with splattering and loss of the pre-catalyst. Henceforth, the secondary aim of the work was to simplify the overall procedure, thus developing a one-pot aziridination reaction avoiding the generation of the pre-catalyst. In the process of the optimization, a simplified procedure II (Table 2.1, entry 2, Chapter 2 and Scheme 6.1) was devised using benzhydryl phenyl imine 78a. The procedure II involves the direct generation of the boroxinate catalyst 188a by mixing 1 equiv of (S)-VAPOL, 3 equiv of 449 B(OPh)3 and 20 equiv of imine 78a in toluene at 25 °C for 5 min. Thereafter, EDA 85 (24 equiv) is added and the resulting mixture is stirred for 24 h at 25 °C. The reaction was performed open to air. It gave aziridine 86a in 82% yield and 92% ee. A number of solvents (hexanes, dioxane, toluene, ether, DME etc.) were also examined. 8 Scheme 6.1 Catalytic asymmetric aziridination of imine 78a using procedure II O Ph B(OPh)3 (S)-VAPOL (20 mol%) (5 mol%) toluene open to air N 78a Bh 10 min OEt Bh Bh N2 85 + N 25 °C, 24 h Ph CO2Et 86a 82% y, 92% ee NH CO2Et (Ph)H Ph(H) 87a(88a) The application of procedure II to the reaction of N-DAM imines 110 was then tested (Table 6.1). Unfortunately, low conversions were observed when the reaction was performed open to air (Table 6.1, entries 1,3,5,7). It was then thought to carry out the reaction under argon atmosphere. Although a slight improvement was observed, the reactions were still far from complete (Table 6.1, entries 2,4,6,8). To our delight, high yield and high enantioselectivity were observed (Table 6.1, entry 7) on increasing the catalyst loading from 5 mol% to 10 mol% for imine 110g (R = 4-Br-C6H4). This modified procedure seemed to be a much simplified procedure when compared to that which employs pre-catalyst preparation. Table 6.1 One-pot aziridination reaction of N-DAM imines 110 using procedure II. O B(OPh)3 (S)-VAPOL (20 mol%) (5 mol%) toluene conditions R N 110 DAM 25 °C 10 min OEt N2 85 DAM N 25 °C, 24 h R CO2Et 113 450 a OPh DAM O B O – B O * N+ H O O B OPh R catalyst 212 Table 6.1 cont’d # Series Conditions R Conversion b (%) 1 2 3 a a d open to air under argon open to air Ph Ph 4-Me-C6H4 27 80 20 Yield 113 c (%) – – – 4 d under argon 4-Me-C6H4 26 – – 5 f open to air 4-NO2-C6H4 28 – – 6 f under argon 4-NO2-C6H4 44 – – 7 g open to air 4-Br-C6H4 15 – – g under argon 4-Br-C6H4 23 – – g under argon 4-Br-C6H4 100 90 95 8 9 e ee 113 d (%) – – – a Unless otherwise specified, all reactions were performed with 5 mol% of catalyst 212 with 0.50 mmol imine 110 (1.0 equiv, 0.5 M in toluene) and 0.6 mmol of EDA 85 (1.2 equiv) at b room temperature. Percent conversion is determined by integration of the methine proton of 2 1 the cis-aziridine relative to the sp -CH proton of the unreacted imine 110 in the H NMR spectrum of the crude reaction mixture. catalyst used. c Isolated Yield. d Determined by HPLC. e 10 mol% Since one of the aims of the work was to utilize as of a low catalyst loading as possible, another procedure IIʹ′ was employed. The catalyst was generated by stirring a mixture of (S)VAPOL (0.025 mmol), B(OPh)3 (0.1 mmol) and imine 110g (R = 4-Br-C6H4, 0.25 mmol) in toluene for 0.5 h. In this way, the catalyst loading was 10 mol% with respect to imine 110g during the preparation of the catalyst. The actual catalyst loading was reduced to 5 mol% by adding imine 110g (0.25 mmol) after 0.5 h. Unfortunately, this trick did not work and the reaction only went to 16 % conversion (Scheme 6.2A). 451 Scheme 6.2 Catalytic asymmetric aziridination of imine 110g (R = 4-Br-C6H4) using (A) procedure IIʹ′ (B) procedure IV (C) procedure Vʹ′ (D) procedure V A DAM N 110g (0.25 mmol) R B(OPh)3 (S)-VAPOL (20 mol%) (5 mol%) toluene 25 °C, 0.5 h under argon O DAM N 110g (0.25 mmol) R OEt DAM N2 85 N 25 °C, 24 h R 25 °C 10 min CO2Et 113g OPh DAM O B O – B O * N+ H O O B R OPh catalyst 212g 16% conversion B B(OPh)3 (20 mol%) H2O (5 mol%) (S)-VAPOL (5 mol%) toluene, 80 °C, 1.0 h 0.5 mm Hg 80 °C, 0.5 h O R DAM OEt N 110g pre-catalyst (5 mol%) toluene, 25 °C 10 min under argon DAM N2 85 N 25 °C, 24 h R CO2Et 113g 90% y, 97% ee pre-catalyst (5 mol%) OPh DAM B O –O B O * N+ H O O B OPh R catalyst 212g C O DAM R N B(OPh)3 110g (S)-VAPOL (20 mol%) (5 mol%) toluene 25 °C 10 min 80 °C, 1 h under argon OEt N2 85 DAM N 25 °C, 24 h R CO2Et 113g 39% conversion 452 OPh DAM O B O – B O * N+ H O O B OPh R catalyst 212g Scheme 6.2 cont’d D R (S)-VAPOL (5 mol%) DAM N 110g B(OPh)3 (20 mol%) toluene 80 °C, 1 h under argon O OEt DAM N2 85 N 25 °C, 24 h R CO2Et 113g OPh DAM O –O B B O * N+ H O O B OPh R catalyst 212g 89% y, 97% ee Furthermore, we thought of performing the reaction using procedure Vʹ′ where a precatalyst is made. The difference between the procedure IV and Vʹ′ was that there was no removal of the volatiles under reduced pressure (Scheme 6.2B vs 6.2C). An improved conversion of 39 % (compared to 16% conversion with procedure IIʹ′) was observed for imine 110g using 5 mol% catalyst (Scheme 6.2C). This increase in conversion speaks to the necessity of the high temperature for generation of an effective catalyst system. Since it is known that the generation of the active catalyst occurs only after the addition of imine, it was thought to heat the ligand, borate and imine altogether (procedure V, Scheme 6.2D). Using procedure V, the reaction of imine 110g with 5 mol% catalyst loading gave 100% conversion affording aziridine 113g in 89% yield and 97% ee (Scheme 6.2D). The basic aspect of procedure V is that the ligand, B(OPh)3 and all of imine for the reaction (Scheme 6.2D) are heated together in toluene at 80 °C for 1 h and then upon cooling to room temperature, the reaction is initiated by the addition of ethyl diazoacetate. Another significant incorporated into procedure V is that the step involving the removal of volatiles has been deleted and this did not have any adverse effect on the outcome of the reaction. This aids in the objective to simplify the system. Additionally, it was observed that 453 the presence of phenol does not significantly affect the outcome of the AZ reaction (Table 6.4). Finally, it should be noted that the water was left out of procedure V. Although the formation of a boroxinate does require three equivalents of water, studies on the efficiency of the formation of 1 boroxinate by H and 11 B NMR spectroscopy revealed that there is sufficient partial hydrolysis in commercial B(OPh)3 to provide the equivalent of three molecules of water. 8 We have never encountered a bottle of commercial B(OPh)3 that was pure. This fact, and the consistency of the impure nature of commercial B(OPh)3 over the years has been responsible for the success and reproducibility of the AZ reaction. The reason that four equivalents of B(OPh)3 is used in procedure IV and V is to compensate for the fact that B(OPh)3 in not pure as supplied from commercial suppliers. In reality, we have not seen any significant difference in the catalyst prepared with either three or four equivalents of B(OPh)3 either in reaction outcome or in its 1 characterization by H or 11 B NMR spectroscopy. 13 Even with two equivalents of B(OPh)3 the reaction outcome is not significantly affected. All of this suggests that all of the boron that happens to be present is converted to the chiral boroxinate even if this leaves some of the ligand unreacted, and if any boron is left over, it not does interfere in terms of background reaction. 13 The catalytic asymmetric aziridinations of the DAM imines 110 derived from aromatic aldehydes were screened in toluene following procedures IV and V and the results are presented in Table 6.2. All of the reactions were carried out for 24 h with 2-5 mol% catalyst but not all substrates required 24 h to go to completion. The reaction of the phenyl imine 110a was complete in 2 h with 3 mol% catalyst (Table 6.2, entry 1). In all cases the reaction went to 454 completion except for entry 11 which went to 97% completion in 24 h with 2 mol% catalyst. The catalyst with VANOL was used for the para-methoxyl substrate 110e since it had been found in our previous studies on DAM imines that this is the slowest substrate and that the VANOL catalyst is approximately twice as fast as the VAPOL catalyst. 11 One of the clear findings of this study is that, at least for DAM imines derived from aryl aldehydes, there is no difference in yields or asymmetric inductions between procedures IV and V for catalyst formation. This is an important observation since procedure V is experimentally much more simple as it does not involve the removal of solvent from the catalyst at high temperature under vacuum. Unfortunately, the asymmetric inductions in toluene do not represent a significant improvement over those previously observed with DAM imines from aryl aldehydes in carbon tetrachloride solvent. 11 This is not to ignore the fact that toluene is a much more desirable solvent than carbon tetrachloride for reasons of both safety and cost. Table 6.2 Asymmetric Aziridination with Aryl DAM imines 110. O DAM N + OEt N2 R 110 2 3 4 Toluene 25 °C, 24 h 85 DAM DAM N R NH CO2Et + (R)H R(H) CO2Et 113 116(117) OPh DAM O B O – N+ B O * H O O B R OPh IMINO-BOROX catalyst 212/212' IV (5) Yield 113 b (%) 95 ee 113 c (%) –92 V (3) V (3) V (3) 90 80 70 94 98 93 Serie s R Ligand Cat. x mol% f a Ph (R)-VAPOL g a b c Ph 1-napthyl 2-Me-C6H4 (S)-VAPOL (S)-VAPOL (S)-VAPOL # 1 IMINO-BOROX catalyst 212/212' (2-5 mol%) a 455 cis/trans d Enamine e (%) 50:1 1(1) >50:1 >50:1 >50:1 2.7(2.7) 1.6(1.6) 1.4 (1.1) Table 6.2 cont’d 5 d 4-Me-C6H4 (S)-VAPOL IV (5) 90 94 >50:1 1(1) 6 d 4-Me-C6H4 (S)-VAPOL V (3) 90 94 >50:1 1(1) 7 e 4-MeO-C6H4 (R)-VANOL IV (5) 80 –93 >50:1 2(1) 8 e 4-MeO-C6H4 (S)-VANOL V (3) 80 93 50:1 3.2(1.6) 9 f 4-NO2-C6H4 (S)-VAPOL IV (5) 85 94 33:1 1.6(1.6) 10 f 4-NO2-C6H4 (S)-VAPOL V (3) 85 95 50:1 <1(<1) 11 g 4-Br-C6H4 (S)-VAPOL IV (5) 90 97 50:1 <1(<1) 12 g 4-Br-C6H4 (S)-VAPOL IV (3) 90 97 50:1 <1(<1) h g IV (3) 94 97 50:1 <1(<1) g g 4-Br-C6H4 4-Br-C6H4 4-Br-C6H4 (S)-VAPOL i (S)-VAPOL (S)-VAPOL IV (2) V (5) 87 89 97 97 50:1 33:1 1(1) 4.5(2.7) 13 14 15 a Unless otherwise specified, all reactions were performed with x mol% of catalyst 212/212ʹ′ with 0.50 mmol imine 110 (1.0 equiv, 0.5 M in toluene) and 0.6 mmol of EDA 85 (1.2 equiv) at room temperature and went to completion. Procedure IV or V (Scheme 6.2B and 6.2D) b c d were followed for the aziridination reaction. Isolated Yield. Determined by HPLC. 1 Ratio determined by integration of the methine protons of cis- and trans-aziridine in the H NMR spectrum of the crude reaction mixture. e Determined by integration of the NH signals 1 of enamines relative to the methine proton of cis aziridine in the H NMR spectrum of the crude reaction mixture. f This reaction was complete in 2 h with 5 mol% catalyst. reaction was complete in 8 h. h g This Pre-catalyst made using Procedure IV except that water was i excluded during the catalyst preparation. 97% complete. At this point we had not yet addressed the critical issue of whether the DAM imines would provide higher inductions for imines from aliphatic aldehydes since we had only screened the aryl imines shown in Table 6.2. The aziridinations of the aliphatic DAM imines 110 using procedure IV and V were carried out as indicated in Table 6.3 in toluene at room temperature for 24 h. Considering previous observations that alkyl substituted imines are generally slower, 5-10 mol% catalyst was used for imines 110o, 110v and 110w. Unfortunately, the results from the 456 alkyl substituted DAM imines 110 do not represent an improvement in the asymmetric inductions over those of the corresponding benzhydryl imines 78 and in fact are slightly lower. 9a In addition, the aziridination of the primary alkyl substituted imine 110o essentially fails in the case of the DAM imine (Table 6.2, entries 1-4). This reaction produces a very complex mixture with both VANOL and VAPOL catalysts and at both room temperature and at 0 °C. A similar complex mixture was produced with DAM imine 110o in carbon tetrachloride solvent with the 11 VAPOL catalyst where the aziridine 113o was isolated in 11% yield and in 63% ee. This is to be compared to the corresponding reaction of the benzhydryl imine 78o (R = n-Pr) prepared from n-butanal which gave the corresponding aziridine 86o in 40% yield and 81% ee. 9a 1 The crude H NMR spectrum of the reaction of imine 110o in entries 1-4 in Table 6.3 reveals the presence of a small amount of aziridine 113o (6-14%) and small amounts of the unreacted imine 110o and of the non-cyclized enamine products 116o and 117o. The only other product that was prominent 1 in the crude H NMR was, identified after some effort, as the vinyl imine 333o whose structure was confirmed by independent synthesis (see experimental). This compound presumably results from an aldol type condensation of two molecules of imine 110o (via an enamine). In contrast, high yields of aziridines were obtained with the 2° and 3° aliphatic imines 110v and 110w, but unfortunately, the asymmetric inductions were not significantly different than those previously observed in carbon tetrachloride. 11 Thus our attempts to improve the asymmetric inductions with aliphatic imines by employing the dianisylmethyl (DAM) substituted imines were surceased. Later on, tetramethyldianisylmethyl (MEDAM) protecting was found to be optimum 457 9c for both aromatic and aliphatic imines. Nonetheless, a very simplified one-pot aziridination protocol was identified in these studies with DAM imines. Table 6.3 Asymmetric Aziridination with Alkyl DAM imines 110. O DAM N + OEt IMINO-BOROX catalyst 212/212' (5-10 mol%) Toluene 25 °C, 24 h N2 R 110 DAM N R 85 DAM + (R)H Series R Ligand 1 2 g 3 f o o o n-propyl n-propyl n-propyl (R)-VANOL (R)-VANOL (S)-VAPOL V (10) IV (10) IV (10) Yield 113 b (%) nd 14 11 4 5 h 6 g o v v n-propyl cyclohexyl cyclohexyl (R)-VANOL (S)-VANOL (R)-VANOL IV (10) V (5) IV (5) 10 83 88 7 i w t-butyl (S)-VANOL V (10) h w t-butyl (R)-VANOL IV (10) 8 CO2Et + N Et H nPr 333o 116(117) Cat. x mol% # DAM NH R(H) CO2Et 113 a ee 113 c (%) nd –52 73 cis/trans d Enamine e (%) nd nd nd 3(1) 3(1) <1(2) –66 82 –80 nd 50:1 50:1 2(1) <1(<1) <1(<1) 60 70 20:1 <1(<1) 87 –83 50:1 <1(<1) a Unless otherwise specified, all reactions were performed with x mol% of catalyst 212/212ʹ′ with 0.50 mmol imine 110 (1.0 equiv, 0.5 M in toluene) and 0.6 mmol of EDA 85 (1.2 equiv) at room temperature. Procedure IV or V (Scheme 6.2B and 6.2D) were followed for the aziridination reaction. The NMR yields of 332o are 7, 4, 7, 8 for entries 1-4 respectively. The NMR yield for unreacted imine 110 are 4, 2, 10, 7, <1, <1, 25, <1 for entries 1-8 respectively. 1 The NMR yield is determined from H NMR spectrum of the crude reaction mixture with Ph3CH as internal standard. b Isolated Yield. c d Determined by HPLC. Ratio determined by 1 integration of the methine protons of cis- and trans- aziridine in the H NMR spectrum of the crude reaction mixture. e Determined by integration of the NH signals of enamines relative to 1 the methine proton of cis aziridine in the H NMR spectrum of the crude reaction mixture. The NMR yield of the aziridine 113o is 6%. 48 h. h i g f This reaction was performed with at 0 °C for Reaction time = 48 h. Reaction time = 55 h. 458 Following the procedure V (Scheme 6.2D), a study of the effect of various additives on the aziridination reaction was performed (Table 6.4). The additives (one equivalent with respect to the imine) were added prior to the addition of ethyl diazoacetate 85. Low conversions were obtained when water and 4-pentylbicyclo [2.2.2]octane-1-carboxylic acid 334b were used as additives (entries 1-2). A drop of 22% ee was observed when benzoic acid 334a was added (entry 3). However, addition of phenol 194a did not alter the result (entry 4). Table 6.4 Effect of various additives on the aziridination reaction. P Ph N 78a/111a # P 78a 111a CHPh2 MEDAM 3 111a MEDAM 4 5 111a 111a MEDAM MEDAM h OEt P N2 85 additive toluene 80 °C, 1 h under argon imine 1 2 O B(OPh)3 (12 mol%) (S)-VAPOL (3 mol%) a N 25 °C, 24 h Ph CO2Et 86a (imine = 78a) 114a (imine = 111a) H2 O 43 Yield azi d (%) nd H2 O 4-pentylbicyclo [2.2.2]octane-1carboxylic acid PhCO2H PhOH 15 nd nd nd nd 22 nd nd nd nd 88 100 77 98 78 96 33:1 50:1 5(2) 4(5) Additive Conv c (%) b ee azi e (%) nd cis/trans f Enamine g (%) nd nd a Unless otherwise specified, all reactions were performed with 3 mol% of catalyst with 0.50 mmol imine 78a/111a (1.0 equiv, 0.5 M in toluene) and 0.6 mmol of EDA 85 (1.2 equiv) at room temperature and went to completion. Procedure V (Scheme 6.2D) was followed for the b c aziridination reaction. One equivalent of the additive was added with respect to the imine. Percent conversion is determined by integration of the methine proton of the cis-aziridine 2 1 relative to the sp -CH proton of the unreacted imine in the H NMR spectrum of the crude reaction mixture. d Isolated Yield. e f Determined by HPLC. Ratio determined by integration 459 Table 6.4 cont’d 1 of the methine protons of cis- and trans- aziridine in the H NMR spectrum of the crude g reaction mixture. Determined by integration of the NH signals of enamines relative to the 1 h methine proton of cis aziridine in the H NMR spectrum of the crude reaction mixture. Procedure IV (Scheme 6.2B) was followed for the aziridination reaction with 5 mol% catalyst. 6.2 Racemic Aziridination with various Lewis/Brønsted acids During one of the studies, we found that the MEDAM group, which is the optimum for our aziridination reaction, is not as good as benzhydryl protecting group for a racemic aziridination with various Lewis or Brønsted acids (Table 6.5). We already know that the rate-limiting step in the case of the Wulff catalytic asymmetric aziridination reaction is the ring-closure step and carbon-carbon bond formation step for MEDAM imine 111a and benzhydryl imine 78a respectively. It would be interesting to find out the rate-limiting step in the case Yb(OTf)3 catalyzed racemic aziridination reaction using benzhydryl imine 78a. An experiment was performed (Table 6.5, entry 8) at a 10 mmol scale and the KIE studies were on progress at the time of writing of this dissertation. Table 6.5 Racemic Aziridination with various Lewis/Brønsted acids. P N Ph 78a 111a O + OEt N2 catalyst (x mol%) solvent 25 °C, 24 h P P N Ph 85 CO2Et 86a 114a 460 a + (Ph)H NH CO2Et Ph(H) 87a(88a) 118a(119a) Table 6.5 cont’d # imine P catalyst (x mol%) e 111a MEDAM 0.055 toluene e BF3•Et2O (10) Yield azi b (%) 5 111a MEDAM BF3•Et2O (10) 0.4 toluene e 111a MEDAM 111a MEDAM BF3•Et2O (100) TfOH (25) 0.4 e 111a MEDAM 78a Conc (M) solvent cis/trans c Enamine d (%) 3.8:1 3(1) 6 6.3:1 <1(<1) toluene 24 9.9:1 2(<1) 0.2 toluene 29 6.9:1 7(8) Yb(OTf)3 (10) 0.1 hexanes 33 7.6:1 <1(<1) CHPh2 Yb(OTf)3 (10) 0.1 hexanes 63 16:1 <1(4) 78a CHPh2 Yb(OTf)3 (20) 0.1 hexanes 68 20:1 5(6) 78a CHPh2 Yb(OTf)3 (20) 0.1 hexanes 72 17:1 5(5) 9 10 78a CHPh2 Yb(OTf)3 (10) 0.1 toluene 42 7.7:1 10(13) 78a CHPh2 Yb(OTf)3 (10) 0.1 toluene 41 6.6:1 8(11) 11 78a CHPh2 B(OPh)3 (40) 0.5 toluene 78 >50:1 8(2) 1 2 3 4 5 6 7 8 f f a Unless otherwise specified, all reactions were performed with x mol% of catalyst with 0.50 mmol imine 78a/111a (1.0 equiv, C M in solvent) and 0.6 mmol of EDA 85 (2 equiv) at room temperature. The amount of unreacted imine 78a/111a was 90%, 75%, 40%, 22%, 63%, 7%, b 1 <1%, <1%, 2%, 13% and <1% for entries 1-11 respectively. Determined from H NMR of crude reaction mixture with Ph3CH as the internal standard. c 1 Ratio determined by integration of the methine protons of cis- and trans-aziridine in the H NMR spectrum of the crude reaction mixture. d Determined by integration of the NH signals of enamines relative to the 1 methine proton of cis-aziridine in the H NMR spectrum of the crude reaction mixture. equiv EDA used. 6.3 f e 1.2 EDA added at 0 ºC. Catalytic asymmetric [3+2] cycloaddition Over the last several years we have developed a general method for the catalytic asymmetric synthesis of aziridines that is based on the reaction of stabilized diazo compounds with imines and which is mediated by asymmetric catalysts generated from the VANOL and 461 VAPOL ligands and various boron compounds. 8-9 The reactions are also highly diastereoselective giving cis- and trans-2,3-disubstituted aziridines depending upon the kind of diazo compounds used. The scope of the reaction is broad and includes imines derived from a variety of aldehydes including electron-rich and electron-poor aromatic aldehydes and 1°, 2° and 3° aliphatic aldehydes. 9a It must be noted that while aziridines 114t 14 15 and 124ʹ′a are obtained in high yields and ees from the reaction between imines 111t (derived from dihydrocinnaldehyde 127t) and 122ʹ′a (derived from 3-phenyl-2-propynal 102a) and EDA, imine 335a (derived from cinnamaldehyde 336a) failed to give any aziridine when reacted with EDA under aziridination reaction conditions (Scheme 6.3A). In this case, starting material i.e. imine was recovered. A similar trend was observed when diazoacetamide 123a was utilized for aziridination reaction 9f with imines 112z 15 and 122z and likewise, there was no reaction with the imine 335z (derived from trans-crotonaldehyde 336c) (Scheme 6.3B). The reason for the failure of the aziridination reaction with imines derived from α,β-unsaturated aldehydes has not been determined. However, there are six different products possible from the reaction between the imine 335 and ethyl diazoacetate 85 as shown in Scheme 6.3C. Apart from aziridines 337 and enamines 338339, the products include the diazo compound 340, the pyrazoline 341 and the cyclopropane 342. Scheme 6.3 (A) Reaction between EDA and different imines (B) Reaction between diazoacetamide and different imines (C) Possible products from the reaction between EDA and conjugated imine 335 462 Scheme 6.3 cont’d A Ph P 111t N CO2Et Ph 112t (Ref 14) IMINO BOROX catalyst + P N O OEt Toluene –10 °C, 24 h (P = MEDAM) Ph P 85 Ph P 122'a N Ether –20 °C, 24 h (P = BUDAM) N2 Toluene 25 °C, 24 h (P = MEDAM) N N CO2Et Ph 124'a (Ref 15) P 335a No reaction (this work) B H3C P 112z N H3C CONHPh 125z (Ref 9f) IMINO BOROX catalyst + P N O Toluene 0 °C, 24 h (P = BUDAM) NHPh N2 123a Toluene 25 °C, 24 h (P = MEDAM) N C4H9 N 335z 463 122z Toluene –20 °C, 24 h C4H9 (P = MEDAM) H3C No reaction (this work) P P P N CONHPh 124z (Ref 15) Scheme 6.3 cont’d C EtO2C * R * * N P R 342 IMINO BOROX catalyst P O N + OEt N2 335 85 (P = MEDAM) P N R 337 P N NH * * EtO2C R 341 N P P R CO2Et (R)H NH CO2Et R(H) NH CO2Et 338(339) N2 340 It must be pointed out that there is no prior report of a reaction between a diazo compound and imine derived from α,β-unsaturated aldehydes. However, pyrazolines and cyclopropanes have been observed from the reaction between α,β-unsaturated aldehydes and EDA with the outcome depending upon the substitution pattern of the aldehyde and the reaction conditions (Scheme 6.4 and 6.5). With no alpha substitution, it has been reported that [3+2] adduct is the 16 major product which polymerizes very quickly (Scheme 6.4A and 6.4B). However, in the year 2006, Hossain and coworkers showed that cyclopropanes can be obtained in high yields from 17 these aldehydes if the reaction is performed in the presence of HBF4 at –78 °C. In 2006, Maruoka and coworkers reported the formation of a chiral all-carbon quaternary center via TfOH 2 catalyzed insertion of aryldiazoacetates into an sp 18 carbon–CHO bond (Scheme 6.4C). Nonetheless, based on the reported observations with aldehydes (Scheme 6.4), a similar outcome 464 can be assumed in the cases of the reaction between imine 335 derived from α,β-unsaturated aldehydes 336 and EDA. In other words, probably, a very small amount of the imine 335 undergoes [3+2] cycloaddition and the resulting adduct might bind to the catalyst thereby completely killing the reaction. Scheme 6.4 (A) Reaction between EDA and unsubstituted acroleins EDA and β-substituted acroleins β-disubstituted acroleins 16-17 16-17 (B) Reaction between (C) Reaction between di-substituted aryldiazoacetate and 18 A Hexanes EtO2C or CCl4 O O HN N + * CHO Polymer 343b OEt N2 336b 85 10 % HBF4 CH2Cl2, –78 °C EtO2C * * CHO 100% yield Trans:cis=1.5:1 344b B Hexanes 336c + EtO2C or CCl4 O O HN N OEt N2 ** CHO Polymer 343c 85 10 % HBF4 CH2Cl2, –78 °C 465 EtO2C * * CHO 344c 60% yield Scheme 6.4 cont’d C O 20 % TfOH + Ph O Toluene –78 °C, 30 min N2 336d CHO OR 345 While [3+2] adducts Ph R= CO2R 346 89% y, 87% de 19 Ph have been observed from the reaction of mono-substituted diazo compounds with α-substituted acroliens, di-substituted diazo compounds have been reported to form cyclopropanes 20 for the same reaction (Scheme 6.5). cycloadditions reported using acroleins 21 There are several other [3+2] 22 and other carbonyl compounds. Scheme 6.5 (A) Reaction between 348 or EDA and α-substituted acroleins 347 (B) Reaction between EDA and α,β-substituted acroleins 352 (C) Reaction between di-substituted aryldiazoacetate and α-substituted acroleins 347 A O R O + OtBu N2 347 348 (S)-55 : Ti(OiPr)4 (2:1, 5-10 mol%) N NH tBuO2C CH2Cl2, –40 °C 1–5h OH OH R CHO 349 6 examples Yield = 43-82% ee = 83-94% O + OEt N2 347 H Ph catalyst 350a/350b (20 mol%) O R 85 CH2Cl2, –78 °C 0.5 – 2 h (S)-55 N NH EtO2C R CHO + TfNH – N B H Ph O 351 5 examples Yield = 72-97% ee = 76-95% 466 350a (R'=H) 350b (R'=Me) R' Scheme 6.5 cont’d B H Ph O R1 R2 O+ catalyst 350a (20 mol%) OEt C3H7CN, –93 °C 0.5 – 1 h N2 352 85 EtO2C N NH 1 R CHO R2 + TfNH – 353 N B H Ph O 350a 7 examples Yield = 73-93% ee = 85-99% C R O O 347 TiCl4 (20 mol%) CH2Cl2, 0 °C, 30 min + Ar OtBu N2 354 or Tf2NH (20 mol%) C2H5CN, –78 °C, 30 min CHO Ar tBuO2C R 355 29 examples Yield = 21-69% trans:cis = > 20:1 Given the reported reactions of α,β-unsaturated aldehydes described above, the thought then arose to attempt the reaction of an imine generated from α-substituted acroleins with ethyl diazoacetate in the presence of IMINO-BOROX catalyst. At this point, it must be remembered that we did obtain a conjugated imine 333o as the byproduct during the aziridination reaction of imine 110o with EDA (Table 6.3, entry 1-4). This was found to be one of the reasons for the low yields obtained from the aziridination reaction with aliphatic imines. We then thought to react the imine 333o with EDA, and surprisingly, we observed the [3+2] adduct 356o in 41% yield in the presence of IMINO-BOROX catalyst 357o. The asymmetric induction could not be measured. In HPLC analysis, multiple absorption peaks were observed, probably, due to the decomposition of the [3+2] adduct 356o. There was no sign of any aziridine from NMR analysis 467 of the crude reaction mixture. This was unexpected and lead to the discovery of a novel and unprecedented [3+2] cycloaddition reaction catalyzed by our IMINO BOROX catalyst derived from vaulted ligands. Scheme 6.6 [3+2] cycloaddition reaction between EDA and imine 328o Et Pr IMINO-BOROX catalyst 357o (10 mol%) O N DAM + OEt N2 333o 85 Toluene 25 °C, 48 h N NH EtO2C Et N DAM Pr 356o 41% y OPh DAM O B O – B O * N+ H O O B OPh R IMINO-BOROX catalyst 357o Et OH * Pr OH R (S)-VANOL Thereafter, as a part of optimization, we subjected the reaction of the imine derived from (E)-2-methylbut-2-enal 352b with ethyl diazoacetate 85 to different conditions (Table 6.6). Low yields were obtained with both VANOL and VAPOL catalysts when imine 359a, derived from MEDAM amine 126c, was employed (entries 1-2). However, imine 358a derived from BUDAM amine 126d gave the [3+2] adduct 360a in 59% yield and 50% ee using the VAPOL catalyst (entry 4). The results in the table show that the reaction performed with the VAPOL catalyst 468 gives a higher yield than the reaction with the VANOL catalyst (entry 4 vs. 3). There was no reaction observed in the absence of catalyst or in the presence of only (S)-VAPOL as the catalyst (entries 5-6). Not much improvement was observed upon changing the solvent to dichloromethane and performing the reactions at –78 °C (entries 7-10). Even lowering the concentration to 0.1 M did not assist in any improvement of the yield (entry 10). A common observation in the reactions in dichloromethane is that there was an unknown side-product 366a present in the reaction mixture. The structure of the unknown side-product is suspected to be cyclopropane, however, this was not confirmed. Table 6.6 Initial optimization of the [3+2] cycloaddition reaction. O N P + OEt 358a (P = BUDAM) 359a (P = MEDAM) N2 IMINO BOROX catalyst (10 mol%) 85 Solvent temp, 24h N NH N EtO2C preLigand (10 mol%) tolulene, 80 °C, 1 h catalyst then 05 mm Hg 80 °C, 0.5 h Imine IMINO-BOROX catalyst OH Ligand R 361a 361a 360a ee c (%) nd nd d 52 toluene 360a 59 25 toluene 360a <1 50 – BUDAM 25 toluene 360a <1 – BUDAM –78 CH2Cl2 360a 50 50 Cat. Ligand P 1 2 3 362a 363a 364a (S)-VANOL (S)-VAPOL (S)-VANOL MEDAM MEDAM BUDAM Temp (°C) 25 25 25 4 365a (S)-VAPOL BUDAM e 58 (S)-VAPOL only f – g 365a 7 * IMINO-BOROX catalyst OH Yield b (%) 35 33 34 # 6 P OPh P O B O – B O * N+ H O O B OPh R 360a (P = BUDAM) 361a (P = MEDAM) B(OPh)3 (4 equiv) H2O (1 equiv) 5 a Solvent Prod. toluene toluene toluene 25 BUDAM no catalyst (S)-VAPOL 469 d d Table 6.6 cont’d h 8 9 365a (S)-VAPOL BUDAM –78 CH2Cl2 360a 21 nd i 365a (S)-VAPOL BUDAM –78 CH2Cl2 360a 25 nd j 365a (S)-VAPOL BUDAM –78 CH2Cl2 360a 46 nd 10 a Unless otherwise specified, all reactions were performed with 10 mol% of catalyst with 0.20 mmol imine 358a/359a (1.0 equiv, 0.4 M in toluene) and 0.4 mmol of EDA 85 (2 equiv) b at room temperature. The pre-catalyst is made using method C (Chapter 2). The NMR yield 1 is determined by the H NMR spectra of the crude reaction mixture with Ph3CH as internal standard. c Determined by HPLC. d The sample was prepared by passing the crude product e through a plug of neutral Al2O3 using 10:1 hexanes:EtOAc as the eluent. The reaction was f g performed in presence of (S)-VAPOL only. No catalyst was used for the reaction. This reaction was allowed to warm to 25 ºC and then stirred for 15 min at 25 °C followed by h dilution with hexanes. Reaction time = 3 h. An unknown product 366a (40%) was observed along with 18% of unreacted imine 358a. j i A small amount of unknown side product 366a was observed. The concentration of the reaction is 0.1 M. A small amount of unknown side product 366a was also observed. To our delight, the [3+2] cycloaddition reaction was also found to give comparable results when the reaction was performed in a multicomponent fashion (Scheme 6.7). Scheme 6.7 Multicomponent [3+2] cycloaddition reaction. O O (S)-VAPOL (10 mol %) BUDAM B(OPh)3 (30 mol %) NH2 126d Toluene 80 °C, 0.5 h OEt 352a 4 Å MS N2 85 25 °C, 24 h N NH EtO2C N BUDAM 360a 60% y, 50%ee In an attempt to purify and isolate the product, we decided to either hydrolyze or reduce the resulting [3+2] adduct 360a which itself is an imine. Several conditions were tried for 470 hydrolysis, however, a complex mixture of products was obtained along with the BUDAM amine 1126d (Scheme 6.8A). Nonetheless, it was observed that the [3+2] adduct 360a can be easily reduced to amine 367a using NaBH4 (Scheme 6.8B). Scheme 6.8 Attempts towards the (A) hydrolysis of adduct 360a (B) reduction of adduct 360a. A Silica gel or neutral alumina 25 °C, 24 h 1M or 3M HCl N NH N EtO2C 25 °C, 24 h BUDAM-NH2 + complex mixture 126d BUDAM-NH2 + complex mixture 126d BUDAM 360a B NaBH4, EtOAc –78 °C to 0 °C 24 h N NH EtO2C H N BUDAM 367a 43% y, 50%ee (over two steps) In the end, an unprecedented multicomponent [3+2] cycloaddition has been discovered and presented here. The project is still in an infant state and has the potential to broaden the scope of our BOROX catalysis. Manzacidins 19a Hopefully, this methodology would provide an easy access to 23 and the family of bromopyrrole alkaloids namely, Clathramides. Also, it is worth mentioning that this work is a perfect example of why a crude NMR spectrum should never be ignored even if the reaction fails to give the desired product. 471 6.4 Attempts towards catalytic asymmetric Ugi 3CR, Ugi-type 2CR and Ugi-type 3CR. In the process of the broadening the scope of our BOROX catalyst, we decided to explore the possible applications of the catalyst on other asymmetric reactions. One of such reactions is the Ugi four component coupling reaction (Ugi-4CR). The Ugi-4CR is one of the most widely 24 used multicomponent reactions. An enantioselective variant of this fundamental reaction is still unknown. The Ugi reaction, discovered by Ivar Ugi in 1959, is classified as an isocyanidebased multicomponent reaction. 25 It allows the formation of an α-N-acylamino amide E (peptide derivatives) by the coupling of isocyanides D with carbonyl compounds (usually an aldehyde of type A), primary amine B and carboxylic acid C (Scheme 6.9X). It introduces a high degree of diversity yielding compounds which can serve as scaffolds for the synthesis of natural products, therapeutic agents, and combinatorial libraries. Mechanistically, the first step involves the condensation of aldehyde A and amine B, followed by the protonation of the imine F by acid C (Scheme 6.9Y). The next step involves the nucleophilic addition of isocyanide D to activated iminium G, followed by the trapping of the nitrilium species H by the carboxylate anion. The final irreversible acyl transfer (known as the Mumm rearrangement) results in the formation of the α-N-acylamino amide E. Scheme 6.9 (X) Ugi-4CR reaction (Y) Proposed mechanism X O R1 A + H H2N R2 B + O H + R3 O – C + N D C 472 O Ugi-4CR R4 R3 R1 N R2 O E H N R4 Scheme 6.9 cont’d Y O R1 H A + H2N R2 N R2 R1 –H2O N R1 B O R3 O H N R4 H R2 O C R3 H R1 H F R2 H G – C + N 4 R D O H R2 – N R3 O + R1 N 4 R R2 R3 H 1) Mumm N Rearrangement O 1 O 2) Proton transfer R N O E N R4 I H It was thus envisioned to examine the reaction using our IMINO-BOROX catalyst 104a or chiral VAPOL phosphoric acid 35 (Scheme 6.10). The proposed Ugi reaction would involve the pre-formed imine F instead of an amine and aldehyde, thereby making it as a three component coupling (3CR) instead of four component coupling (4CR). Scheme 6.10 Proposed Ugi-3CR N R1 R2 + H F O H O C Ph Ph + R3 – C + N IMINO-BOROX catalyst R4 R3 N * R2 O or VAPOL-PO3H D OPh P O B O– N+ B O H O O B R OPh 104a IMINO-BOROX catalyst 473 Ph Ph R1 O E O O O P OH 35 (S)-VAPOL-PO3H H N R4 Finding a chiral inductor or catalyst for Ugi reaction would represent a major achievement not only for organic synthesis but also for the pharmaceutical industry. As stated by Ugi, “until today the problem of control of the newly formed stereocenter has not been solved conclusively”. 6.4.1 24d Thus, the aim of this project is to find a chiral variant of the Ugi reaction. Attempts towards catalytic asymmetric Ugi -3CR In the initial screening, the Ugi-3CR reaction was performed using benzoic acid 334a and t-butyl isocyanide 368a. The results are summarized in Table 6.7 (entries 1-5). A 20% yield of amide 369a was obtained in the absence of any kind of catalyst (entry 1). The background reaction must have been facilitated by the benzoic acid as the promoter of the reaction. In the first experiment using 10 mol% IMINO-BOROX catalyst 190a, an increase in the yield (40%) was observed at room temperature (entry 2). Unfortunately, no enantioselectivity was observed. As the carboxylic acid itself can catalyze the Ugi reaction, it was then thought that the uncatalyzed background reaction might be competing with the asymmetric reaction. In order to suppress the background reaction, if any, a stoichiometric amount of the catalyst was used. The 1 H NMR analysis of the crude reaction mixture shows no sign of the desired product (entry 3). Even the slow addition of the carboxylic acid 334a over a period of 3 h did not bring any change in the outcome (entry 4). Meanwhile, an 8% yield of the racemic product 369a was obtained when (R)-VAPOL phosphoric acid 35 was employed as the Brønsted acid catalyst (entry 5). It must be noted that compound 370a, which could result from the reaction of imine 119a and isocyanide 368a, has not been observed in the first five entries of the Table 6.7. 474 Table 6.7 Preliminary results towards the Ugi-3CR reaction. IMINO-BOROX catalyst 190a or VAPOL-PO3H 35 (x mol%) Ar – Ar + C + N N Ph R4 Toluene, T °C, t h R3 Ar O O N * Ar Ph 369 368 111a a H O N * R4 R4 + Ar N N H H Ar Ph 370 O + R3 Ar = 3,5-Me2-4-OMe-C6H4 Ar2CH = MEDAM H O 334 Product Yield 369 b (%) ee 369 c (%) # R R Temp Cat. x mol% 1 Ph tBu 25 none 369a 20 – 2 Ph tBu 25 10 369a 40 <1 3 Ph tBu 25 100 369a <1 – d Ph tBu 25 100 369a <1 – e Ph tBu 25 20 369a 8 <1 4-pentylbicyclo [2.2.2]octyl 2-Naphthyl 25 none 369b <1 – 4-pentylbicyclo [2.2.2]octyl 2-Naphthyl 25 10 369b <1 – 8 4-pentylbicyclo [2.2.2]octyl 2-Naphthyl 25 20 369b <1 – 9 4-pentylbicyclo [2.2.2]octyl 2-Naphthyl 40 20 369b <1 – 4 5 3 6 7 f 4 a Unless otherwise specified, all reactions were performed with x mol% of catalyst 190a with 0.50 mmol imine 111a (1.0 equiv, 0.3 M in toluene), 0.5 mmol acid 334 (1.0 equiv) and 0.5 mmol of isocyanide 368 (1.0 equiv) at room temperature. The acid component 334 was added after 5 min of the addition of the isocyanide 368. PhCOOH was sublimed prior to use. b c d Ar2CH = MEDAM. Isolated Yield. Determined by HPLC. The acid component 334a was added slowly over a period of 3 h via syringe pump. the catalyst. Reaction time = 48 h. f e (R)-VAPOL-PO3H 26% yield of 370b was isolated . 475 35 was used as In order to suppress the background reaction, it was envisioned to utilize a weaker acid than benzoic acid. Hence, 4-pentylbicyclo[2.2.2]octane-1-carboxylic acid 334b (pKa of bicyclo[2.2.2]octane-1-carboxylic acid = 6.75) 26 was examined. At the same time, the isocyanide component was switched to a weak and unreactive 2-napthyl isocyanide 368b. As expected, there was no reaction observed in the absence of the catalyst (Table 6.7, entry 6). A complex mixture of six different compounds was obtained when the reaction was performed with 10 mol% IMINO-BOROX catalyst 190a (entry 7). One of the fractions was isolated as an 1 orange solid 370b (72 mg, 26%). The H NMR analysis of this compound revealed the absence of the acid component suggesting that this compound could be a product of imine 111a and 2naphthyl isocyanide 368b. The compound was then completely characterized (see experimental). The asymmetric induction of 370b was found to be 8% ee. The next two reactions were attempted with 20 mol % catalyst, one at room temperature and the other at 40°C 1 (entries 8-9). The H NMR spectrum of both the crude reaction mixtures were very much similar to that of the reaction with 10 mol% catalyst. 6.4.2 Attempts towards catalytic asymmetric Ugi-type 2CR and Ugi-type 3CR We have seen that α−amino amide 370b (Table 6.7, entry 7 and Table 6.8, entry 1) is formed, possibly, due to the reaction between imine 111a and isocyanide 368b. Based on this observation, we decided to examine an Ugi-type two-component reaction (Ugi-type-2CR) as shown in Scheme 6.11. Unfortunately, no α−amino amide 370 or 371 was observed when imine 476 111a or 78a was reacted with isocyanides 368a or 368b using our IMINO-BOROX catalyst (Table 6.8, entries 2-4). The starting materials were recovered instead. Scheme 6.11 Proposed Ugi-type 2CR N R1 R2 – C + N + H F IMINO-BOROX catalyst or VAPOL-PO3H R4 R2 Ugi-type-2CR D Table 6.8 Preliminary results towards the Ugi-2CR and Ugi-3CR. O R1 + R2 H 127 2 3 4 5 6 7 a R3 – C + N + 126 Ugi-type-2CR or Ugi-type-3CR 368 * N H R1 J R4 a (S)-VAPOL-B(OPh)3 catalyst (20 mol%) R4 O R2 R3 O N * R1 N H R4 370 (R3=H; R2=MEDAM) 371 (R3=H; R2=CHPh2) 372 (R3=Bn; R2=Bn) 370b Yield b (%) 26 ee c (%) 8 2-naphthyl 370b <1 – H tBu 370a <1 – Ph2CH H tBu 371a <1 Ph H tBu 371a f Ph2CH <1 (<1) Ph PhCH2 tBu 372a f PhCH2 74 (44) Ph PhCH2 PhCH2 tBu 372a 76 (72) # 1 N H H N 1 2 3 4 R R R R Product d,e Ph MEDAM H 2-naphthyl d Ph MEDAM H d Ph MEDAM d Ph – g h i – (–) g 17 (19) 18 (40) h i Unless otherwise specified, all reactions were performed with 20 mol% of (S)-VAPOL- B(OPh)3 catalyst with 0.50 mmol amine 126 (1.0 equiv, 0.1 M in toluene), 0.50 mmol aldehyde 127 (1.0 equiv) and 0.50 mmol of isocyanide 368 (1.0 equiv) at room temperature for 24 h. The (S)-VAPOL-B(OPh)3 catalyst was prepared by heating 1 equiv of (S)-VAPOL, 4 equiv of B(OPh)3 and 1 equiv of H2O in toluene at 80 °C for 1 h, followed by removing all volatiles under high vacuum (0.1 mm Hg) for 0.5 h at 80 °C. 477 b Isolated Yield. c Determined Table 6.8 cont’d by HPLC. d Reaction performed with pre-formed imines 78a and 111a. d 0.50 mmol of acid 334b also added to the reaction mixture; same as entry 7 of Table 6.7. f g Yield/ee in parenthesis is given for the reaction performed in presence of 4 Å MS. Ratio of 126:127:368 = 2:1:1.5. Reactions were performed by Li Huang. reaction performed in presence of 3 Å MS. i h Yield/ee in parenthesis is given for the Yield/ee is given for the reaction where the catalyst was prepared by 1 equiv of (S)-VAPOL, 3 equiv of BH3•Me2S, 2 equiv of phenol and 3 equiv of H2O in toluene at 100 °C for 1 h, followed by removing all volatiles under high vacuum (0.1 mm Hg) for 0.5 h at 100 °C. Yield/ee in parenthesis is given for the reaction where 2 equiv of 2,4,6-Me3-C6H2OH is used for the catalyst preparation. While the current work was in progress, List and co-workers reported an example of a catalytic achiral three-component Ugi-type reaction between an amine 126, aldehyde 127 and 27 isocyanide 368. Although p-methoxyaniline was their optimized amine, they did screen benzhydryl amine 126c to afford 373b in 36% yield when benzaldehyde 127a and tert-butyl isocyanide 368a were used as the other components (Scheme 6.12). However, they were able to obtain an asymmetric induction up to 18% only when they utilized 3,3ʹ′-TRIP-BINOL-PO3H 27 376. 27 Scheme 6.12 Catalytic Ugi-type three-component reaction. O Ph H 127a + H2N R2 + 126 – C + N catalyst 374 or 375 or 376 (10 mol%) tBu Toluene, 80 °C 368a 478 O H tBu N * N R2 Ph H 373 Scheme 6.12 cont’d iPr iPr iPr O O P H O HO O P H HO O O P O OH iPr 374 iPr 375 iPr 376 R2 catalyst % yield % ee PhCH2 Ph2CH 4-MeO-C6H4 4-MeO-C6H4 4-MeO-C6H4 374 374 374 375 376 42 36 91 90 15 – – – 04 18 The work reported by List and coworkers prompted us to screen our proposed Ugi-2CR reaction as a Ugi-3CR reaction starting from an amine and an aldehyde instead of an imine. This was important, as water is ostensibly needed as the nucleophile to attack the nitrilium ion. However, no desired product 371a was obtained even when the reaction was done in a multicomponent fashion (Table 6.8, entry 5). To our surprise and delight, Li Huang, a former group member, was able to obtain the α-amino amide 372a when a secondary amine 126h was 28 used instead of a primary amine (entries 6-7). However, the asymmetric induction was found only to be 18%. After a lot of initial optimization, an improved result of 40% ee was obtained. Based on the failure of the reaction with a primary amine and success with secondary amine, a mechanism involving an aminal intermediate has been proposed. A detailed discussion can be 29 found in Li Huang’s dissertation. It must be noted that there are some secondary amine related 479 Ugi-type three-component reactions in both racemic List’s work. and asymmetric 31 forms reported prior to Recently, Maruoka and coworkers reported a catalytic asymmetric Ugi-type reaction involving azomethine imines. 6.5 30 32 Attempts towards catalytic asymmetric Passerini reaction One of the early examples of a multicomponent reaction is the Passerini reaction. 33 It is a three-component reaction involving an aldehyde, acid and an isocyanide resulting in the formation of the acyloxycarboxamides (Scheme 6.13X). Apart from diastereoselective Passerini reactions, there have been few reports of asymmetric versions of this reaction. 34 A few of Passerini-type reactions have also been reported where the acid component has either been left 35 out or been replaced by acids other than carboxylic acids. 34c Wang and and co-workers, 36 Prior to the work reported by all the reported examples needed an aldehyde with at least one chelating site. Hence, it was then thought to examine VAPOL phosphoric acids to find a general asymmetric Passerini reaction. The reaction involving benzaldehyde 127a, benzoic acid 334a and tert-butyl isocyanide 368a afforded acyloxycarboxamide 377a in 35% yield and 6% ee (Scheme 6.13Y). Due to time constraints, this reaction was not studied further. Scheme 6.13 (X) Passerini reaction (Y) Attempts towards the asymmetric Passerini reaction. X O R1 A + H O H + R3 O C – C + N Passerini R4 O R3 R1 O * O K D 480 H N R4 Scheme 6.12 cont’d Y O O + + H H Ph Ph O 127a 334a – C + N catalyst 35 (20 mol%) Toluene 80 °C, 48 h tBu O Ph Ph O * H N tBu O 368a 377a 35% y, 6% ee Ph Ph O O O P OH 35 (S)-VAPOL-PO3H 6.6 Attempts towards kinetic resolution of imines Up to this point, we have performed the aziridination reaction between imines derived from achiral amines and EDA 85 using IMINO-BOROX catalysts. It would be interesting to see the effect of chiral imines on the catalytic asymmetric aziridination reaction. The reaction with chiral imines would present an opportunity for the matched and mismatched cases. Chiral imines can be prepared either by using chiral aldehydes with achiral amines or by using chiral amines and achiral aldehydes. The former case has been examined by a current group member namely Munmun Mukherjee and she found that the reaction is primarily a catalyst controlled 37 reaction. The latter study had been initiated by Dr. Yu Zhang, a former group member, and was studied in detail by another former group member, namely Li Huang. 38 During the studies of aziridination reaction performed with chiral imine (S)-378, Dr. Yu Zhang found a strong 38 matched and mismatched case depending upon the ligand used (Table 6.9). 481 As shown in Table 6.9, the matched case is where the (S)-enantiomer of the imine is matched with the (R)enantiomer of the ligand (R with S and S with R). Only a single diastereomer 380 was obtained in the matched case. For the mismatched case, the diastereomeric ratio was found to be 69:31 and 52:48 in the case of the VAPOL and VANOL catalysts, respectively. Nonetheless, the presence of such a strong matched case prompted us to examine this reaction in more detail as it might provide an access to chiral imines/amines via possible kinetic resolution of racemic imines/amines. Table 6.9 Matched and mis-matched aziridinations of the phenylneopentyl imine (S)-378. a IMINO-BOROX Ph tBu Ph tBu Ph catalyst O tBu tBu NH (10 mol %) + + N N Ph + CO2Et OEt N (Ph)H CCl4 Ph N2 CO2Et Ph CO2Et Ph Ph(H) 25 °C, 24 h (S)-378 85 379 B(OPh)3 (3 equiv) pre-catalyst Ligand (10 mol%) tolulene, 80 °C, 1 h then 05 mm Hg 80 °C, 0.5 h # Ligand 379 : 380 1 2 3 4 5 (S)-VAPOL (R)-VAPOL (S)-VANOL (R)-VAPOL 69 : 31 <2 : 98 52 : 48 <2 : 98 B(OPh)3 only Yield 379 c (%) 56 d <2 36 d <2 nd b 8 : 92 a 381(382) 380 Imine (S)-378 IMINO-BOROX catalyst Yield 380 d (%) 25 c 80 33 c 85 nd Enamines d (%) nd <2 11/2 <2 nd This set of data is taken from thesis of Dr. Yu Zhang. Unless otherwise specified, all reactions were performed with 10 mol% of IMINO-BOROX catalyst with 1 mmol imine (S)378 (1.0 equiv, 0.5 M in toluene) and 1.1 mmol of EDA 85 (1.1 equiv) at room temperature for 24 h. The pre-catalyst catalyst was prepared by heating 1 equiv of ligand and 3 equiv of B(OPh)3 in toluene at 80 °C for 1 h, followed by removing all volatiles under high vacuum (0.1 mm Hg) for 0.5 h at 80 °C. nd = not determined. The cis:trans selectivity was >50:1 in b 1 c all cases. Determined from the H NMR spectrum of the crude reaction mixture. Isolated d 1 Yield. Yield from H NMR spectrum of the crude reaction mixture and based on the isolated yield of 379 or 380. 482 There are not many methods available for kinetic resolution of amines. Most of the methods are based on the utilization of the enzymes. 39 In terms of asymmetric methods using catalysts other than enzymes, the normal practice is the selective derivatization of the amines, usually by an acetyl-transfer reagent. 40 Based on the results obtained from diastereoselective aziridination reaction, it was envisioned that a protocol for kinetic resolution of imines could possibly be developed. Hence it was then proposed that the reaction between racemic imine rac378 and a substoichiometric amount of EDA, in presence of catalyst derived from (S)-ligand, would lead to the chiral aziridine ent-380 and chiral amine (S)-384 after the hydrolysis of the unreacted imine (S)-378 (Scheme 6.14A). Hence, the experiments related to the proposed kinetic resolution were performed and presented in Table 6.10 and 6.11. The s-factor was calculated based on the equation given in Scheme 6.14B. The s-factor is equal to the ratio of the rate of faster reacting enantiomer and the rate of slower reacting enantiomer. 41 Scheme 6.14 (A) Proposed Kinetic resolution of imine rac-378. (B) Equation for the calculation of s factor. A O tBu Ph N rac-378 1 IMINO-BOROX catalyst (from (S)-Ligand) (10 mol %) solvent, 25 °C, 24 h Ph + tBu N OEt N2 2 Hydrolysis Ph Ph + CO2Et ent-380 85 (0.5 equiv) 483 tBu Ph NH2 (S)-384 Scheme 6.14 cont’d B s= ln [(1–C)(1– eeSM)] ln [(1–C)(1+ eeSM)] C = eeSM / eeSM + eeP eeSM = ee of the unreacted starting material eeP = ee of the product formed In the first experiment, the reaction between rac-378 and 0.5 equiv of EDA afforded the chiral aziridine ent-380 in 33% yield and 94% ee (Table 6.10, entry 2). The diastereomeric ratio of ent-380:379 was found to be 20:1. Subsequent hydrolysis of the unreacted imine (S)-378 by dilute HCl resulted in chiral amine (S)-384 in 34% yield and 66% ee (Table 6.10, entry 2). The s-factor calculated according to equation in Scheme 6.14B is 43 (C = Conv = 42). The observed ee of the amine (S)-384 was moderate and was found to be directly proportional to the amount of the EDA used (Table 6.10, entries 1-3). However, the yield of (S)-384 was substantially decreased as the equiv of EDA was increased. However, this survey was conducted with carbon tetrachloride as solvent. Since we have subsequently found that toluene is in many respects superior to carbon tetrachloride for the AZ reaction, 9a we decided to re-examine the possibility of kinetic resolution where toluene as the solvent. Also, we decided to protect the resultant amine (S)-384 with Boc2O in order to avoid any loss in the yield during the isolation of the amine. 484 42 Table 6.10 Kinetic resolution of phenylneopentyl imine rac-378 furnishing amine (S)-384. O tBu Ph Ph + N OEt 2 0.4 N HCl/THF 25 °C, 2.5 h N2 rac-378 1 IMINO-BOROX catalyst (from (S)-VAPOL) (10 mol %) CCl4, 25 °C, 24 h tBu Ph tBu N Ph CO2Et ent-380 85 (x equiv) Ph N + Ph a CO2Et 379 tBu + Ph NH2 (S)-384 B(OPh)3 (3 equiv) (S)-VAPOL (10 mol%) tolulene, 80 °C, 1 h then 05 mm Hg 80 °C, 0.5 h # EDA (x equiv) 1 2 3 0.4 0.5 0.6 Conv 32 50 51 b Yield ent-380 c (%) 30 33 41 pre-catalyst ee ent-380 (%) d 94 94 94 Imine rac-378 IMINO-BOROX catalyst Yield 384 c (%) ee 384 d (%) 38 34 26 48 66 80 ent-380:379 e 50:1 20:1 13:1 a Unless otherwise specified, all reactions were performed with 10 mol% of IMINO-BOROX catalyst (derived from (S)-VAPOL) with 1 mmol imine rac-378 (1.0 equiv, 0.5 M in toluene) and x mmol of EDA 85 (x equiv) at room temperature for 24 h. The pre-catalyst catalyst was prepared by heating 1 equiv of ligand and 3 equiv of B(OPh)3 in toluene at 80 °C for 1 h, b followed by removing all volatiles under high vacuum (0.1 mm Hg) for 0.5 h at 80 °C. Percent conversion is determined by integration of the methine proton of cis-aziridine relative 2 1 to the sp -CH proton of the unreacted imine rac-378 in the H NMR spectrum of the crude reaction mixture. e c Isolated yield after chromatography on silica gel. 1 d Determined by HPLC. Determined from the H NMR spectrum of the crude reaction mixture. 485 As discussed earlier, the AZ reaction was performed in toluene with 0.5 equiv of EDA and it resulted in chiral aziridine ent-380 in 35% yield and 97% ee (Table 6.11, entry2). The diastereomeric ratio of ent-380:379 was found to be 10:1 which is a little lower than in CCl4 (Table 6.10). After hydrolysis of imine (S)-378 and subsequent protection of the resulting amine, the Boc protected amine (S)-385 was obtained in 44% yield and 54% ee (Table 6.11, entry 2). The s-factor calculated according to equation in Scheme 6.14B is 84 (C = Conv = 36). Although a high s-factor was observed in this case, the overall trend is similar to that in Table 6.10, i.e. the ee of the amine (S)-385 was moderate and directly proportional to the amount of the EDA used (Table 6.11, entries 1-4). It must be pointed out that the isolation of amine after boc protection has greatly simplified the analysis and no column chromatography is needed, as the resulting amine is quite pure. Hence, this project needs a little more optimization in order to increase the enantioselectivity of the amine (S)-385. Table 6.11 Kinetic resolution of phenylneopentyl imine rac-378 furnishing amine (S)-385. O tBu Ph N rac-378 1 IMINO-BOROX catalyst (from (S)-VAPOL) (10 mol %) Toluene, 25 °C, 24 h Ph + tBu 85 (x equiv) 2 0.4 N HCl/THF 25 °C, 3 h tBu N OEt N2 Ph 3 Boc2O, H2O 25 °C, 3 h CO2Et Ph ent-380 CO2Et 379 tBu + Ph N + Ph Ph NHBoc (S)-385 B(OPh)3 (4 equiv) H2O (1 equiv) (S)-VAPOL (10 mol%) tolulene, 80 °C, 1 h then 05 mm Hg 80 °C, 0.5 h pre-catalyst 486 Imine rac-378 a IMINO-BOROX catalyst Table 6.11 cont’d # 1 2 3 4 EDA (x equiv) 0.4 0.5 0.6 0.7 Conv 36 44 54 61 b Yield ent-380 c (%) 28 35 45 50 ee ent-380 Yield 385 d e (%) (%) 97 54 97 44 96 34 (32) 97 26 ee 385 d (%) 43 54 77 89 ent-380:377 f 10:1 10:1 10:1 8:1 a Unless otherwise specified, all reactions were performed with 10 mol% of IMINO-BOROX catalyst (derived from (S)-VAPOL) with 1 mmol imine rac-378 (1.0 equiv, 0.5 M in toluene) and x mmol of EDA 85 (x equiv) at room temperature for 24 h. The pre-catalyst catalyst was prepared by heating 1 equiv of ligand and 4 equiv of B(OPh)3 and 1 equiv of H2O in toluene at 80 °C for 1 h, followed by removing all volatiles under high vacuum (0.1 mm Hg) for 0.5 h b at 80 °C. Percent conversion is determined by integration of the methine proton of cis2 1 aziridine relative to the sp -CH proton of the unreacted imine rac-378 in the H NMR c d spectrum of the crude reaction mixture. Isolated yield after chromatography on silica gel. Determined by HPLC. e Isolated yield after purification by extraction. Yield in parenthesis is f the isolated yield after purification by chromatography on silica gel. Determined from the 1 H NMR spectrum of the crude reaction mixture. 6.7 Conclusions The present chapter includes some failed and some successful catalytic asymmetric reactions. Nonetheless, this chapter serves as the stepping-stone towards the broadening of the scope of the unique BOROX catalysis developed in the Wulff group. Hopefully, reactions like [3+2] cycloadditions, Ugi-type reactions and kinetic resolution of imines will be developed in near future and thereby expanding the breath of our catalyst system. Additionally, two more reactions have been developed using the indirect IMINO-BOROX catalysis and SULFOXBOROX catalysis respectively and these are the first true multicomponent aziridination reaction (Chapter 7) and the asymmetric epoxidation of aldehydes (Chapter 8) 487 APPENDIX 488 6.8 Experimental 6.8.1 General information ....................................................................................................... 490 6.8.2 Synthesis of amines 126b and rac-384 and imines 110a-w, 111a, 333o, 358a, 359a and rac-378 .......................................................................................................................... 490 6.8.3 Different procedures for aziridination with imine 110g (Table 6.1 and Scheme 6.2) ... 503 6.8.4 Synthesis of aziridines 113g (Table 6.2-6.3) ................................................................. 509 6.8.5 [3+2] cycloaddition of imine 333o, 358a and 359a (Scheme 6.6 and Table 6.6) .......... 519 6.8.6 Multicomponent [3+2] cycloaddition of aldehyde 352a (Scheme 6.7).......................... 523 6.8.7 Hydrolysis and reduction of [3+2] adduct 360a (Scheme 6.8) ...................................... 524 6.8.8 Attempts towards catalytic asymmetric Ugi 3CR, Ugi -type 2CR and Ugi -type 3CR and Passerini reaction (Table 6.7-6.8 and Scheme 6.13) ..................................................... 526 6.8.9 Attempts towards kinetic resolution of imines (Table 6.10-6.11) ................................. 533 489 6.8.1 General Information Same as Chapter 2 6.8.2 Synthesis of amines 126b and rac-384 and imines 110a-w, 111a, 333o, 358a, 359a and rac-378 a) Synthesis of DAM amine 126b MeO MeO OMe OMe LiAlH4, THF, 0 ºC then reflux, 12 h OH O 331 332 1) MsCl, TEA –78 ºC to –20 ºC 40 min MeO OMe 2) NH3 (Liq.) –78 ºC to 25 ºC 20 h NH2 126b Bis(4-methoxyphenyl)methanol 332: To a 500 mL flame-dried round bottom flask filled with argon was added LiAlH4 (3.3 g, 88 mmol) and dried THF (250 mL) in an ice bath followed by stirring for 1 h. Simultaneously, 4,4'-dimethoxyl benzophenone 331 (19.4g, 80.0 mmol) and dried THF (350 mL) was added in a separate 1000 mL flame-dried round bottom flask filled with argon at 0 ºC. LiAlH4 solution has been transferred to the ketone solution via cannula under the argon pressure. The flask containing LiAlH4 solution was washed with dry THF (25 mL × 2). The reaction mixture was stirred at room temperature for 4 h followed by reflux for 12 h. The 490 reaction was cooled to room temperature and then to 0 ºC. To the reaction mixture was added dropwise H2O (3.5 mL), 4 N NaOH (3.5 mL) and H2O (8.8 mL). The reaction mixture was further diluted by adding Et2O (300 mL). The reaction mixture was then filtered through Celite and the Celite bed was washed with CH2Cl2 (10 mL × 3). The filtrate was dried using anhydrous MgSO4, filtered and concentrated in vacuo to afford the crude alcohol. Purification by silica gel chromatography (1:2 EtOAc/hexanes as eluent) afforded 332 as white solid (mp. 6970 ºC) in 95% yield (18.6 g, 76.0 mmol). 1 Spectral data for 332: Rf = 0.42 (1:3 EtOAc/hexanes); H NMR (CDCl3, 300 MHz) δ 2.08 (d, 1H, J = 2.3 Hz), 3.76 (s, 6H), 5.76 (d, 1H, J = 2.3 Hz), 6.84 (d, 4H, J = 9.0 Hz), 7.25 (d, 4H, J = 8.8 Hz); 13 C (CDCl3, 75 MHz) δ 55.22, 75.30, 113.79, 127.76, 136.47, 158.91. These spectral 43 data match those previously reported for this compound. Bis(4-methoxyphenyl)methylamine 126b: To a 500 mL flame-dried three-neck round bottom flask equipped with a condenser filled with argon was added 4,4'-dimethoxybenzhydrol 332 (19.1 g, 78.2 mmol) and THF (250 mL). Et3N (10.3 g, 101.7 mmol) was added dropwise at –78 °C followed by dropwise addition of mesylchloride (11.62 g, 101.7 mmol) via syringe with vigorous stirring. The mixture was warmed up to –20 ºC and stirred for 40 min at this temperature, then cooled to –78 ºC. Gaseous ammonia was introduced at a rate such that a dryice cooled condenser provided steady drop-wise addition of liquid NH3 and this addition was continued for a period of 20 min. The reaction mixture was allowed to warm gradually to 491 ambient temperature after which it was stirred for an additional 20 h. The reaction was quenched by the addition of concentrated NH4OH (200 mL) then extracted with EtOAc (100 mL × 3). The combined organic layer was dried over anhydrous MgSO4 and concentrated in vacuo to afford crude amine as a white solid. The amine 126b was purified by chromatography on a column (65 mm × 400 mm, with pre-neutralized (2% Et3N) silica gel, 1:1 EtOAc/hexanes as eluent). An initial band containing a yellow impurity along with a small amount of alcohol 332 was discarded and elution continued to give the product 126b as white solid (mp. 60-61ºC) in 79% yield (15 g, 62 mmol). 1 Spectral data for 126b: Rf = 0.17 (1:1 hexanes/EtOAc). H NMR (CDCl3, 300 MHz) δ 1.78 (br s, 2H), 3.82 (s, 6H), 5.18 (s, 1H), 6.90 (d, 4H, J = 8.8 Hz), 7.33 (d, 4H, J = 8.5 Hz); 13 C (CDCl3, 75 MHz) δ 55.14, 58.39, 113.67, 127.74, 138.11, 158.35. These spectral data match those 11 previously reported for this compound. b) Synthesis of amine rac-384 PhMgBr, Et2O CN LiAlH4, THF reflux, 4 h then reflux, 20 h NMgBr 382 383 NH2 rac-284 α-tert-butylbenzylamine rac-384: To a 250 mL flamed-dried three-neck round bottom flask filled with argon was added PhMgBr 309 (20 mL, 60 mmol, 3M in Et2O) and dry Et2O (40 mL) via syringe. Trimethyl acetonitrile 382 (4.24 g, 50.0 mmol) was added to the flask drop-wise via 492 syringe with the stirring of the Grignard reagent. The solution was the heated to reflux after addition was complete. After 4 h, a solution of LiAlH4 (2.4 g, 60.0 mmol) in dry THF (40 mL) was transferred to the reaction flask via cannula. The solution was then heated and refluxed for another 20 h. After 20 h, the solution was allowed to cool to room temperature. To the flask was carefully added H2O (2.5 mL), 20% NaOH solution (2.5 mL) and then H2O (7.5 mL) in an ice bath. The white mud-like mixture was then filtered, the residue was washed with Et2O until there was no presence of detectable amine in the filtered Et2O (monitored by TLC spotting). The ether layer was dried over anhydrous Na2SO4. It was then filtered and concentrated in vacuo to give a light yellow liquid as the crude product. Purification by distillation furnished rac-384 (bp. 47 – 48 °C at 0.15 mm Hg) as a colorless oil in 80% yield (6.53 g, 40 mmol). 1 Spectral data for rac-384: H NMR (CDCl3, 300 MHz) δ 10.89 (s, 9H), 1,42 (brs, 2H), 3.69 (s, 1H), 7.20-7.29 (m, 5H); 13 C NMR (CDCl3, 75 MHz) δ 26.42, 34.89, 65.20, 126.60, 127.37, 44 128.13, 143.68. These spectral data match those previously reported for this compound. c) Synthesis of imines 110a-w, 111a, 333o, 358a, 359a and rac-378 All liquid aldehydes were distilled before use and the solid aldehydes were used as purchased from Aldrich. 493 General Procedure for the synthesis of aldimines – Illustrated for the synthesis of Nbenzylidene-bis-(4-methoxyphenyl)methylamine 110a. OMe MeO O MgSO4 + OMe H2N 127a CH2Cl2 25 °C, 24 h N OMe 110a 126b N-benzylidene-bis-(4-methoxyphenyl)methylamine 110a: To a 50 mL flame-dried round bottom flask filled with argon was added DAM amine 126b (2.43 g, 10.00 mmol), MgSO4 (2.0 g, 16.7 mmol, freshly flame-dried) and dry CH2Cl2 (30 mL). After stirring for 10 min, benzaldehyde 127a (1.07 g, 10.1 mmol, 1.01 equiv) was added. The reaction mixture was stirred at room temperature for 24 h. The reaction mixture was filtered through Celite and the Celite bed was washed with CH2Cl2 (10 mL × 3) and then the filtrate was concentrated by rotary evaporation to give the crude imine as an off-white solid. Crystallization (1:25 CH2Cl2/hexanes) and collection of the first crop afforded 110a as white solid crystals (mp. 60-61 °C) in 91% isolated yield (3.02 g, 9.1 mmol). 1 Spectral data for 110a: H NMR (CDCl3, 300 MHz) δ 3.76 (s, 6H), 5.51(s, 1H), 6.84 (d, 4H, J = 8.8 Hz), 7.25-7.27 (m, 4H), 7.37-7.40 (m, 3H), 7.79–7.82 (m, 2H), 8.37 (s, 1H); 494 13 C (CDCl3, 75 MHz) δ 55.17, 76.55, 113.71, 128.35, 128.43, 128.61, 128.70, 130.60, 136.28, 158.43, 160.24. These spectral data match those previously reported for this compound. 11 N-(1-naphthylidene)-bis(4-methoxyphenyl)methylamine OMe 110b: Imine 110b was prepared according to the procedure described above for imine 110a. Crystallization (1:8 N OMe 110b CH2Cl2/hexanes) and collection of the first crop afforded 110b as white solid (mp. 92.5-93.5 ºC) in 82% isolated yield (3.12 g, 8.20 mmol). 1 Spectral data for 110b: H NMR (CDCl3, 300 MHz) δ 3.77 (s, 6H), 5.60 (s, 1H), 6.86 (d, J = 8.8 Hz, 4H), 7.35 (d, J = 8.5 Hz, 4H), 7.47-7.58 (m, 3H), 7.85-7.95 (m, 3H), 9.02 (s, 1H), 9.09 (d, J = 8.5 Hz, 1H); 13 C (CDCl3, 75 MHz) δ 55.20, 77.98, 113.79, 113.88, 124.68, 125.16, 125.98, 127.16, 128.56, 128.65, 128.74, 129.66, 131.10, 133.81, 136.48, 158.48, 160.35. These spectral data match those previously reported for this compound. 11 N-(o-tolylbenzylidene)-bis(4-methoxyphenyl)methylamine OMe 110c: Imine 110c was prepared according to the procedure Me described above for imine 110a. Crystallization (1:8 CH2Cl2 / N OMe 110c hexanes) and collection of the first crop afforded 110c as white solid crystals (mp 64-65 ºC) in 80% isolated yield (2.76 g, 8.00 mmol). 495 1 Spectral data for 110c: H NMR (CDCl3, 300 MHz) δ 2.55 (s, 3H), 3.78 (s, 6H), 5.53 (s, 1H), 6.88 (d, J = 8.8 Hz, 4H), 7.14-7.16 (m, 1H), 7.21-7.25 (m, 2H), 7.29 (d, J = 8.5 Hz, 4H), 7.957.98 (m, 1H), 8.72 (s, 1H); 13 C (CDCl3, 75 MHz) δ 19.64, 55.21, 77.41, 113.73, 126.02, 128.28, 128.55, 130.15, 130.78, 134.22, 136.57, 137.79, 158.43, 159.09. These spectral data match those previously reported for this compound. 11 N-(4-methylbenzylidene)-bis(4-methoxyphenyl) methyl OMe amine 110d: Imine 110d was prepared according to the procedure described above for imine 110a. Crystallization N Me OMe 110d (1:5 CH2Cl2 / hexanes) and collection of the first crop afforded 110d as white solid crystals (mp 110-111 ºC) in 94% isolated yield (3.24 g, 9.40 mmol). 1 Spectral data for 110d: H NMR (CDCl3, 300 MHz) δ 2.36 (s, 3H), 3.76 (s, 6H), 5.50 (s, 1H), 6.84 (d, J = 8.8 Hz, 4H), 7.19 (d, J = 7.8 Hz, 2H), 7.28 (d, J = 8.3 Hz, 4H), 7.70 (d, J = 8.0 Hz, 2H), 8.34 (s, 1H); 13 C (CDCl3, 75 MHz) δ 21.48, 55.24, 76.51, 113.76, 128.39, 128.69, 129.20, -1 133.85, 136.50, 140.89, 158.49, 160.19; IR (thin film, cm ) 2834 m, 1638 m, 1609 m, 1509 vs, + 1246 vs, 1171 s, 1035 s, 815 w; Mass spectrum, m/z (% rel intensity) 345 M (2), 227 (100), 212 (30), 169 (41), 141 (39), 115 (31). HRMS calcd for C23H24NO2 (M+H) m/z 346.1807, mass 346.1816. These spectral data were not reported before. 496 N-(4-methoxybenzylidene)-bis(4-methoxyphenyl) OMe methyl amine 110e: Imine 110e was prepared according to the procedure described above for imine 110a. N Crystallization (1:8 CH2Cl2/hexanes) and collection of MeO OMe the first crop afforded 110e as white solid crystals (mp 110e 129.5-130.5 ºC) in 92% isolated yield (3.32 g, 9.20 mmol). 1 Spectral data for 110e: H NMR (CDCl3, 300 MHz) δ 3.76 (s, 6H), 3.81 (s, 3H), 5.47 (s, 1H), 6.83 (d, J = 8.8 Hz, 4H), 6.89 (d, J = 8.8 Hz, 2H), 7.25 (d, J = 8.5 Hz, 4H), 7.75 (d, J = 8.8 Hz, 2H), 8.29 (s, 1H); 13 C (CDCl3, 75 MHz) δ 55.20, 55.29, 76.40, 113.68, 113.81, 128.47, 128.63, 129.92, 136.52, 158.37, 159.54, 161.30. These spectral data match those previously reported for this compound. 11 N-(4-nitrobenzylidene)-bis(4-methoxyphenyl)methyl OMe amine 110f: Imine 110f was prepared according to the procedure N described above for imine 110a. Crystallization (1:5 EtOAc/hexanes) and collection of the O2N OMe first crop afforded 110f as a light yellow solid (mp 99- 110f 100 ºC) in 91% isolated yield (3.42 g, 9.10 mmol). 1 Spectral data for 110f: H NMR (CDCl3, 300 MHz) δ 3.76 (s, 6H), 5.57 (s, 1H), 6.85 (d, J = 8.8 Hz, 4H), 7.26 (d, J = 8.8 Hz, 4H), 7.96 (d, J = 8.8 Hz, 2H), 8.24 (d, J = 8.8 Hz, 2H), 8.44 (s, 1H); 497 13 C (CDCl3, 75 MHz) δ 55.19, 76.75, 113.84, 123.73, 128.55, 129.01, 135.52, 141.73, 148.95, 11 157.98, 158.65. These spectral data match those previously reported for this compound. N-(4-bromobenzylidene)-bis(4-methoxyphenyl)methyl OMe amine 110g: Imine 110g was prepared according to the procedure described above for imine 110a. Crystallization N (1:10 CH2Cl2/ hexanes) and collection of the first crop Br OMe afforded 110g as white solid crystals (mp 125.5-126.5 ºC) 110g in 85% isolated yield (3.49 g, 8.50 mmol). 1 Spectral data for 110g: H NMR (CDCl3, 300 MHz) δ 3.76 (s, 6H), 5.51 (s, 1H), 6.85 (d, J = 8.8 Hz, 4H), 7.26 (d, J = 8.8 Hz, 4H), 7.52 (d, J = 8.3 Hz, 2H), 7.67 (d, J = 8.5 Hz, 2H), 8.31 (s, 1H); 13 C (CDCl3, 75 MHz) δ 55.20, 76.56, 113.77, 125.02, 128.58, 129.78, 131.70, 135.20, 136.02, 11 158.51, 159.01. These spectral data match those previously reported for this compound. N-cyclohexylmethylidene-bis(4-methoxyphenyl)methyl OMe amine 110v: Imine 110v was prepared according to the procedure described above for imine 110a. N Crystallization (hexanes) and collection of the first crop afforded 110v as white OMe 110v solid crystals (mp 77.5-78.5 ºC) in 84% isolated yield (2.83 g, 8.40 mmol). 498 1 Spectral data for 110v: H NMR (CDCl3, 300 MHz) δ 1.25-1.37 (m, 6H), 1.68-1.90 (m, 4H), 2.31-2.33 (m, 1H), 3.82 (s, 6H), 5.27 (s, 1H), 6.87 (d, J = 8.8 Hz, 4H), 7.22 (d, J = 8.8 Hz, 4H), 13 7.68 (d, J = 5.1 Hz, 1H); C (CDCl3, 75 MHz) δ 25.34, 25.94, 29.67, 43.39, 55.09, 76.58, 113.58, 128.46, 136.39, 158.28, 168.48. These spectral data match those previously reported for this compound. 11 N-(1,1-dimethylethylidene)-bis(4-methoxyphenyl)methylamine OMe 110w: Imine 110w was prepared according to the procedure described above for imine 110a. N Crystallization (hexanes) and collection of the first crop afforded 110w as white solid crystals OMe (mp. 75.5-76.5 ºC) in 76% isolated yield (2.37 g, 7.60 mmol). 110w 1 Spectral data for 110w: H NMR (CDCl3, 300 MHz) δ 1.08 (s, 9H), 3.76 (s, 6H), 5.24 (s, 1H), 6.81 (d, J = 8.8 Hz, 4H), 7.18 (d, J = 8.8 Hz, 4H), 7.62 (s, 1H); 13 C (CDCl3, 75 MHz) δ 26.94, 36.31, 55.16, 75.99, 113.59, 128.43, 136.70, 158.25, 171.09. These spectral data match those previously reported for this compound. 11 Synthesis of imine 111a: See Chapter 2 Synthesis of imine 333o: OMe MeO O Pr 4 Å MS + OMe Et H2N 352b toluene 25 °C, 12 d Pr N Et OMe 333o 126b 499 (E)-N-((E)-2-ethylhex-2-en-1-ylidene)-1,1-bis(4-methoxyphenyl)methanamine 333o: To a 10 mL flame-dried round bottom flask filled with argon was added bis(4- methoxyphenyl)methylamine 126b (243 mg, 1.00 mmol), 4Å MS (250 mg, freshly flame-dried) and dry toluene (1 mL). After stirring for 10 min, (E)-2-ethylhex-2-enal 352b (126 mg, 1.05 mmol, purchased from Frinton Laboratories Inc.) was added. The reaction mixture was stirred at room temperature for 12 days. The resulting imine 333o was used directly for the next step. A sample was isolated utilizing the filter syringe (Corning® syringe filters, Aldrich) in order to obtain spectral data. 1 Spectral data for 333o: H NMR (CDCl3, 500 MHz) δ 0.92 (t, J = 7.0 Hz, 3H), 1.04 (t, J = 7.5 Hz, 3H), 1.43 (sextet, J = 7.0 Hz, 2H), 2.19 (q, J = 7.0 Hz, 2H), 2.45 (q, J = 7.0 Hz, 2H), 3.76 (s, 6H), 5.3 (s, 1H), 5.76 (t, J = 7.0 Hz, 3H), 6.82 (d, J = 7.5 Hz, 4H), 7.22 (d, J = 7.5 Hz, 2H), 7.82 (s, 1H); 13 C (CDCl3, 125 MHz) δ 13.79, 13.86, 19.33, 22.45, 30.20, 55.14, 76.32, 113.63, + 128.44, 137.08, 141.58, 142.34, 158.30, 163.79; HRMS (ESI-TOF) m/z 352.2273 [(M+H ); calcd. for C23H30NO2 : 352.2277] Synthesis of imine 358a: (E)-1,1-bis(3,5-di-tert-butyl-4-methoxyphenyl)-N-((E)-2- OMe tBu tBu methylbut-2-en-1-ylidene)methanamine 358a: tBu N was prepared according to the procedure described above for imine 110a except for the following differences: a) 1.5 equiv of OMe 358a Imine 358a tBu 500 aldehyde 352a used; b) the reaction was performed in benzene (40 mL). The reaction was 1 monitored by H NMR. Crystallization (hexanes) and collection of the first crop afforded 358a as white solid crystals (mp. 131-132 ºC) in 80% isolated yield (4.27 g, 8.00 mmol). 1 Spectral data for 358a: H NMR (CDCl3, 500 MHz) δ 1.39 (s, 36H), 1.85 (dd, J = 6.9, 1.0 Hz, 3H), 1.95 (t, J = 1.1 Hz, 3H), 3.67 (s, 6H), 5.28 (s, 1H), 5.96-6.00 (m, 1H), 7.17 (s, 4H), 7.99 (s, 1H); 13 C (CDCl3, 125 MHz) δ 11.50, 14.20, 32.09, 35.76, 64.10, 77.55, 125.95, 135.96, 137.31, 138.02, 142.91, 158.11, 164.70; IR (thin film, cm-1) 2961vs, 2870s, 1649m, 1628m, 1446m, + 1412s, 1221s, 1115m; HRMS (ESI-TOF) m/z 534.4298 [(M+H ); calcd. for C36H56NO2: 534.4311]; Synthesis of imine 359a: (E)-1,1-bis(4-methoxy-3,5-dimethylphenyl)-N-((E)-2- OMe methylbut-2-en-1-ylidene)methanamine 359a: Imine 359a was prepared according to the procedure described above for N imine 110a except for the following differences: a) 1.5 equiv of OMe 359a aldehyde 352a used; b) the reaction was performed in benzene 1 (40 mL). The reaction was monitored by H NMR. Crystallization (hexanes) and collection of the first crop afforded 359a as white solid crystals (mp. 101-103 ºC) in 75% isolated yield (2.74 g, 7.50 mmol). 501 1 Spectral data for 359a: H NMR (CDCl3, 500 MHz) δ 1.84 (dd, J = 6.9, 0.7 Hz, 3H), 1.96 (s, 3H), 2.27 (s, 12H), 3.70 (s, 6H), 5.20 (s, 1H), 5.93-5.97 (m, 1H), 6.98 (s, 4H), 7.91 (s, 1H); 13 C 3 (CDCl3, 125 MHz) δ 11.51, 14.15, 16.19, 59.56, (one sp carbon not located), 127.76, 130.45, 136.22, 137.26, 139.72, 155.65, 164.68; IR (thin film, cm-1) 2941vs, 2860s, 1645s, 1626vs, + 1483vs, 1221s, 1144vs; HRMS (ESI-TOF) m/z 366.2439 [(M+H ); calcd. for C24H32NO2: 366.2433]; Synthesis of imine rac-378: N-benzylidene-2,2-dimethyl-1-phenylpropan-1-amine N rac-378: Imine rac-378 was prepared according to the procedure described above for imine 110a. Crystallization (hexanes) and collection of the rac-378 first crop afforded rac-378 as white solid crystals (mp. 69-70 ºC) in 80% isolated yield (2.01 g, 8.00 mmol). 1 Spectral data for rac-378: H NMR (CDCl3, 300 MHz) δ 0.94 (s, 9H), 3.93 (s, 1H), 7.18-7.43 (m, 8H), 7.75-7.78 (m, 2H), 8.23 (s, 1H); 13 C (CDCl3, 75 MHz) δ 26.98, 35.73, 84.85, 126.58, 127.42, 128.21, 128.42, 128.87, 130.29, 136.68, 142.44, 159.27. These spectral data match those 38 previously reported for the (S)-378. 502 6.8.3 Different procedures for aziridination with imine 110g (Table 6.1 and Scheme 6.2) Procedure II: O B(OPh)3 (20 mol%) (S)-VAPOL (5 mol%) toluene open to air or under argon R DAM N 110g 25 °C 10 min OEt N2 85 DAM N 25 °C, 24 h R CO2Et 113g OPh DAM O B O – B O * N+ H O O B R OPh catalyst 199g (2R,3R)-Cis-1-(N-1-bis(4-methoxyphenyl)methyl)-2-carboxyethyl-3-p-bromophenyl aziridine 113g: To a 25 mL oven-dried round bottom flask was added (S)-VAPOL (13.5 mg, 0.025 mmol), B(OPh)3 (29 mg, 0.1 mmol) and aldimine 110g (205 mg, 0.5 mmol). The mixture was dissolved in toluene (1 mL) at room temperature. The reaction mixture was stirred for 5 min to give a light orange solution. To this solution was rapidly added EDA 85 (62 µL, 0.60 mmol) and the resulting mixture was stirred for 24 h at room temperature. The reaction was quenched by addition of 6 mL hexane. The reaction mixture was then transferred to a 100 mL round bottom flask. The reaction flask was rinsed twice with 5 mL of dichloromethane and the rinse was added to the 100 mL round bottom flask. The resulting solution was then concentrated in vacuo followed by exposure to high vacuum (0.05 mm Hg) for 5 min to afford the crude aziridine as an off-white solid. While the reaction gave 15% conversion with 5 mol% catalyst loading and open to air, 23% conversion was obtained when the reaction was performed under argon with 5 mol% catalyst loading. However, the reaction gave complete conversion using 10 mol% catalyst loading under argon. 503 1 The conversion was determined from the H NMR spectrum of the crude reaction mixture by integration of the aziridine ring methine protons relative to either the imine methine proton or the 1 proton on the imine carbon. The cis/trans ratio was determined by comparing the H NMR integration of the ring methine protons for each aziridine in the crude reaction mixture. The cis (J = 7-8 Hz) and the trans (J = 2-3 Hz) coupling constants were used to differentiate the two isomers. The yields of the acyclic enamine side products 116g and 117g were determined by 1H NMR analysis of the crude reaction mixture by integration of the N-H proton relative to the that of the cis-aziridine methine protons with the aid of the isolated yield of the cis-aziridine. Purification of the crude aziridine by silica gel chromatography (20 mm × 200 mm column, 9:1 hexanes/EtOAc as eluent, after elution of the first fraction, which contains EDA and / or enamine side products 116g and 117g, the eluent was changed to 5:1 hexanes / EtOAc) afforded pure aziridine 113g as a white solid (mp. 49-50 ºC) in 90% isolated yield (223 mg, 0.45 mmol). cis/trans: 50:1. Enamine side products: <1 % yield of 116g and < 1% yield of 117g. The optical purity of 113g was determined to be 97% ee by HPLC analysis (CHIRALPAK AD column, 90:10 hexane/iPrOH at 226nm, flow-rate: 1.0 mL/min). Retention times, Rt = 8.27 min (major enaniomer, 113g) and Rt = 26.32 min (minor enantiomer, ent-113g). 1 Spectral data for 113g: Rf = 0.25 (1:5 EtOAc/hexane); H NMR (CDCl3, 500 MHz) δ 1.00 (t, J = 7.1 Hz, 3H), 2.62 (d, J = 6.6 Hz, 1H), 3.07 (d, J = 6.6 Hz, 1H), 3.71 (s, 3H), 3.76 (s, 3H), 3.83 (s, 1H), 3.93 (q, J = 7.1 Hz, 2H), 6.76 (d, J = 8.3 Hz, 2H), 6.84 (d, J = 8.3 Hz, 2H), 7.25 (d, J = 8.8 Hz, 2H), 7.30 (d, J = 8.8 Hz, 2H), 7.35 (d, J = 8.3 Hz, 2H), 7.43 (d, J = 8.8 Hz, 2H); 504 13 C (CDCl3, 75 MHz) δ 13.99, 46.46, 47.34, 55.12, 55.19, 60.68, 76.32, 113.82, 121.27, 128.08, 2 128.37, 129.54, 130.86, 134.16, 134.67, 134.88, 158.65, 158.75, 167.51 (one sp carbon not located); [α ]20 +15.0 (c 1.0, EtOAc) on 97% ee material (HPLC). These spectral data match D those previously reported for this compound. 11 Procedure IIʹ′: DAM N 110g (0.25 mmol) R B(OPh)3 (20 mol%) (S)-VAPOL (5 mol%) toluene 25 °C, 0.5 h under argon DAM N 110g (0.25 mmol) R 25 °C 10 min O OEt N2 85 DAM N 25 °C, 24 h R CO2Et 113g OPh DAM O –O B B O * N+ H O O B R OPh catalyst 199g (2R,3R)-Cis-1-(N-1-bis(4-methoxyphenyl)methyl)-2-carboxyethyl-3-p-bromophenyl aziridine 113g: To a 25 mL flame-dried Schlenk flask was added (S)-VAPOL (13.5mg, 0.025 mmol), B(OPh)3 (29 mg, 0.1 mmol) and aldimine 110g (102.5 mg, 0.25 mmol). The mixture was dissolved in dry toluene (0.5 mL) at room temperature. The reaction mixture was stirred for 0.5 h. To this solution was added aldimine 110g (102.5 mg, 0.25 mmol) and dry toluene (0.5 mL) at room temperature. The reaction mixture was stirred for 5 min. To this solution was rapidly added EDA 85 (62 µL, 0.6 mmol) and the resulting mixture was stirred for 24 h at room temperature. The reaction was quenched by addition of 6 mL hexane. The reaction mixture was then transferred to a 100 mL round bottom flask. The reaction flask was rinsed twice with 5 mL of dichloromethane and the rinse was added to the 100 mL round bottom flask. The resulting 505 solution was then concentrated in vacuo followed by exposure to high vacuum (0.05 mm Hg) for 5 min to afford the crude aziridine as an off-white solid. The reaction gave 16 % conversion only. Procedure IV: B(OPh)3 (20 mol%) H2O (5 mol%) (S)-VAPOL (5 mol%) toluene, 80 °C, 1.0 h 0.5 mm Hg 80 °C, 0.5 h O R DAM N 110g pre-catalyst (5 mol%) toluene, 25 °C 10 min under argon OEt N2 85 DAM N 25 °C, 24 h R CO2Et 113g pre-catalyst (5 mol%) OPh DAM O B O – B O * N+ H O O B OPh R catalyst 199g (2R,3R)-Cis-1-(N-1-bis(4-methoxyphenyl)methyl)-2-carboxyethyl-3-p-bromophenyl aziridine 113g: To a 25 mL flame-dried Schlenk flask flushed with argon was added (S)- VAPOL (13.5 mg, 0.025 mmol) and B(OPh)3 (29 mg, 0.1 mmol). Under an argon flow, dry toluene (2 mL) was added to dissolve the two reagents and this was followed by the addition of water (0.45 µL, 0.025 mmol). The flask was sealed, and then placed in an 80 ºC for 1 h. After 1 hour, a vacuum (0.5 mm Hg) was applied carefully to remove the volatiles. The vacuum is maintained for a period of 30 min at a temperature of 80 ºC. The flask was then filled with argon and the catalyst mixture was allowed to cool to room temperature. To the flask containing the catalyst was first added the aldimine 110g (205 mg, 0.50 mmol) and then dry toluene (1 mL). The reaction mixture was stirred for 5 min to give a light orange solution. To this solution was rapidly added EDA 85 (62 µL, 0.60 mmol) and the resulting mixture was stirred for 24 h at room temperature. Immediately upon addition of ethyl 506 diazoacetate the reaction mixture became an intense yellow and the formation bubbles from the release of nitrogen was noted. The reaction was quenched by addition of 6 mL hexane. The reaction mixture was then transferred to a 100 mL round bottom flask. The reaction flask was rinsed twice with 5 mL of dichloromethane and the rinse was added to the 100 mL round bottom flask. The resulting solution was then concentrated in vacuo followed by exposure to high vacuum (0.05 mm Hg) for 5 min to afford the crude aziridine as an off-white solid. The reaction resulted 113g in 95% yield and 92% ee following the standard purification procedure. Procedure Vʹ′: O DAM R N B(OPh)3 110g (S)-VAPOL (20 mol%) (5 mol%) toluene 25 °C 10 min 80 °C, 1 h under argon OEt N2 85 DAM N 25 °C, 24 h R CO2Et 113g OPh DAM O B O – B O * N+ H O O B OPh R catalyst 199g (2R,3R)-Cis-1-(N-1-bis(4-methoxyphenyl)methyl)-2-carboxyethyl-3-p-bromophenyl aziridine 113g: To a 25 mL flame-dried Schlenk flask flushed with argon was added (S)- VAPOL (13.5 mg, 0.025 mmol) and B(OPh)3 (29 mg, 0.1 mmol). Under an argon flow, dry toluene (0.5 mL) was added to dissolve the two reagents. The flask was sealed, and then placed in an 80 ºC for 1 h. The pre-catalyst mixture was then allowed to cool to room temperature and filled with argon. To the flask containing the pre-catalyst was first added the aldimine 110g (205 mg, 0.5 mmol) and then dry toluene (0.5 mL). The reaction mixture was stirred for 5 min to give a light orange solution. To this solution was rapidly added EDA 85 (62 µL, 0.6 mmol) and the resulting mixture was stirred for 24 h at room temperature. The reaction was quenched by addition of 6 mL hexane. The reaction mixture was then transferred to a 100 mL round bottom 507 flask. The reaction flask was rinsed twice with 5 mL of dichloromethane and the rinse was added to the 100 mL round bottom flask. The resulting solution was then concentrated in vacuo followed by exposure to high vacuum (0.05 mm Hg) for 5 min to afford the crude aziridine as an off-white solid. The reaction gave 39 % conversion only. Procedure V: R (S)-VAPOL (5 mol%) DAM N 110g B(OPh)3 (20 mol%) toluene 80 °C, 1 h under argon O OEt DAM N2 85 N 25 °C, 24 h R CO2Et 113g OPh DAM O B O – B O * N+ H O O B OPh R catalyst 199g (2R,3R)-Cis-1-(N-1-bis(4-methoxyphenyl)methyl)-2-carboxyethyl-3-p-bromophenyl aziridine 113g: To a 25 mL flame-dried Schlenk flask was added (S)-VAPOL (8 mg, 0.015 mmol), B(OPh)3 (17.4 mg, 0.06 mmol) and aldimine 110g (205 mg, 0.5 mmol). The mixture was dissolved in dry toluene (1 mL) at room temperature. The flask was sealed, and then placed in an 80 ºC for 1 h. The catalyst mixture was then allowed to cool to room temperature and filled with argon. To this solution was rapidly added EDA 85 (62 µL, 0.60 mmol) and the resulting mixture was stirred for 24 h at room temperature. The reaction was quenched by addition of 6 mL hexane. The reaction mixture was then transferred to a 100 mL round bottom flask. The reaction flask was rinsed twice with 5 mL of dichloromethane and the rinse was added to the 100 mL round bottom flask. The resulting solution was then concentrated in vacuo followed by exposure to high vacuum (0.05 mm Hg) for 5 min to afford the crude aziridine as an off-white 508 solid. The reaction resulted 113g in 89% yield and 94% ee following the standard purification procedure. 6.8.4 Synthesis of aziridines 113g (Table 6.2-6.3) MeO (2R,3R)-Cis-1-(N-1-bis(4-methoxyphenyl)methyl)-2- OMe carboxyethyl-3-phenylaziridine 113a. Imine 110a (166 mg, N 0.500 mmol) was reacted according to the general procedure V CO2Et described above with (S)-VAPOL as ligand. After 113a purification, the product was afforded as white solid (mp 8990 ºC) in 90% isolated yield (188 mg, 0.450 mmol) ; cis/trans: ≥ 50:1. Enamine side products: 2.7% yield of 116a and 2.7% yield of 117a. The optical purity of 113a was determined to be 94% ee by HPLC analysis (CHIRALPAK AD column, 90:10 hexane/2-propanol at 226nm, flowrate: 1.0 mL/min): retention times; Rt = 8.80 min (major enantiomer, 113a) and Rt = 15.70 min (minor enantiomer, ent-113a) 1 Spectral data for 113a: Rf = 0.28 (1:5 EtOAc/hexanes). H NMR (CDCl3, 500 MHz) δ 0.93 (t, 3H, J = 7.1 Hz), 2.59 (d, 1H, J = 6.8 Hz), 3.13 (d, 1H, J = 6.8 Hz), 3.67 (s, 3H), 3.75 (s, 3H), 3.81 (s, 1H), 3.91-3.98 (m, 2H), 6.74 (d, 2H, J = 8.8 Hz), 6.82 (d, 2H, J = 8.8 Hz), 7.14-7.24 (m, 3H), 7.31-7.35 (m, 4H), 7.43 (d, 2H, J = 8.8 Hz); 13 C (CDCl3, 75 MHz) δ 13.94, 46.39, 48.02, 55.15, 55.22, 60.54, 76.44, 113.80, 127.27, 127.75, 127.79, 128.16, 128.49, 134.93, 135.13, 2 135.16, 158.61, 158.71, 167.83 (one sp carbon not located); [α ]20 +36.5 (c 1.0, EtOAc) on D 509 94% ee material (HPLC). compound. These spectral data match those previously reported for this 11 MeO (2R,3R)-Cis-1-(N-1-bis(4-methoxyphenyl)methyl)-2- OMe carboxyethyl-3-1-naphthylaziridine 113b: Imine 110b (191 N mg, 0.500 mmol) was reacted according to the general CO2Et procedure V described above with (S)-VAPOL as ligand. 113b After purification, the product was obtained as a white solid (mp. 154.5-155 ºC) in 80% isolated yield (187 mg, 0.4 mmol); cis/trans: ≥50:1. Enamine side products: 1.6% yield of 116b and 1.6% yield of 117b. The optical purity of 113b was determined to be 98% ee by HPLC analysis (CHIRALPAK AD column, 90:10 hexane/iPrOH at 226nm, flow-rate: 1.0 mL/min); Retention times: Rt = 14.84 min (major enantiomer, 113b) and Rt = 18.62 min (minor enantiomer, ent-113b). 1 Spectral data for 113b: Rf = 0.22 (1:5 EtOAc/hexanes); H NMR (CDCl3, 300 MHz) δ 0.62 (t, 3H, J = 7.3 Hz), 2.88 (d, 1H, J = 6.8 Hz), 3.66 (d, 1H, J = 6.6 Hz), 3.72 (s, 3H), 3.70-3.74 (m, 2H), 3.78 (s, 3H), 3.99 (s, 1H), 6.81 (d, 2H, J = 8.5 Hz), 6.88 (d, 2H, J = 8.5 Hz), 7.35-7.47 (m, 5H), 7.53 (d, 2H, J = 8.8 Hz), 7.64-7.70 (m, 2H), 7.79 (d, 1H, J = 7.4 Hz), 8.09 (d, 1H, J = 7.7 Hz); 13 C (CDCl3, 125 MHz) δ 13.57, 46.08, 46.40, 55.14, 55.21, 60.30, 76.72, 113.88, 113.91, 123.00, 125.33, 125.38, 125.79, 126.57, 127.54, 128.16, 128.49, 128.86, 130.71, 131.49, 133.09, 134.81, 135.17, 158.69, 158.94, 167.85; [α ]20 +4.5 (c 1.0, EtOAc) on 98% ee material (HPLC). D These spectral data match those previously reported for this compound. 510 11 MeO (2R,3R)-Cis-1-(N-1-bis(4-methoxyphenyl)methyl)-2- OMe carboxyethyl-3-o-tolylaziridine 113c: Imine 110c (173 mg, N 0.500 mmol) was reacted according to the general procedure V CO2Et described above with (S)-VAPOL as ligand. After 113c purification, the product was obtained as a white solid (mp. 123-124 ºC) in 70% isolated yield (151 mg, 0.35 mmol). cis/trans: ≥ 50:1. Enamine side products: 1.4% yield of 116c and 1.1% yield of 117c. The optical purity of 113c was determined to be 93% ee by HPLC analysis (CHIRALPAK AD column, 90:10 hexane/iPrOH at 226nm, flow-rate: 1.0 mL/min); retention times: Rt = 7.14 min (major enantiomer, 113c) and Rt = 10.83 min (minor enantiomer, ent-113c). 1 Spectral data for 113c: Rf = 0.26 (1:5 EtOAc/hexane); H NMR (CDCl3, 500 MHz) δ 0.87 (t, 3H, J = 7.1 Hz), 2.27 (s, 3H), 2.67 (d, 1H, J = 6.8 Hz), 3.14 (d, 1H, J = 6.8 Hz), 3.72 (s, 3H), 3.77 (s, 3H), 3.84 (s, 1H), 3.87 (q, 2H, J = 7.1 Hz), 6.78 (d, 2H, J = 8.8 Hz), 6.84 (d, 2H, J = 8.5 Hz), 7.01-7.08 (m, 3H), 7.37 (d, 2H, J = 8.8 Hz), 7.47 (d, 3H, J = 9.0 Hz); 13 C (CDCl3, 125 MHz) δ 13.83, 18.75, 45.72, 46.91, 55.17, 55.23, 60.38, 76.72, 113.86, 113.90, 125.34, 127.09, 128.14, 128.55, 128.69, 129.09, 133.29, 134.99, 135.25, 136.02, 158.67, 158.89, 168.03; [α ]20 D +38.6 (c 1.0, EtOAc) on 93% ee material (HPLC). These spectral data match those previously reported for this compound. 11 511 MeO (2R,3R)-Cis-1-(N-1-bis(4-methoxyphenyl)methyl)-2- OMe carboxyethyl-3-p-tolylaziridine 113d: Imine 17c (173 mg, N 0.500 mmol) was reacted according to the general procedure V CO2Et described above with (S)-VAPOL as ligand. After 113d purification, the product was obtained as a white solid in 90% isolated yield (194 mg, 0.450 mmol). cis/trans: ≥ 50:1. Enamine side products: 1% yield of 116d and 1 % yield of 117d. The optical purity 113d was determined to be 94 % ee by HPLC analysis (CHIRALPAK AD column, 90:10 hexane/iPrOH at 226nm, flow-rate: 1.0 mL/min); retention times: Rt = 7.85 min (major enantiomer, 113d) and Rt = 15.25 min (minor enantiomer, ent-113d). 1 Spectral data for 113d: Rf = 0.34 (1:5 EtOAc/hexanes); H NMR (CDCl3, 300 MHz) δ 1.01 (t, 3H, J = 7.1 Hz), 2.29 (s, 3H), 2.63 (d, 1H, J = 6.8 Hz), 3.16 (d, 1H, J = 6.8 Hz), 3.71 (s, 3H), 3.77 (s, 3H), 3.86 (s, 1H), 3.95 (q, 2H, J = 7.1 Hz), 6.78 (d, 2H, J = 8.8 Hz), 6.87 (d, 2H, J = 8.8 Hz), 7.06 (d, 2H, J = 7.8 Hz), 7.29 (d, 2H, J = 8.0 Hz), 7.37 (d, 3H, J = 8.8 Hz), 7.49 (d, 3H, J = 8.5 Hz); 13 C (CDCl3, 75 MHz) δ 13.93, 21.06, 46.33, 47.98, 55.04, 55.12, 60.42, 76.44, 113.73, 2 127.61, 128.14, 128.40, 128.42, 132.07, 134.96, 135.13, 136.77, 158.57, 158.65, 167.83 (one sp -1 carbon not located); IR (thin film, cm ) 2995 w, 1745 m, 1609 w, 1510 vs, 1301 w, 1247 s, 1175 s, 1035 m, 825 w; HRMS calcd for C27H29NO4Na m/z 454.1994, mass 454.1988; [α ]20 D +22.2 (c 1.0, EtOAc) on 94% ee material (HPLC). 512 MeO OMe (2R,3R)-Cis-1-(N-1-bis(4-methoxyphenyl)methyl)-2carboxyethyl-3-p-methoxyphenyl aziridine 113e: Imine N 110e (181 mg, 0.500 mmol) was reacted according to the CO2Et general procedure V described above with (R)-VANOL as MeO 113e ligand. The silica gel for column chromatography was pre- conditioned by preparing a slurry in a 1:9 mixture of Et3N:CH2Cl2 which was loaded into a column (35 mm × 350 mm), the solvent was drained and then the silica gel was dried by flushing with nitrogen for one hour. The silica gel column was then saturated with a 1:9 mixture of ethyl acetate:hexane, the crude aziridine was loaded onto the column and then elution with the same solvent mixture until the elution of the first fraction, which contains EDA and / or enamine side products 116e and 117e, the eluent was changed to 5:1 hexanes / EtOAc) afforded pure aziridine 113e as a semi solid in 80% isolated yield (179 mg, 0.4 mmol); cis/trans: 50:1. Enamine side products: 3.2% yield of 116e and 1.6% yield of 117e. The optical purity of 113e was determined to be 93% ee by HPLC analysis (CHIRALPAK AD column, 90:10 hexane/iPrOH at 226nm, flow-rate: 1.0 mL/min); retention times, Rt = 10.69 min (major enantiomer, 113e) and Rt = 32.38 min (minor enantiomer, ent-113e). 1 Spectral data for 113e: Rf = 0.2 (1:5 EtOAc/hexanes); H NMR (CDCl3, 300 MHz) δ 1.02 (t, 3H, J = 7.1 Hz), 2.61 (d, 1H, J = 6.6 Hz), 3.14 (d, 1H, J = 6.6 Hz), 3.70 (s, 3H), 3.74 (s, 3H), 3.76 (s, 3H), 3.85 (s, 1H), 3.95 (q, 2H, J = 7.1 Hz), 6.79 (dd, 4H, J = 8.8 Hz, 2.4 Hz), 6.86 (d, 2H, J = 8.8 Hz), 7.32 (d, 2H, J = 8.8 Hz); 7.36 (d, 2H, J = 8.5 Hz), 7.48 (d, 2H, J = 8.5 Hz) ; 13 C (CDCl3, 75 MHz) δ 13.94, 46.26, 47.67, 55.01, 55.04, 55.08, 60.43, 76.34, 113.11, 113.68, 513 113.70, 127.14, 128.09, 128.38, 128.79, 134.89, 135.10, 158.51, 158.59, 158.76, 167.90; [α ]20 D +27.1 (c 2.0, EtOAc) on 95% ee material (HPLC). These spectral data match those previously reported for this compound. MeO 11 OMe (2R,3R)-Cis-1-(N-1-bis(4-methoxyphenyl)methyl)-2carboxyethyl-3-p-nitrophenylaziridine 113f: Imine 110f N (188 mg, 0.500 mmol) was reacted according to the general CO2Et O2N 113f procedure V described above with (S)-VAPOL as ligand. After purification, the product was obtained as a yellow powder (mp. 56-57 ºC) in 85% isolated yield (197 mg, 0.430 mmol); cis/trans: 50:1. Enamine side products: <1% yield of 116f and <1% yield of 117f. The optical purity of 113f was determined to be 95% ee by HPLC analysis (CHIRALPAK AD column, 90:10 hexane/iPrOH at 226nm, flow-rate: 1.0 mL/min), Retention times: Rt = 16.47 min (major enantiomer, 113f) and Rt = 54.59 min (minor enantiomer, ent-113f). 1 Spectral data for 113f: Rf = 0.15 (1:5 EtOAc/hexanes); H NMR (CDCl3, 300 MHz) δ 0.99 (t, 3H, J = 7.1 Hz), 2.74 (d, 1H, J = 6.6 Hz), 3.20 (d, 1H, J = 6.8 Hz), 3.70 (s, 3H), 3.77 (s, 3H), 3.88 (s, 1H), 3.92 (q, 2H, J = 7.3 Hz), 6.77 (d, 2H, J = 8.8 Hz), 6.85 (d, 2H, J = 8.8 Hz), 7.31 (d, 2H, J = 8.8 Hz), 7.44 (d, 2H, J = 8.5 Hz), 7.57 (d, 2H, J = 8.5 Hz), 8.09 (d, 2H, J = 8.8 Hz); 13 C (CDCl3, 125 MHz) δ 14.01, 46.96, 47.09, 55.16, 55.24, 60.88, 76.37, 113.99, 123.04, 128.08, 128.38, 128.78, 134.37, 134.64, 142.68, 147.34, 158.87, 158.98, 167.05 (one sp2 carbon not 514 located); [α ]20 –1.4 (c 1.0, EtOAc) on 95% ee material (HPLC). These spectral data match D those previously reported for this compound. 11 B(OPh)3 (40 mol%) H2O (10 mol%) (S)-VAPOL (10 mol%) toluene, 80 °C, 1.0 h 0.5 mm Hg 80 °C, 0.5 h pre-catalyst (10 mol%) O DAM N 110o Pr pre-catalyst (10 mol%) toluene, 0 °C 10 min under argon OEt N2 85 N DAM + Et N 0 °C, 25 h Pr CO2Et 113o DAM Pr 333o (E)-N-butylidene-1,1-bis(4-methoxyphenyl)methanamine 110o: To a 10 mL flame-dried round bottom flask filled with argon was added bis(4-methoxyphenyl)methylamine 126b (243 mg, 1 mmol), 4Å MS (250 mg, freshly dried) and dry toluene (1.5 mL). After stirring for 10 min, butanal 127o (78 mg, 1.05 mmol, freshly distilled) was added. The reaction mixture was stirred at room temperature for 6 h. The resulting imine 110o was used without further purification. 1 Spectral data for 111o: H NMR (CDCl3, 500 MHz) δ 0.95 (t, 3H, J = 7.5 Hz), 1.57 (sextet, 2H, J = 7.5 Hz), 2.26-2.33 (m, 2H), 3.75 (s, 6H), 5.25 (s, 1H), 6.80-6.83 (m, 4H), 7.16-7.19 (m, 4H), 7.83 (t, 1H, J = 5.0 Hz). (2R,3R)-ethyl 1-(bis(4-methoxyphenyl)methyl)-3-propylaziridine-2-carboxylate 113o: To a 25 mL flame-dried home-made Schlenk flask (see Figure 2.26) equipped with a stir bar and flushed with argon was added (S)-VAPOL (54 mg, 0.1 mmol) and B(OPh)3 (116 mg, 0.4 mmol). 515 Under an argon flow through the side-arm of the Schlenk flask, dry toluene (2 mL) was added to dissolve the two reagents and this was followed by the addition of water (1.8 µL, 0.1 mmol). The flask was sealed by closing the Teflon valve, and then placed in an 80 ºC (oil bath) for 1 h. After 1 h, a vacuum (0.5 mm Hg) was carefully applied by slightly opening the Teflon valve to remove the volatiles. After the volatiles are removed completely, a full vacuum is applied and is maintained for a period of 30 min at a temperature of 80 ºC (oil bath). The flask was then allowed to cool to room temperature and open to argon through side-arm of the Schlenk flask. The toluene solution of imine 110o (296 mg, 1 mmol, prepared as described above) was then directly transferred from the reaction flask in which it was prepared to the flask containing the catalyst (precooled at 0 ºC) utilizing a filter syringe (Corning® syringe filters, Aldrich) to remove the 4Å Molecular Sieves. The flask, which had imine 110o, was then rinsed with toluene (0.5 mL) and the rinse was transferred to the flask containing the catalyst under argon flow through side-arm of the Schlenk flask. The reaction mixture was stirred for 5 min to give a light yellow solution. To this solution was rapidly added EDA 85 (124 µL, 1.2 mmol) at 0 ºC followed by closing the Teflon valve. The resulting mixture was stirred for 24 h at room temperature. The reaction was dilluted by addition of hexane (6 mL). The reaction mixture was then transferred to a 100 mL round bottom flask. The reaction flask was rinsed with dichloromethane (5 mL × 2) and the rinse was added to the 100 mL round bottom flask. The resulting solution was then concentrated in vacuo followed by exposure to high vacuum (0.05 mm Hg) for 1 h to afford the crude aziridine as a pale yellow semi solid. Purification of the crude aziridine by silica gel chromatography (35 mm × 400 mm column, 9:1 hexanes/EtOAc as eluent) afforded pure cisaziridine 113o as a white solid (mp 99-100 ºC on 66% ee material) in 11% isolated yield (42 mg, 516 0.11 mmol); cis/trans: not determined. Enamine side products: <1% yield of 116o and 2% yield 1 of 117o. The amount of byproduct 333o was determined to be 7% by integration of the H NMR spectrum of the crude reaction mixture relative to the aziridine 116o with aid of the authentic sample of 333o prepared as described above. The optical purity of 113o was determined to be 73% ee by HPLC analysis (CHIRALPAK AD column, 90:10 hexane/2-propanol at 226nm, flowrate: 1.0 mL/min): retention times; Rt = 5.9 min (major enantiomer, 113o) and Rt = 8.3 min (minor enantiomer, ent-113o). 1 Spectral data for 113o: Rf = 0.28 (1:5 EtOAc/hexanes). H NMR (CDCl3, 500 MHz) δ 0.74 (t, 3H, J = 7.4 Hz), 1.02-1.16 (m, 2H), 1.23 (t, 3H, J = 7.1 Hz), 1.40-1.54 (m, 2H), 1.99 (q, 1H, J = 6.6 Hz), 2.23 (d, 1H, J = 6.9 Hz), 3.56 (s, 1H), 3.74 (s, 6H), 4.11-4.21 (m, 2H), 6.77-6.82 (m, 4H), 7.26 (d, 2H, J = 8.5 Hz), 7.34 (d, 2H, J = 8.8 Hz); 13 C (CDCl3, 75 MHz) δ 13.65, 14.26, 20.35, 29.91, 43.35, 46.74, 55.16, 60.65, 76.70, 113.61, 113.67, 128.09, 128.81, 134.98, 135.46, 3 158.47, 158.73, 169.60 (one sp carbon not located); [α ]20 +70.7 (c 1.0, EtOAc) on 73% ee D material (HPLC). These spectral data match those previously reported for this compound. MeO OMe 11 (2R,3R)-Cis-1-(N-1-bis(4-methoxyphenyl)methyl)-2carboxyethyl-3-cyclohexylaziridine 113v: Imine 110v (169 N mg, 0.500 mmol) was reacted according to the general CO2Et 113v procedure V described above with (S)-VANOL as ligand. After purification, the product was obtained as a white solid 517 (mp. 119.5-121 ºC) in 83% isolated yield (176 mg, 0.42 mmol); cis/trans: 50:1. Enamine side products: < 1% yield of 116v and < 1% yield of 117v. The optical purity of 113v was determined to be 82% ee by HPLC analysis (CHIRALPAK AD column, 98:2 hexane/iPrOH at 226nm, flowrate: 1.0 mL/min); Retention times: Rt = 11.61 min (major enantiomer, 113v) and Rt = 17.90 min (minor enantiomer, ent-113v). 1 Spectral data for 113v: Rf = 0.3 (1:5 EtOAc/hexanes). H NMR (CDCl3, 300 MHz) δ 0.50-0.53 (m, 1H), 0.89-1.11 (m, 4H), 1.22 (t, 3H, J = 7.1 Hz), 1.22-1.24 (m, 2H), 1.31-1.66 (m, 4H), 1.75 (dd, 1H, J = 6.9, 9.0 Hz), 2.20 (d, 1H, J = 6.9 Hz), 3.50 (s, 1H), 3.74 (s, 6H), 4.12-4.24 (m, 2H), 6.78 (d, 2H, J = 8.8 Hz), 6.80 (d, 2H, J = 8.8 Hz), 7.21 (d, 2H, J = 8.5 Hz), 7.34 (d, 2H, J = 8.5 Hz); 13 C (CDCl3, 75 MHz) δ 14.25, 25.35, 25.52, 26.11, 30.10, 30.80, 36.29, 43.35, 52.21, 55.17, 60.64, 76.99, 113.53, 113.62, 127.97, 129.26, 134.82, 135.41, 158.36, 158.78, 169.71; [α ]20 +116.3 (c 1.0, EtOAc) on 99% ee material (HPLC). These spectral data match those D previously reported for this compound. MeO OMe 11 (2R,3R)-Cis-1-(N-1-bis(4-methoxyphenyl)methyl)-2carboxyethyl-3-1,1-dimethylethyl aziridine 113w: Imine N 110w (156 mg, 0.500 mmol) was reacted according to the CO2Et general procedure V described above with (S)-VANOL as 113w ligand. After purification, the product was obtained as a white solid (mp. 81-83 ºC) in 60% isolated yield (119 mg, 0.3 mmol); cis/trans: 20:1. Enamine side products: <1% yield of 116w and <1% yield of 117w. The optical purity of 113w was determined to be 70% ee by HPLC 518 analysis (CHIRALCEL OD-H column, 99:1 hexane/iPrOH at 226nm, flow-rate: 0.7 mL/min); Retention times: Rt = 14.21 min (major enantiomer, 113w) and Rt = 11.54 min (minor enantiomer, ent-113w). 1 Spectral data for 113w: Rf = 0.65 (1:5 EtOAc/hexanes); H NMR (CDCl3, 300 MHz) δ 0.75 (s, 9H), 1.33 (t, 3H, J = 7.1 Hz), 1.78 (d, 1H, J = 7.2 Hz), 2.18 (d, 1H, J = 7.2 Hz), 3.55 (s, 1H), 3.79 (s, 3H), 3.80 (s, 3H), 4.09-4.31 (m, 2H), 6.83-6.89 (m, 4H), 7.33 (d, 2H, J = 8.7 Hz), 7.60 (d, 2H, J = 8.7 Hz); 13 C (CDCl3, 75 MHz) δ 14.15, 27.54, 31.71, 43.46, 55.22, 56.26, 60.65, 2 78.03, 113.64, 128.26, 129.13, 135.30, 136.25, 158.46, 158.84, 170.01 (one sp carbon and one sp3 carbon not located); [α ]20 +142.4 (c 1.0, EtOAc) on 99% ee material (HPLC). D spectral data match those previously reported for this compound. These 11 6.8.5 [3+2] Cycloaddition of imine 333o, 358a and 359a (Scheme 6.6 and Table 6.6) Et Pr IMINO-BOROX catalyst 357o (10 mol%) O N DAM + OEt N2 333o 85 N NH EtO2C Toluene 25 °C, 48 h Et N DAM Pr 356o 41% y B(OPh)3 (4 equiv) H2O (1 equiv) (S)-VANOL (10 mol%) tolulene, 80 °C, 1 h then 05 mm Hg 80 °C, 0.5 h precatalyst R= 519 OPh DAM O B O – B O * N+ H O O B OPh R Imine 333o Et Pr IMINO-BOROX catalyst 357o (4S,5R)-ethyl-5-((E)-((bis(4-methoxyphenyl)methyl)imino)methyl)-5-ethyl-4-propyl-4,5dihydro-1H-pyrazole-3-carboxylate 356o: To a 25 mL flame-dried home-made Schlenk flask (see Figure 2.26) equipped with a stir bar and flushed with argon was added (S)-VANOL (44 mg, 0.1 mmol) and B(OPh)3 (116 mg, 0.4 mmol). Under an argon flow through the side-arm of the Schlenk flask, dry toluene (2 mL) was added to dissolve the two reagents and this was followed by the addition of water (1.8 µL, 0.1 mmol). The flask was sealed by closing the Teflon valve, and then placed in an 80 ºC (oil bath) for 1 h. After 1 h, a vacuum (0.5 mm Hg) was carefully applied by slightly opening the Teflon valve to remove the volatiles. After the volatiles are removed completely, a full vacuum is applied and is maintained for a period of 30 min at a temperature of 80 ºC (oil bath). The flask was then allowed to cool to room temperature and open to argon through side-arm of the Schlenk flask. The toluene solution of imine 333o (352 mg, 1 mmol, prepared as described above) was then directly transferred from the reaction flask in which it was prepared to the flask containing the catalyst utilizing a filter syringe (Corning® syringe filters, Aldrich) to remove the 4Å Molecular Sieves. The flask, which had imine 330o, was then rinsed with toluene (0.5 mL) and the rinse was transferred to the flask containing the catalyst under argon flow through side-arm of the Schlenk flask. The reaction mixture was stirred for 5 min to give a light yellow solution. However, the solution became turbid after 10 min. To this solution was rapidly added EDA 85 (124 µL, 1.2 mmol) followed by closing the Teflon valve. The resulting mixture was stirred for 48 h at room temperature. The color of solution became brown after 1 h. The reaction was dilluted by addition of hexane (6 mL). The reaction mixture was then transferred to a 100 mL round bottom flask. The reaction flask was rinsed with dichloromethane (5 mL × 2) and the 520 rinse was added to the 100 mL round bottom flask. The resulting solution was then concentrated in vacuo followed by exposure to high vacuum (0.05 mm Hg) for 1 h to afford the crude aziridine as a pale yellow semi solid. Purification of the crude [3+2] adduct by neutral alumina chromatography (20 mm × 200 mm column, 3:1 hexanes/EtOAc as eluent) afforded pure adduct 356o as a yellow semi-solid in 41% isolated yield (191 mg, 0.41 mmol); dr: not determined. The optical purity of 356o could not be determined due to messy HPLC signals. 1 Spectral data for 356o: Rf = 0.29 (1:3 EtOAc/hexanes). H NMR (CDCl3, 500 MHz) δ 0.80 (t, J = 7.5 Hz, 3H), 0.89 (t, J = 7.3 Hz, 3H), 1.32-1.39 (m, 5H), 1.58-1.71 (m, 2H), 1.78-1.87 (m, 2H), 3.18 (t, J = 6.2 Hz, 1H), 3.76 (s, 3H), 3.77 (s, 3H), 4.25-4.30 (m, 2H), 5.39 (s, 1H), 6.78-6.84 (m, 5H), 7.13 (dd, J = 16.8, 8.6 Hz, 4H), 7.50 (s, 1H); 13 C (CDCl3, 75 MHz) δ 8.87, 14.24, 14.31, 3 20.50, 23.21, 28.63, 48.41, 55.18, 60.96, 74.72, 74.99, (one sp carbon not located), 113.66, 113.74, 113.81, 128.20, 128.53, 135.66, 135.80, 147.45, 158.52, 162.57, 164.36; IR (thin film, -1 cm ) 3331 br, 2961m, 2836w, 1701m, 1608w, 1510vs, 1464w, 1246vs; HRMS (ESI-TOF) m/z + 466.2703 [(M+H ); calcd. for C27H36N3O4: 466.2706] (4S,5R)-ethyl-5-((E)-((bis(3,5-di-tert-butyl-4- tBu OMe N NH N EtO2C 360a tBu methoxyphenyl)methyl)imino)methyl)-4,5-dimethyl4,5-dihydro-1H-pyrazole-3-carboxylate 360a: Imine 358a (107 mg, 0.200 mmol) was reacted according to tBu tBu OMe the procedure described above for imine 333o with (S)- VAPOL as ligand except with the following differences; a) the reaction is 0.4 M in imine 358a, 521 b) 2 equiv of EDA used, c) purified imine 358a was added in neat form. The reaction resulted 1 adduct 360a in 59% NMR yield which was determined by H NMR spectra with Ph3CH as the internal standard. The resulting crude [3+2] adduct 360a could not be purified on either neutral alumina or silica gel chromatography. However, a sample was prepared by quickly passing the crude product through a plug of neutral alumina for HPLC analysis. The optical purity of 360a was determined to be 50% ee by HPLC analysis (CHIRALCEL OD column, 99:01 hexane/iPrOH at 222nm, flow-rate: 0.7 mL/min). Retention times, Rt = 11.82 min (major enantiomer, 360a) and Rt = 17.27 min (minor enantiomer, ent-360a). 1 Spectral data for 360a: Rf = 0.29 (1:3 EtOAc/hexanes). H NMR (CDCl3, 500 MHz) δ 1.26 (d, J = 7.0 Hz, 3H), 1.35-1.42 (m, 42H), 3.36 (q, J = 7.2 Hz, 1H), 3.70 (s, 3H), 3.70 (s, 3H), 4.29 (q, J = 7.2 Hz, 2H), 5.34 (s, 1H), 6.72 (s, 1H), 7.06 (s, 2H), 7.08 (s, 2H), 7.75 (s, 1H). This compound was not characterized as it’s being in crude form. However, it was further reduced to amine 367a and thereafter the amine 367a is completely characterized and given below. N NH EtO2C ((4S,5R)-ethyl-5-((E)-((bis(4-methoxy-3,5- OMe dimethylphenyl)methyl)imino)methyl)-4,5-dimethyl N -4,5-dihydro-1H-pyrazole-3-carboxylate 361a: Imine 359a (73 mg, 0.200 mmol) was reacted according to 361a OMe the procedure described above for imine 333o with (S)- VAPOL as ligand except with the following differences; a) the reaction is 0.4 M in imine 359a, b) 2 equiv of EDA used, c) purified imine 359a was added in neat form. The reaction resulted 1 adduct 361a in 33% NMR yield which was determined by H NMR spectra with Ph3CH as the 522 internal standard. The resulting crude [3+2] adduct 361a could not be purified on either neutral alumina or silica gel chromatography. No further attempt was made to isolate or analyze adduct 361a. 6.8.6 Multicomponent [3+2] Cycloaddition of aldehyde 352a (Scheme 6.7) O O OEt (S)-VAPOL (10 mol %) BUDAM B(OPh)3 (30 mol %) NH2 126d Toluene 80 °C, 0.5 h 352a 4 Å MS N2 N NH 85 25 °C, 24 h EtO2C N BUDAM 360a 60% y, 50%ee (4S,5R)-ethyl-5-((E)-((bis(3,5-di-tert-butyl-4-methoxyphenyl)methyl)imino)methyl)-4,5dimethyl-4,5-dihydro-1H-pyrazole-3-carboxylate 360a: To a 25 mL flame-dried home-made Schlenk flask (see Figure 2.26) equipped with a stir bar and flushed with argon was added (S)VAPOL 58 (11 mg, 0.02 mmol), commercial B(OPh)3 (17.4 mg, 0.060 mmol) and amine 126d (94 mg, 0.2 mmol) and toluene (0.5 mL). The flask was sealed by closing the Teflon valve, and then placed in an 80 ºC (oil bath) for 1 h. The flask was then allowed to cool to room temperature and open to argon through side-arm of the Schlenk flask. To this flask was then added 4Å MS (50 mg, freshly flame-dried) and aldehyde 352a (19 mg, 0.22 mmol, 1.1 equiv). The resulting mixture was stirred for 5 min at room temperature. To this solution was rapidly added EDA 85 (42 µL, 0.4 mmol). The resulting mixture was stirred for 24 h at room temperature. The reaction was dilluted by addition of hexane (6 mL). The reaction mixture was then transferred to a 100 mL round bottom flask. 523 The reaction flask was rinsed with dichloromethane (5 mL × 2) and the rinse was added to the 100 mL round bottom flask. The resulting solution was then concentrated in vacuo followed by exposure to high vacuum (0.05 mm Hg) for 1 h to afford the crude aziridine as a pale yellow semi solid. The reaction resulted 1 adduct 360a in 60% NMR yield which was determined by H NMR spectra with Ph3CH as the internal standard. A sample was prepared by quickly passing the crude product through a plug of neutral alumina for HPLC analysis. The optical purity of 360a was determined to be 50% ee by HPLC analysis (CHIRALCEL OD column, 99:01 hexane/iPrOH at 222nm, flow-rate: 0.7 mL/min). Retention times, Rt = 11.82 min (major enantiomer, 360a) and Rt = 17.27 min (minor enantiomer, ent-360a). 6.8.7 Hydrolysis and reduction of [3+2] adduct 360a (Scheme 6.8) N NH N EtO2C 1M or 3M HCl BUDAM 25 °C, 24 h BUDAM-NH2 + complex mixture 126d 360a crude from a 0.25 mmol scale reaction a) Hydrolysis: To a 50 mL round bottom flask was taken the crude [3+2] adduct from the 0.25 mmol scale reaction and THF (1 mL). To this solution was added HCl (0.1 mL, 1 M) dropwise and the resulting mixture stirred for 24 h. A continuous stirring was maintained during the addition of the acid. After 24 h, the reaction mixture was extracted with ether (15 mL × 3) to get crude product. The combined organic layer was then washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to afford the crude reaction mixture. A complex 524 1 mixture of compounds along with BUDAM amine 126d was observed based on the H NMR analysis of crude reaction mixture. N NH N EtO2C BUDAM N NH NaBH4, EtOAc EtO2C –78 °C to 0 °C 24 h 360a H N BUDAM 367a 43% y, 50%ee (over two steps) crude from a 0.25 mmol scale reaction b) Reduction: To a 50 mL round bottom flask was taken the crude [3+2] adduct from the 0.25 mmol scale reaction and EtOAc (1 mL). To this solution was added NaBH4 (11 mg, 0.28 mmol) at –78 ºC and the resulting mixture allowed to warm to 0 ºC over a period of 30 min. The reaction was stirred for 24 h at 0 ºC. After 24 h, the reaction was quenched by the addition of aqueous NH4Cl (3 mL) and extracted with EtOAc (5 mL × 3). The combined organic layer was then washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to afford crude amine 367a. Purification by silica gel chromatography (20 mm × 200 mm column, 8:1 hexanes/EtOAc as eluent) afforded pure amine 367a as a white foamy solid in 43% isolated yield (70 mg, 0.11 mmol, over two steps). The optical purity of 367a was determined to be 50% ee by HPLC analysis (CHIRALCEL OD column, 99:01 hexane/iPrOH at 222nm, flow-rate: 0.7 mL/min). Retention times, Rt = 6.66 min (major enantiomer, 367a) and Rt = 12.04 min (minor enantiomer, ent-367a). 1 Spectral data for 367a: Rf = 0.31 (1:8 EtOAc/Hexanes) H NMR (CDCl3, 500 MHz) δ 1.15 (d, J = 7.3 Hz, 3H), 1.17 (s, 3H), 1.35-1.37 (m, 39H), 2.51 (d, J = 12.1 Hz, 1H), 2.56 (d, J = 12.1 525 Hz, 1H), 3.13 (q, J = 7.3 Hz, 1H), 3.66 (s, 6H), 4.24-4.30 (m, 2H), 4.62 (s, 1H), 7.16 (s, 2H), 7.19 (s, 2H), 7.73 (s, 1H); 13 C NMR (CDCl3, 125 MHz) δ 11.39, 14.25, 18.27, 31.99, 32.02, 32.04, 32.08, 32.10, 35.73, 35.93, 44.11, 55.04, 60.73, 64.04, 64.06, 64.36, 67.60, 69.42, (one 3 sp carbon not located), 125.45, 125.56, 129.00, 132.32, 143.19, 143.27, 158.30, 158.33, 162.81, 163.24. IR (thin film, cm-1) 3332br, 2961m, 1701m, 1653w, 1559m, 1456s, 1412s, 1223vs; + HRMS (ESI-TOF) m/z 650.4890 [(M+H ); calcd. for C40H64N3O4: 650.4897]. 6.8.8 Attempts towards catalytic asymmetric Ugi 3CR, Ugi-type 2CR and Ugi-type 3CR and Passerini reaction (Table 6.7-6.8 and Scheme 6.13) a) Ugi-3CR: i) with isocyanide 368a and acid 334a Ar N IMINO-BOROX catalyst 190a (10 mol%) – Ar + C + N 368a 111a MeO Ar tBu Toluene, 25 °C, 24 h Ph + Ph Ph O O N * Ar Ph 369a H O N * tBu tBu + Ar N N H H Ar Ph 370a O O 334a Ar = 3,5-Me2-4-OMe-C6H4 Ar2CH = MEDAM H N-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-N-(2Ph O O N * Ph N H tBu (tert-butylamino)-2-oxo-1-phenylethyl )benzamide 369a: To a 25 mL flame-dried home-made Schlenk flask (see Figure 2.26) flushed with argon was added imine 111a (194 OMe mg, 0.500 mmol), (S)-VAPOL (27 mg, 0.05 mmol) and B(OPh)3 (58 mg, 0.2 mmol) and toluene (1 mL). The stopcock was sealed, and the flask was 526 then placed in an 80 °C oil bath for 1 h. The flask was then cooled to room temperature. Isocyanide 368a (57 µL, 0.50 mmol) was then added and the mixture was stirred for 5 min at room temperature. Benzoic acid 334a (61 mg, 0.5 mmol) was then added in one portion followed by the addition of toluene (0.5 mL). The reaction mixture was then stirred for 24 h. After 24 h, the reaction was quenched by the addition of water (3 mL). The solution was diluted with EtOAc (2 mL). The organic layer was then separated, and the aqueous layer was extracted by EtOAc (5 mL × 3). The combined organic solution was then washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford crude product. Purification by silica gel chromatography (35 mm × 350 mm column, 5:1 hexanes/EtOAc as eluent) afforded pure amide 369a (mp. 174-176 ºC) as a white solid in 40% isolated yield (119 mg, 0.20 mmol). The optical purity of 369a was determined to be <1% ee by HPLC analysis (CHIRALCEL OD column, 99:01 hexane/iPrOH at 222nm, flow-rate: 0.7 mL/min). Retention times, Rt = 23.61 min (369a) and Rt = 31.49 min (ent-369a). 1 Spectral data for 369a: Rf = 0.21 (1:5 EtOAc/Hexanes) H NMR (CDCl3, 500 MHz) δ 1.20 (s, 9H), 1.94 (s, 6H), 2.29 (s, 6H), 3.50 (s, 3H), 3.76 (s, 3H), 4.87 (s, 1H), 5.55 (s, 1H), 6.06 (s, 1H), 6.42 (s, 2H), 7.01 (s, 4H), 7.38-7.31 (m, 6 H), 7.48-7.45 (m, 2 H); 13 C NMR (CDCl3, 125 MHz) δ 15.79,16.33, 28.44, 51.07, 59.36, 59.65, 65.87, 66.81, 126.5, 127.12, 127.68, 128.39, 128.61, 128.95, 129.67, 130.14, 130.52, 130.75, 134.05, 134.28, 136.81, 155.95, 156.24, 168.47, 172.72; IR (thin film, cm-1) 3424m, 2928m, 1682s, 1637s, 1487s, 1419m, 1223s; Mass spectrum m/z (% + rel intensity) 592.7 (100) M , 278.4, 260.4. Anal. calcd for C38H44N2O4: C, 77.00; H, 7.48; N, 4.73. Found: C, 76.04; H, 7.84; N, 4.26. 527 2-((bis(4-methoxy-3,5-dimethylphenyl)methyl)amino)-N- MeO H N * O Ph N H tBu (tert-butyl)-2-phenylacetamide 370a: There was no sign of 1 370a based on H NMR analysis of crude reaction mixture. OMe ii) with isocyanide 368b and acid 334b Ar – Ar + C + N N Ph IMINO-BOROX catalyst 190a (10 mol%) R4 R3 Ar Toluene, 25 °C, 24 h O N * Ar 368b 111a O Ph 369b H O N * R4 R4 + Ar N N H H Ar Ph 370b O + R3 O 334b Ar = 3,5-Me2-4-OMe-C6H4 Ar2CH = MEDAM H R3 = 4-pentylbicyclo[2.2.2]octyl R4 = 2-Naphthyl The reaction was performed as described above with acid 334b and isocyanide 368b. A complex mixture of six different compounds was obtained. None of them was 369b. One of the fractions obtained was amide 370b. N-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-N-(2(naphthalene-2-ylamino)-2-oxo-1-phenyl MeO O pentyl bicyclo[2.2.2]octane-1-carboxamide O N * Ph 1 N H ethyl )-4369b: There was no sign of 360a based on H NMR analysis of crude reaction mixture. OMe 528 2-((bis(4-methoxy-3,5-dimethylphenyl)methyl) MeO H N * O Ph amino)-N-(naphthalen-2-yl)-2-phenyl N H acetamide 370b: Purification by silica gel chromatography (35 mm × 350 mm column, 5:1 hexanes/EtOAc as OMe eluent) afforded pure amide 370b (mp. 87-89 ºC) as a yellow solid in 26% isolated yield (72 mg, 0.13 mmol). The optical purity of 370b was determined to be 8% ee by HPLC analysis (CHIRALCEL OD-H column, 99:01 hexane/iPrOH at 222nm, flow-rate: 0.7 mL/min). Retention times, Rt = 50.17 min (major enantiomer, 370b) and Rt = 89.96 min (minor enantiomer, ent-370b). 1 Spectral data for 370b: Rf = 0.55 (1:5 EtOAc/Hexanes) H NMR (CDCl3, 500 MHz) δ 2.28 (s, 6H), 2.29 (s, 6H), 3.65 (s, 3H), 3.73 (s, 3H), 4.37 (s, 1H), 4.74 (s, 1H), 6.97 (s, 2H), 7.04 (s, 2H), 7.33-7.42 (m, 7H), 7.45-7.48 (m, 1H), 7.49 (dd, J = 8.8, 2.1 Hz, 1H), 7.79 (t, J = 9.2 Hz, 3H), 8.26 (d, J = 1.6 Hz, 1H), 9.51 (s, 1H); 13 C NMR (CDCl3, 125 MHz) δ 16.23, 16.27, 59.53, 59.64, 64.90, 66.11, 116.07, 119.46, 124.89, 126.47, 127.47, 127.49, 127.58, 127.71, 128.28, 128.68, 128.99, 130.58, 131.07, 131.08, 133.85, 135.05, 137.68, 137.96, 139.21, 156.19, 170.55 2 -1 (two sp carbon not located); IR (thin film, cm ) 3312br, 2926m, 1684s, 1632m, 1603m, 1529s, + 1485s, 1221s; HRMS (ESI-TOF) m/z 559.2961 [(M+H ); calcd. for C37H39N2O3: 559.2961]. [α ]20 –0.8 (c 1.0, CH2Cl2) on 8% ee material. D € 529 b) Ugi-type-2CR: Ar N Ar NC + IMINO-BOROX catalyst 190a (10 mol%) Toluene, 25 °C, 24 h Ph 368b 111a H O Ar N * N H Ar Ph 370b Ar = 3,5-Me2-4-OMe-C6H4 Ar2CH = MEDAM 2-((bis(4-methoxy-3,5-dimethylphenyl)methyl) MeO H N * O Ph amino)-N-(naphthalen-2-yl)-2-phenyl acetamide N H 370b: To a 25 mL flame-dried home-made Schlenk flask (see Figure 2.26) flushed with argon OMe was added imine 111a (194 mg, 0.500 mmol), (S)- VAPOL (27 mg, 0.05 mmol) and B(OPh)3 (58 mg, 0.2 mmol) and toluene (1 mL). The stopcock was sealed, and the flask was then placed in an 80 °C oil bath for 1 h. The flask was then cooled to room temperature. Isocyanide 368b (77 mg, 0.5 mmol) was then added and the mixture was stirred for 5 min at room temperature. The reaction mixture was then stirred for 24 h. After 24 h, the reaction was quenched by the addition of water (3 mL). The solution was diluted with EtOAc (2 mL). The organic layer was then separated, and the aqueous layer was extracted by EtOAc (5 mL × 3). The combined organic solution was then washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford crude reaction mixture. 530 1 Unfortunately, no 370b was observed based on the H NMR analysis of the crude reaction mixture. c) Ugi-type-3CR: O Ph + H 127a Ph Ph NH2 126a + – C + N (S)-VAPOL-B(OPh)3 catalyst (20 mol%) tBu Toluene, 25 °C, 24 h with or without 368a 4Å MS H N * Ph Ph O Ph N H tBu 371a 2-(benzhydrylamino)-N-(tert-butyl)-2-phenylacetamide: To a 25 mL flame-dried home-made Schlenk flask (see Figure 2.26) equipped with a stir bar and flushed with argon was added (S)VAPOL (54 mg, 0.1 mmol) and commercial B(OPh)3 (116 mg, 0.1 mmol) and water (1.8 µL, 0.1 mmol). Under an argon flow through the side-arm of the Schlenk flask, dry toluene (2 mL) was added through the top of the Teflon valve. The flask was sealed by closing the Teflon valve, and then placed in an 80 ºC oil bath for 1 h. After 1 h, a vacuum (0.5 mm Hg) was carefully applied by slightly opening the Teflon valve to remove the volatiles. After the volatiles were removed completely, a full vacuum was applied and maintained for a period of 30 min at a temperature of 80 ºC (oil bath). The flask was then allowed to cool to room temperature and opened to argon through the side-arm of the Schlenk flask. To the flask containing the precatalyst was added amine 127a (92 mg, 0.50 mmol), benzaldehyde 126a (51 µL, 0.50 mmol), isocyanide 368a (57 µL, 0.50 mmol) and toluene (1 mL). The stopcock was sealed, and the reaction mixture was then stirred for 24 h. After 24 h, the reaction was quenched by the addition of water (3 mL). The solution was diluted with EtOAc (2 mL). The organic layer was then 531 separated, and the aqueous layer was extracted by EtOAc (5 mL × 3). The combined organic solution was then washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in 1 vacuo to afford crude reaction mixture. Unfortunately, no 371a was observed based on the H NMR analysis of the crude reaction mixture. The imine 78a was observed. d) Passerini reaction O Ph + H 127a O H O + Ph 334a – C + N catalyst 35 (20 mol%) Toluene 80 °C, 48 h tBu 368a O Ph Ph O * H N tBu O 377a 35% y, 6% ee Ph Ph O O O P OH 35 (S)-VAPOL-PO3H 2-(tert-butylamino)-2-oxo-1-phenylethyl benzoate 377a: To a 25 mL flame-dried Schlenk flask flushed with argon was added (S)-VAPOL Phosphoric acid 35 (0.1 mmol) and toluene (1 mL). To the catalyst solution was added benzaldehyde 126a (51 µL, 0.50 mmol), isocyanide 368a (57 µL, 0.50 mmol) and the mixture was stirred for 5 min at room temperature. Benzoic acid 334a (61 mg, 0.50 mmol) was then added in one portion followed by the addition of toluene (0.5 mL). The mixture was then stirred for 48 h. The reaction was quenched by the addition of 532 sat. NaHCO3 (3 mL). The solution was diluted with EtOAc (2 mL). The organic layer was then separated, and the aqueous layer was extracted by EtOAc (5 mL × 3). The combined organic solution was then washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford crude product. Purification by silica gel chromatography (35 mm × 350 mm column, 9:1 hexanes/EtOAc as eluent) afforded product 377a (mp. 149-150 ºC) as a white solid in 35% isolated yield (54.5 mg, 0.175 mmol). The optical purity of 377a was determined to be 6% ee by HPLC analysis (CHIRALCEL OD column, 99:01 hexanes/iPrOH at 222 nm, flow-rate: 0.7 mL/min). Retention times, Rt = 42.42 min (major enaniomer, 377a) and Rt = 52.24 min (minor enantiomer, ent-377a). Spectral data for 377a: Rf = 0.24 (1:9 EtOAc/Hexanes) 1H NMR (CDCl3, 300 MHz) δ 1.35 (s, 9 H), 5.98 (br s, 1H), 6.20 (s, 1H), 7.34-7.52 (m, 7H), 7.59 (t, 1H, J = 7.5 Hz), 8.07 (d, 2H, J = 7.2 Hz); 13 C (CDCl3, 75 MHz) δ 28.69, 51.63, 76.09, 164.87, 167.30. These spectral data match those previously reported for this compound. 45 6.8.9 Attempts towards kinetic resolution of imines (Table 6.10-6.11) a) Kinetic resolution of phenylneopentyl imine rac-378 furnishing amine (S)-384 O tBu Ph N rac-378 Ph + OEt N2 1 IMINO-BOROX catalyst (from (S)-VAPOL) (10 mol %) CCl4, 25 °C, 24 h 2 0.4 N HCl/THF 25 °C, 2.5 h tBu Ph tBu N N + Ph CO2Et Ph ent-380 85 (x equiv) Ph NH2 (S)-384 533 CO2Et 379 tBu + Ph Aziridination: To a 25 mL flame-dried home-made Schlenk flask (see Figure 2.26) equipped with a stir bar and flushed with argon was added (S)-VAPOL (54 mg, 0.1 mmol) and B(OPh)3 (87 mg, 0.3 mmol). Under an argon flow through the side-arm of the Schlenk flask, dry toluene (2 mL) was added to dissolve the two reagents. The flask was sealed by closing the Teflon valve, and then placed in an 80 ºC (oil bath) for 1 h. After 1 h, a vacuum (0.5 mm Hg) was carefully applied by slightly opening the Teflon valve to remove the volatiles. After the volatiles are removed completely, a full vacuum is applied and is maintained for a period of 30 min at a temperature of 80 ºC (oil bath). The flask was then allowed to cool to room temperature and open to argon through side-arm of the Schlenk flask. To the flask containing the pre-catalyst was added aldimine rac-378 (mg, 1.00 mmol) and CCl4 (2 mL) under argon flow through sidearm of the Schlenk flask. The reaction mixture was stirred for 5 min to give a light yellow solution. To this solution was rapidly added EDA 85 (52 µL, 0.5 mmol) followed by closing the Teflon valve. The resulting mixture was stirred for 24 h at room temperature. The reaction was dilluted by addition of hexane (6 mL). The reaction mixture was then transferred to a 100 mL round bottom flask. The reaction flask was rinsed with dichloromethane (5 mL × 2) and the rinse was added to the 100 mL round bottom flask. The resulting solution was then concentrated in vacuo followed by exposure to high vacuum (0.05 mm Hg) for 1 h to afford the crude mixture. 1 The conversion was 50% of rac-378 as determined by the H NMR of the crude reaction mixture. Hydrolysis: To a 50 mL round bottom flask was taken the crude reaction mixture and THF (10 mL). To this solution was added HCl (2 mL, 0.4 N) dropwise and the resulting mixture stirred 534 for 2.5 h. A continuous stirring was maintained during the addition of the acid. After 2.5 h, the reaction mixture was extracted with ether (15 mL × 3) to get crude aziridine ent-380. The aqueous layer was treated with saturated aqueous Na2CO3 to bring the solution up to pH = 9. The resulting aqueous layer was further extracted with ether (10 mL × 8). The combined organic layer was then washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to afford the crude amine (S)-384. Purification: a) aziridine ent-380: Purification of the crude aziridine by silica gel chromatography (20 mm × 200 mm column, 35:1 hexanes/EtOAc as eluent) afforded pure cis-aziridine ent-380 as a white solid (mp 47-52 ºC) in 41% isolated yield (138 mg, 0.41 mmol); dr (ent-380:379) = 20:1. The optical purity of ent-380 was determined to be 94% ee by HPLC analysis (CHIRALPAK AD column, 99.5:0.5 hexane/2-propanol at 225nm, flow-rate: 1.0 mL/min): retention times; Rt = 6.8 min (major enantiomer, ent-380) and Rt = 8.8 min (minor enantiomer, 380). 1 Spectral data for ent-380: Rf = 0.12 (1:35 EtOAc/hexanes). H NMR (CDCl3, 300 MHz) δ 0.99 (t, J = 7.1 Hz, 3H), 1.03 (s, 9H), 2.60 (s, 1H), 2.68 (d, J = 6.6 Hz, 1H), 2.73 (d, J = 6.6 Hz, 1H), 3.95 (q, J = 7.1 Hz, 2H), 7.11-7.39 (m, 10H); 13 C (CDCl3, 75 MHz) δ 13.94, 27.27, 36.45, 44.52, 51.73, 60.43, 83.47, 126.84, 126.93, 127.22, 127.48, 127.68, 129.22, 135.54, 140.12, 167.82; [α ]20 +82.5 (c 1.0, CHCl3 on 94% ee material (HPLC). These spectral data match D those previously reported for this compound. 38 535 b) amine (S)-384: Purification of the crude amine by silica gel chromatography (20 mm × 200 mm column, 4:1:0.1 hexanes/EtOAc/MeOH as eluent) afforded pure amine (S)-384 as a colorless oil in 34% isolated yield (56 mg, 0.34 mmol). The optical purity of (S)-384 was determined to be 66% ee by HPLC analysis (CHIRALCEL OD-H column, 99:1 hexane/2propanol at 250nm, flow-rate: 1.0 mL/min): retention times; Rt = 7.9 min (major enantiomer, (S)-384) and Rt = 4.2 min (minor enantiomer, (R)-384). 1 Spectral data for (S)-384: Rf = 0.24 (4:1:0.1 hexanes/EtOAc/MeOH). H NMR (CDCl3, 300 MHz) δ 10.89 (s, 9H), 1,42 (brs, 2H), 3.69 (s, 1H), 7.20-7.29 (m, 5H); 13 C NMR (CDCl3, 75 MHz) δ 26.42, 34.89, 65.20, 126.60, 127.37, 128.13, 143.68. These spectral data match those 44 previously reported for this compound. b) Kinetic resolution of phenylneopentyl imine rac-378 furnishing amine (S)-385 O tBu Ph N rac-378 1 IMINO-BOROX catalyst (from (S)-VAPOL) (10 mol %) Toluene, 25 °C, 24 h Ph + tBu 85 (x equiv) 2 0.4 N HCl/THF 25 °C, 3 h 3 Boc2O, H2O 25 °C, 3 h tBu N OEt N2 Ph N + Ph CO2Et Ph ent-380 CO2Et 379 tBu + Ph Ph NHBoc (S)-385 Aziridination: Same as above except that the pre-catalyst was made using (S)-VAPOL (54 mg, 0.1 mmol), B(OPh)3 (116 mg, 0.4 mmol) and water (1.8 µL, 0.1 mmol). The reaction was 536 performed in toluene. 1 The conversion was 44% of rac-378 as determined by the H NMR of the crude reaction mixture. dr (ent-380:379): 10:1. Hydrolysis and Boc protection: To a 50 mL round bottom flask was taken the crude reaction mixture and THF (10 mL). To this solution was added HCl (4 mL, 0.4 N) dropwise and the resulting mixture stirred for 3 h. A continuous stirring was maintained during the addition of the acid. After 2.5 h, the reaction mixture was extracted with ether (15 mL × 3) to get crude aziridine ent-380. The aqueous layer was treated with saturated aqueous Na2CO3 to bring the solution up to pH = 9. The resulting aqueous layer was further extracted with ether (10 mL × 8). The combined organic layer was then washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to afford the crude amine (S)-384. To the flask containing crude amine was added H2O (0.5 mL). The resulting mixture was stirred for 5 min at room temperature. To this mixture was added Boc2O (126 µL, 0.55 mmol) at room temperature. Transparent droplets were formed and after stirring the reaction mixture, a white emulsion appeared on the surface of the walls of the flask with slow effervescence. A white solid settled down and indicated the completion of the reaction (time = 3 h). The resulting was extracted with EtOAc (5 mL × 3). The combined organic layer was then washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to afford the pure amine (S)-385. Purification: a) aziridine ent-380: Same as above 537 b) amine (S)-385: No purification was carried as the obtained amine was very pure. The reaction afforded pure amine (S)-385 (mp. 111-112 ºC on 77% ee material) as a white solid in 44% isolated yield (116 mg, 0.44 mmol). The optical purity of (S)-385 was determined to be 54% ee by HPLC analysis (PIRKLE COVALENT (R,R) WHELK-O 1 column, 99:1 hexane/2-propanol at 225nm, flow-rate: 1.0 mL/min): retention times; Rt = 9.83 min (major enantiomer, (S)-385) and Rt = 27.17 min (minor enantiomer, (R)-385). 1 Spectral data for (S)-385: Rf = 0.28 (1:9 EtOAc/hexanes). H NMR (DMSO-d6, 500 MHz) δ 0.83 (s, 9H), 1.37 (s, 9H), 4.39 (d, J = 10.1 Hz, 1H), 7.20 (t, J = 6.8 Hz, 2H), 7.26-7.30 (m, 3H), 7.37 (d, J = 10.0 Hz, 1H); 13 C (DMSO-d6, 125 MHz) δ 26.57, 28.28, 34.84, 62.94, 77.57, 126.42, 127.24, 128.43, 140.97, 155.41.; IR (thin film, cm-1) 3285br, 2972s, 1899vs, 1495m, + 1366s, 1173s; HRMS (ESI-TOF) m/z 264.1960 [(M+H ); calcd. for C16H26NO2 : 264.1964]; [α ]20 –21.3 (c 1.0, EtOAc) on 77% ee material (HPLC). D 538 REFERENCES 539 REFERENCES (1) Osborn, H. M. I.; Sweeney, J. Tetrahedron: Asymmetry 1997, 8, 1693-1715. (2) (a) Pellissier, H. Tetrahedron 2010, 66, 1509-1555. (b) Müller, P.; Fruit, C. Chem. Rev. 2003, 103, 2905-2919. (3) (a) Evans, D. A.; Faul, M. M.; Bilodeau, M. T.; Anderson, B. A.; Barnes, D. M. J. Am. Chem. Soc. 1993, 115, 5328-5329. (b) Li, Z.; Conser, K. R.; Jacobsen, E. N. J. Am. Chem. Soc. 1993, 115, 5326-5327. (c) Noda, K.; Hosoya, N.; Irie, R.; Ito, Y.; Katsuki, T. Synlett 1993, 469-471. (d) Kawabata, H.; Omura, K.; Uchida, T.; Katsuki, T. Chem.–Asian. J. 2007, 2, 248-256. (e) Subbarayan, V.; Ruppel, J. V.; Zhu, S.; Perman, J. A.; Zhang, X. P. Chem. Commun. 2009, 42664268. (4) Deiana, L.; Dziedzic, P.; Zhao, G. L.; Vesely, J.; Ibrahem, I.; Rios, R.; Sun, J. L.; Cordova, A. Chem.–Eur. J. 2011, 17, 7904-7917. (5) (a) Hansen, K. B.; Finney, N. S.; Jacobsen, E. N. Angew. Chem., Int. Ed. 1995, 34, 676-678. (b) Aggarwal, V. K.; Alonso, E.; Fang, G. Y.; Ferrara, M.; Hynd, G.; Porcelloni, M. Angew. Chem., Int. Ed. 2001, 40, 1433-1436. (c) Aggarwal, V. K.; Ferrara, M.; O'Brien, C. J.; Thompson, A.; Jones, R. V. H.; Fieldhouse, R. J. Chem. Soc., Perkin Trans. 1 2001, 1635-1643. (d) Aggarwal, V. K.; Winn, C. L. Acc. Chem. Res. 2004, 37, 611-620. (6) (a) Casarrubios, L.; Perez, J. A.; Brookhart, M.; Templeton, J. L. J. Org. Chem. 1996, 61, 8358-8359. (b) G. Rasmussen, K.; Anker Jorgensen, K. J. Chem. Soc., Perkin Trans. 1 1997, 1287-1292. (c) Juhl, K.; G. Hazell, R.; Anker Jorgensen, K. J. Chem. Soc., Perkin Trans. 1 1999, 2293-2297. (d) Mayer, M. F.; Hossain, M. M. J. Organomet. Chem. 2002, 654, 202-209. (e) Morales, D.; Pérez, J.; Riera, L.; Riera, V.; Corzo-Suárez, R.; García-Granda, S.; Miguel, D. Organometallics 2002, 21, 1540-1545. (f) Krumper, J. R.; Gerisch, M.; Suh, J. M.; Bergman, R. G.; Tilley, T. D. J. Org. Chem. 2003, 68, 9705-9710. (g) Redlich, M.; Hossain, M. M. Tetrahedron Lett. 2004, 45, 8987-8990. (7) (a) Williams, A. L.; Johnston, J. N. J. Am. Chem. Soc. 2004, 126, 1612-1613. (b) Wipf, P.; Lyon, M. A. ARKIVOC 2007, xii, 91-98. (c) Hashimoto, T.; Uchiyama, N.; Maruoka, K. J. Am. Chem. Soc. 2008, 130, 14380-14381. (d) Akiyama, T.; Suzuki, T.; Mori, K. Org. Lett. 2009, 11, 2445-2447. (e) Zeng, X.; Zeng, X.; Xu, Z.; Lu, M.; Zhong, G. Org. Lett. 2009, 11, 3036–3039. (f) Johnston, J. N.; Muchalski, H.; Troyer, T. L. Angew. Chem., Int. Ed. 2010, 49, 2290-2298. 540 (8) Hu, G.; Gupta, A. K.; Huang, R. H.; Mukherjee, M.; Wulff, W. D. J. Am. Chem. Soc. 2010, 132, 14669–14675. (9) (a) Zhang, Y.; Desai, A.; Lu, A.; Hu, G.; Ding, Z.; Wulff, W. D. Chem. –Eur. J. 2008, 14, 3785-3803. (b) Zhang, Y.; Lu, Z.; Desai, A.; Wulff, W. D. Org. Lett. 2008, 10, 5429-5432. (c) Mukherjee, M.; Gupta, A. K.; Lu, Z.; Zhang, Y.; Wulff, W. D. J. Org. Chem. 2010, 75, 56435660. (d) Ren, H.; Wulff, W. D. Org. Lett. 2010, 12, 4908-4911. (e) Hu, G.; Huang, L.; Huang, R. H.; Wulff, W. D. J. Am. Chem. Soc. 2009, 131, 15615-15617. (f) Desai, A. A.; Wulff, W. D. J. Am. Chem. Soc. 2010, 132, 13100-13103. (g) Vetticatt, M. J.; Desai, A. A.; Wulff, W. D. J. Am. Chem. Soc. 2010, 132, 13104-13107. (h) Desai, A. A.; Morán-Ramallal, R.; Wulff, W. D. Org. Synth. 2011, 88, 224-237. (10) (a) Antilla, J. C.; Wulff, W. D. Angew. Chem., Int. Ed. 2000, 39, 4518-4521. (b) Deng, Y. H.; Lee, Y. R.; Newman, C. A.; Wulff, W. D. Eur. J. Org. Chem. 2007, 2068-2071. (11) Lu, Z.; Zhang, Y.; Wulff, W. D. J. Am. Chem. Soc. 2007, 129, 7185-7194. (12) Hattori, K.; Yamamoto, H. J. Org. Chem. 1992, 57, 3264-3265. (13) Hu, G. PhD Dissertation, Michigan State University, 2007. (14) Gupta, A. K.; Mukherjee, M.; Wulff, W. D. Org. Lett. 2011, 13, 5866-5869. (15) Guan, Y.; Wulff, W. D., Unpublished results. (16) Noels, A. F.; Braham, J. N.; Hubert, A. J.; Teyssie, P. Tetrahedron 1978, 34, 3495-3497. (17) Branstetter, B.; Hossain, M. M. Tetrahedron Lett. 2006, 47, 221-223. (18) Hashimoto, T.; Naganawa, Y.; Maruoka, K. J. Am. Chem. Soc. 2008, 130, 2434-2435. (19) (a) Kano, T.; Hashimoto, T.; Maruoka, K. J. Am. Chem. Soc. 2006, 128, 2174-2175. (b) Gao, L.; Hwang, G. S.; Lee, M. Y.; Ryu, D. H. Chem. Commun. 2009, 5460-5462. (20) Hashimoto, T.; Naganawa, Y.; Kano, T.; Maruoka, K. Chem. Commun. 2007, 5143-5145. 541 (21) (a) Kano, T.; Hashimoto, T.; Maruoka, K. J. Am. Chem. Soc. 2005, 127, 11926-11927. (b) Chen, W.; Yuan, X. H.; Li, R.; Du, W.; Wu, Y.; Ding, L. S.; Chen, Y. C. Adv. Synth. Catal. 2006, 348, 1818-1822. (22) (a) Sibi, M. P.; Stanley, L. M.; Soeta, T. Org. Lett. 2007, 9, 1553-1556. (b) Sibi, M. P.; Stanley, L. M.; Soeta, T. Adv. Synth. Catal. 2006, 348, 2371-2375. (23) (a) Cafieri, F.; Fattorusso, E.; Taglialatela-Scafati, O. J Nat Prod 1998, 61, 122-125. (b) Cafieri, F.; Fattorusso, E.; Mangoni, A.; TaglialatelaScafati, O. Tetrahedron 1996, 52, 1371313720. (24) (a) El Kaim, L.; Grimaud, L. Tetrahedron 2009, 65, 2153-2171. (b) Domling, A. Chem. Rev. 2006, 106, 17-89. (c) Zhu, J. Eur. J. Org. Chem. 2003, 2003, 1133-1144. (d) Domling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3169-3210. (25) Ugi, I. Angew. Chem., Int. Ed. 1962, 1, 8-21. (26) Braude, E. A.; Nachod, F. C.; Phillips, W. D.; Zuckerman, J. J. Determination of Organic Structures by Physical Methods; Academic Press: New York, 1955. (27) Pan, S. C.; List, B. Angew. Chem., Int. Ed. 2008, 47, 3622-3625. (28) Huang, L.; Wulff, W. D., Unpublished results. (29) Mukherjee, M. PhD Dissertation, Michigan State University, 2012. (30) (a) McFarland, J. W. J. Org. Chem. 1963, 28, 2179-2181. (b) Keung, W.; Bakir, F.; Patron, A. P.; Rogers, D.; Priest, C. D.; Darmohusodo, V. Tetrahedron Lett. 2004, 45, 733-737. (c) Giovenzana, G. B.; Tron, G. C.; Paola, S. D.; Menegotto, I. G.; Pirali, T. Angew. Chem., Int. Ed. 2006, 45, 1099-1102. (d) Diorazio, L. J.; Motherwell, W. B.; Sheppard, T. D.; Waller, R. W. Synlett 2006, 2006, 2281,2283. (e) Tanaka, Y.; Hasui, T.; Suginome, M. Org. Lett. 2007, 9, 4407-4410. (f) Tanaka, Y.; Hidaka, K.; Hasui, T.; Suginome, M. Eur. J. Org. Chem. 2009, 11481151. (31) Yue, T.; Wang, M.-X.; Wang, D.-X.; Masson, G.; Zhu, J. Angew. Chem., Int. Ed. 2009, 48, 6717-6721. 542 (32) Hashimoto, T.; Kimura, H.; Kawamata, Y.; Maruoka, K. Angew. Chem., Int. Ed. 2012, ASAP. (33) Passerini, M. Gazz. Chim. Ital. 1921, 51, 126. (34) (a) Kusebauch, U.; Beck, B.; Messer, K.; Herdtweck, E.; Dömling, A. Org. Lett. 2003, 5, 4021-4024. (b) Andreana, P. R.; Liu, C. C.; Schreiber, S. L. Org. Lett. 2004, 6, 4231-4233. (c) Wang, S. X.; Wang, M. X.; Wang, D. X.; Zhu, J. P. Angew. Chem., Int. Ed. 2008, 47, 388-391. (35) (a) Yue, T.; Wang, M.-X.; Wang, D.-X.; Masson, G.; Zhu, J. J. Org. Chem. 2009, 74, 83968399. (b) Denmark, S. E.; Fan, Y. J. Org. Chem. 2005, 70, 9667-9676. (c) Denmark, S. E.; Fan, Y. J. Am. Chem. Soc. 2003, 125, 7825-7827. (36) Yue, T.; Wang, M. X.; Wang, D. X.; Zhu, J. P. Angew. Chem., Int. Ed. 2008, 47, 94549457. (37) Mukherjee, M.; Wulff, W. D., Unpublished results. (38) Huang, L.; Zhang, Y.; Staples, R. J.; Huang, R. H.; Wulff, W. D. Chem.–Eur. J. 2012, 18, 5302-5313. (39) (a) Lee, J. H.; Han, K.; Kim, M. J.; Park, J. Eur. J. Org. Chem. 2010, 999. (b) Turner, N. J. Nat. Chem. Biol. 2009, 5, 567. (c) Höhne, M.; Bornscheuer, U. T. ChemCatChem 2009, 1, 42. (d) Gotor-Fernandez, V.; Gotor, V. Curr. Opin. Drug Discovery Dev. 2009, 12, 784. (40) (a) Fu, G. C.; Arp, F. O. J. Am. Chem. Soc 2006, 128, 14264-14265. (b) Anstiss, M.; Nelson, A. Org. Biomol. Chem. 2006, 4, 4135. (c) Fu, G. C.; Arai, S.; Bellemin-Laponnaz, S. Angew. Chem., Int. Ed. 2001, 40, 234-236. (d) Yang, X.; Bumbu, V. D.; Birman, V. B. Org. Lett. 2011, 13, 4755. (e) Birman, V. B.; Jiang, H.; Li, X.; Guo, L.; Uffman, E. W. J. Am. Chem. Soc 2006, 128, 6536-6537. (f) Fowler, B. S.; Mikochik, P. J.; Miller, S. J. J. Am. Chem. Soc. 2010, 132, 2870. (g) Binanzer, M.; Hsieh, S. Y.; Bode, J. W. J. Am. Chem. Soc. 2011, 133, 19698. (h) Mioskowski, C.; Sabot, C.; Subhash, P. V.; Valleix, A.; Arseniyadis, S. Synlett 2008, 268-272. (i) List, B.; Hoffmann, S.; Nicoletti, M. J. Am. Chem. Soc 2006, 128, 13074-13075. (j) Backvall, J. E.; Paetzold, J. J Am Chem Soc 2005, 127, 17620-17621. (k) Mioskowski, C.; Srseniyadis, S.; Valleix, A.; Wagner, A. Angew. Chem., Int. Ed. 2004, 43, 3314-3317. (l) Krasnov, V. P.; Levit, G. L.; Andreeva, I. N.; Grishakov, A. N.; Charushin, V. N.; Chupakhin, O. N. Mendeleev Commun. 2002, 12, 27-28. (m) Mittal, N.; Sun, D. X.; Seidel, D. Org. Lett. 2012, 14 3084–3087. (41) Kagan, H. B.; Fiaud, J. C. Top. Stereochem. 1988, 18, 249. 543 (42) Chakraborti, A. K.; Chankeshwara, S. V. Org. Lett. 2006, 8, 3259-3262. (43) Denegri, B.; Kronja, O. J. Org. Chem. 2007, 72, 8427-8433. (44) Dalmolen, J.; Tiemersma-Wegman, T. D.; Nieuwenhuijzen, J. W.; van der Sluis, M.; van Echten, E.; Vries, T. R.; Kaptein, B.; Broxterman, Q. B.; Kellogg, R. M. Chem.–Eur. J. 2005, 11, 5619-5624. (45) Lagiakos, H. R.; Aguilar, M.-I.; Perlmutter, P. J. Org. Chem. 2009, 74, 8001-8003. 544 CHAPTER 7   INDIRECT IMINO-BOROX CATALYSIS MULTICOMPONENT CATALYTIC ASYMMETRIC AZIRIDINATION (MCAZ) I would like you to do one reaction for the grant! -William D. Wulff 7.1 Introduction In recent times, multicomponent reactions have been quite extensively studied and applied 1 in the field of asymmetric catalysis. An ideal multicomponent reaction is one which a) involves readily available starting materials and catalyst, b) is experimentally simple to perform, c) time and cost effective, d) atom-economical, e) is not effected by a diverse range of functionalities in 1d the substrates. Other than the aforementioned criteria; the reaction also has to be regio- and chemoselective enough such that the compatibility of the several components is matched to the point that any formation of the side products resulting from unwanted reactions between various components is avoided. 2 Apart from asymmetric aziridinations using chiral auxiliaries, considerable advances have 3 been made in the field of catalytic asymmetric aziridination over the past few years. there are two main approaches towards catalytic asymmetric aziridination: 4 Primarily, a) addition of 5 nitrogen to olefins via nitrene transfer with organometallic catalysts or organocatalysis b) addition of carbon to imines via metal-carbene transfer (carbene generated from diazo compound 6 or sulfur ylides) or the reaction of a diazo compound with an imine activated by either Lewis 545 7 8 acid or Brønsted acid. It must noted that the asymmetric aziridination reaction between the imines and diazo compounds in the presence of an acid catalyst must not be mistaken for Aza3a Darzens reaction as both are mechanistically distinct. reaction is reported with chiral auxiliaries. 3a In fact, asymmetric Aza-Darzens As discussed in previous chapters, our aziridination 9 protocol is a Brønsted acid catalyzed reaction (Figure 7.1A). However, to the best of our knowledge, no example of a multicomponent catalytic asymmetric aziridination has been reported. 1,10 Nishimura and coworkers have reported a stoichiometric asymmetric multicomponent aziridination of olefins. 11 A true multicomponent reaction involves the reaction of three or more reagents added simultaneously. 1 Multi-component reactions that involve reaction between two reagents and then interception of the resulting intermediate by the addition of a third reagent are sequential component reactions. 1,8d Herein, we report the first multi-component catalytic asymmetric aziridination (MCAZ) which satisfies all the criteria discussed above and incorporates the most simplified protocol yet developed for our catalytic asymmetric aziridination reaction (Figure 7.1B). 12 Figure 7.1 (A) Catalytic asymmetric aziridination of imines. (B) three-component catalytic asymmetric aziridination. (C) five-component catalyst assembly/catalytic asymmetric aziridination. A O R N Ar Ar 78/111 previous work + OEt N2 85 58 or 59 B(OPh)3 catalyst Ar Ar N R CO2Et 86/114 546 Figure 7.1 cont’d B Ar Ar Ar O O + NH2 + H R OEt N2 127 126a/126c 58 or 59 B(OPh)3 Ar N catalyst CO2Et R 85 86/114 unsolved challenge C O OEt OH * 85 OH Ar 58 or 59 Ar B(OPh)3 187a N2 N R Ar O R NH2 H 126a/126c 127 Ph Ph Ar OH OH Ph Ph OH 58 OH 59 new finding 547 CO2Et 86/114 In the course of studying factors that affect catalyst formation and in investigating the processes involved in the three-component catalytic asymmetric aziridination, and in examining the relationship between these two processes, we have discovered that this reaction is actually a five-component process in which the catalyst is assembled by the amine from the ligand and B(OPh)3 and then the catalyst causes imine formation and then finally, aziridine formation (Figure 7.1C). 7.2 13 The real need for a true multicomponent aziridination reaction Up to this point, all of the aziridination reactions we have reported have involved pre- formed imines. 9 A drawback to the use of imines of course is the requirement of an additional step. The difficulty in the purification of imines can vary from drawback to limitation. The method of choice for purification is crystallization since most imines tend to decompose on silica gel or upon distillation. For non-crystalline imines this usually necessitates the use of nonpurified imines. This is especially true for imines from unbranched aliphatic aldehydes and, as a result, lower yields and inductions are often observed. 9a,9c A more serious stricture is that for some unbranched alphatic imine substrates, no aziridines are observed at all. 14 After a rigorous 1 analysis of the H NMR spectra of the crude reaction mixtures from aziridination reactions performed in our lab over the last five years, we found that in the cases of imines derived unbranched alkyl aldehydes, the imines undergo self-condensation to give rise to a conjugated imine under the aziridination reaction conditions. For example, when imine 110o was reacted with EDA 85, the crude reaction mixture reveals the formation of the aziridine 113o and vinyl 9c imine 333o whose structure was confirmed by independent synthesis (Scheme 7.1A and 7.1B). This mixture of species appears to kill the catalyst and this may very well be due to the amine 126b, which is released in the formation of the condensation product 333o. More importantly, in 548 some cases, the imine can’t be generated in a clean fashion. For example, when aldehyde 127t is treated with amine 126c, long before complete formation of the imine 111t can be realized, selfcondensation of the imine begins to occur which gives rise to the conjugated imine 386t along with release of amine 126c (Scheme 7.1B and 7.1C). This imposes a serious limitation on the implementation of the AZ reaction in organic synthesis and the molecules in Figure 7.2 are illustrative of the point. 15 Scheme 7.1 (A) Self-condensation of imine 110o during aziridination. (B) Self condensation of 1 imine 111t during imine formation. (C) H NMR spectra of the formation of imine 111t at t = 4 h and 21 h A O DAM N + OEt 110o DAM DAM N Toluene 0 °C, 24 h N2 nPr (S)-VAPOL B(OPh)3 (10 mol%) + NH CO2Et (nPr)H nPr(H) nPr CO2Et 113o 85 116o(117o) 11% y, 73% ee DAM 2% y N Et H + + DAM NH2 nPr 333o 7% y B 126b 8% y Ar Ar H2N H a 126c O H Ph 127t 4 Å MS toluene, 25 °C, t h Hf Hb Ar Ar Ph N H c + Ar N H e Ph Ph 111t 386t Ar + Ar H2N H a 126c 549 Hd Ar Scheme 7.1 cont’d HC C HB HA HD after 21 h HF HC HB HA after 4 h ppm Figure 7.2 (A) Biologically important alkyl aziridines. 387: antimicrobial activity against Grampositive bacteria. 15b 388 and 389: cytotoxic and antimicrobial activity. arachidonate epoxygenase. 15d 15c 390: inhibitor of (B) Sphinganine family (391-394) of biologically important 15e compounds resulting from the ring-opening from alkyl aziridines. H N O OH O 6 OH OH H N CO2Me 7 5 387 H N H N 3 3 MeO2C 7 388 RO2C 2 389 OH 12 OH NH2 OH OH 12 OH NH2 12 390 OH OH NH2 12 OH NH2 391 392 393 394 L-threo-sphinganine D-erythro-sphinganine L-erythro-sphinganine D-threo-sphinganine (safingol) (sphinganine) 550 Additionally, an ideal multicomponent reaction is supposed to be experimentally simple to perform. The shortcoming of the optimized protocol for the catalytic asymmetric aziridination reaction include the need to generate a pre-catalyst (mixture of B1 106/107 and B2 108/109, Scheme 7.2) from the VAPOL or VANOL ligand and B(OPh)3. Henceforth, the secondary aim of the work was to simplify the overall procedure, thus developing a multicomponent aziridination reaction avoiding the generation of the pre-catalyst and thus validating its practical utility. 7.3 Can any or all the components of the proposed MCAZ reaction generate the boroxinate catalyst? The VAPOL ligand and commercial B(OPh)3 will react when heated to give a pre-catalyst which is a mixture of the mesoborate 106 (B1) and the pyroborate 108 (B2) with the latter typically predominating in ratios ranging from 4:1 to 20:1 depending on the exact protocol for 9a catalyst formation (Scheme 7.2). Treatment of the mixture of 106 and 108 with imine 78a/111a at room temperature leads to the formation of the chiral boroxinate 188a/190a (B3). 9f,9h Since this species has a boroxine ring as its core, we have decided to classify this family of catalysts as BOROX catalysts (Chapter 2). The BOROX species 188a/190a is an ion pair consisting of a protonated base (imine) as the cation and a chiral borate as the anion in the form of a boroxinate: a boroxine in which one of the borons is four-coordinate. It has been shown that the active catalyst in the catalytic aziridination reaction 9f,9h is an IMINO-BOROX catalyst 188a/190a. This BOROX species is presumed to be the active catalyst in an aza-DielsAlder reaction as well. 16 We have recently reported that the chiral boroxinate 188a/190a (B3) can also be generated upon treatment of a mixture of the VAPOL ligand 58 and 3 equivalents of 551 B(OPh)3 with the imine 78a/111a at room temperature in a few minutes, conditions under which VAPOL and B(OPh)3 do not react. 9f Scheme 7.2 Generation of IMINO-BOROX catalysts 190a and 188a Ph Ph Ph N PG 78a/111a Ph B(OPh)3 (3 equiv) Ph solvent 25 °C, 10 min OH OH B3 190a (imine = 111a) 188a (imine = 78a) (S)-VAPOL 58 1) B(OPh)3 2) 0.1 mm Hg 80 °C, 0.5 h (3 equiv) toluene 80 °C, 1 h Ph N PG 78a/111a O B OPh + Ph Ph O Ph Ph 3 2 OPh 1– + O O B 4 [H-imine] B O O O B OPh B1 106 OPh O B O B O OPh B2 108 pre-catalyst OMe N N OMe 78a 111a 552 The proposed multicomponent aziridination reaction involves amine 126, aldehyde 127 and EDA 85 (Figure 7.1B). The question then naturally arises: whether an amine would induce chiral boroxinate complex, and if yes, then whether other species like aldehyde 127 and EDA 85 would also generate a boroxinate which, in turn, could interfere the boroxinate formation from the amine? A series of NMR experiments were then carried out in search of the answers to these proposed questions. In the absence of a base, mixing (S)-VAPOL and B(OPh)3 does not result in any detectable amount of a boroxinate (B3) species (Chapter 2). Given the greater basicity of an amine versus an imine, it was anticipated that the MEDAM amine 126c could also generate the boroxinate catalyst 215b (Scheme 7.3) from VAPOL and B(OPh)3 in much the same way as does imine 111a (Scheme 7.2) and indeed this was confirmed by NMR analysis (Table 2.7 and Figure 2.9, Chapter 2). In fact, primary, secondary and tertiary amines all induce the formation of an AMINO-BOROX catalyst of the type 215 (B3) which displays a characteristic bay region 1 proton doublet at δ ~10.3 ppm in H NMR and a sharp resonance in the 11 B NMR spectrum at δ ~ 5-6 ppm (Table 2.7 and Figure 2.9, Chapter 2). Scheme 7.3 Generation of AMINO-BOROX catalysts 215a and 215b PG NH2 Ph Ph OH OH 126a/126c (2 equiv) B(OPh)3 (3 equiv) CDCl3 25 °C, 10 min Ph Ph 3 2 OPh 1 – PG O B 4 O B O NH3 O O B + OPh B3 215a (PG = Bh) 215b (PG = MEDAM) (S)-VAPOL 58 553 Aldehydes 127 are not strong enough bases to induce boroxinate formation (Figure 2.19, Chapter 2). Ethyl diazoacetate (EDA) does not induce the formation of a boroxinate, but, nonetheless there is a very rapid reaction (≤10 min) leading to the alkylation of one of the phenol functions of VAPOL via a formal insertion of a carbene into the O-H bond which results in the formation of the ester 230 in 80% yield (Scheme 7.4A). It seems like the initial analysis indicates the feasibility of the first multicomponent aziridination reaction. However, there are certain possible complications for the reaction and these are described below. 7.4 Possible complications for the five-component catalyst assembly/aziridination As discussed above, the mono-alkylated VAPOL derivative 230 is formed upon treatment of VAPOL with EDA in the presence of B(OPh)3 (Scheme 7.4A). However, there is no reaction between VAPOL and EDA in the absence of B(OPh)3. Nonetheless, this presents at least one potential problem in a five-component catalyst assembly/aziridination of the type shown in Figure 7.1C. The VAPOL ligand could be disenabled by a B(OPh)3 induced reaction with EDA before the amine can assemble the catalyst from the ligand and B(OPh)3. Scheme 7.4 (A) Alkylation of the VAPOL by EDA. (B) Common products obtained from the reaction between benzaldehyde and EDA. A O OEt N2 Ph Ph OH OH + B(OPh)3 (3 equiv) 85 (2 equiv) CDCl3 25 °C, 10 min Ph Ph O OH O 230 80% (S)-VAPOL 58 554 OEt Scheme 7.4 cont’d B Ph B(OPh)3 O O H + (14 mol%) OEt 127a Ph CDCl3 25 °C, 10 min N2 85 (1.14 equiv) + CO2Et 395a 3% CO2Et + H Ph Ph H 397a 8% CO2Et 396a 47% OH OH + O O OH CO2Et CO2Et + Ph Ph N2 398a 1% 399a 2% A second possible complication is an unwanted reaction between the aldehyde and EDA. In fact, several different products are known from the reaction of benzaldehyde and EDA mediated by Lewis or Brønsted acids. 17 Indeed, in a control experiment, the reaction of benzaldehyde and 1.14 equiv of ethyl diazoacetate mediated by 14 mol% B(OPh)3 gave the five products shown in Scheme 7.4B with the major component as the β-keto ester 396a and its tautomer 397a in a total of 55% yield. In a separate control experiment it was found that there is no reaction between benzaldehyde and EDA in the presence of VAPOL. Nor is there any reaction between benzaldehyde and EDA in either the presence or absence of 4 Å molecular sieves at 25 °C after 24 h. Thus the possible reaction between the aldehyde and EDA mediated by B(OPh)3 is a real concern for the success of the multi-component catalyst assembly/aziridination outlined in Figure 7.1C. 555 7.5 Optimization and substrate scope of aryl substrates in the MCAZ reaction With the demonstration that an amine can induce catalyst assembly, the possibility of a multi-component aziridination (MCAZ) was then explored (Table 7.1). Given the problems with aliphatic aldehydes described above, the multi-component aziridination was first examined with aromatic substrates. 7.5.1 Different protocols for the multicomponent cis-aziridination (MCAZ) During optimization, various protocols were examined for the MCAZ reaction. A few selected protocols are presented in Table 7.1. In the first experiment, the VAPOL ligand A (58) was mixed with 3 equiv of B(OPh)3 B (187a) and 20 equiv of amine C (126c) and stirred in toluene at 80 °C for 0.5 h to ensure formation of the boroxinate catalyst and thus avoid any possibility of alkylation of VAPOL by the EDA. This was followed by the addition of the benzaldehyde D (127a) and 4 Å MS which was stirred for 2 h to ensure imine formation. Upon addition of EDA E (85) the mixture was stirred at 25 °C for 24 h to give the aziridine 114a in 92% yield and 95% ee (procedure I). A true multi-component reaction involves the reaction of three or more reagents added simultaneously. 1c,1d Multi-component reactions that involve reaction between two reagents and then interception of the resulting intermediate by the addition of a third reagent are sequential component reactions. 1c,1d,8d,10-11 Hence, procedure I in Table 7.1 can be viewed as an example of a sequential component aziridination reaction as the addition of EDA was delayed for 2 h to ensure formation of the imine. 8d However, when EDA was added immediately after the aldehyde, essentially the same results were obtained (procedures I vs IIA). This suggests that the 556 present work is an example of a true MCAZ. The data in Table 7.1 reveals that essentially the same results are obtained whether the pre-catalyst is first generated and employed in the multicomponent aziridination or whether the boroxinate catalyst is directly generated by treating a mixture of VAPOL and B(OPh)3 with the amine C (procedures IIA vs. IIB). It was also revealed that no advantage is to be gained by generating the AMINO-BOROX catalyst by heating to 80 °C rather than simply stirring at room temperature (procedures IIA vs. IIIA and IIB vs. IIIB). The use of the aldehyde D as the limiting reagent (0.6 equiv) leads to the complete shutdown of the reaction (procedure IIIC). This suggests that the amine C is a competitive inhibitor of the imine in binding to the boroxinate catalyst and this issue will be taken up in greater detail below (Tables 7.8 and 7.9). A comment is needed about the water added for catalyst generation in procedures IIB and IIIB in Table 7.1. Three equivalents of H2O are required to create the three B-O-B linkages in the boroxinate 215b from B(OPh)3. The addition of three equivalents of H2O is absolutely required if the B(OPh)3 is pure but, commercial B(OPh)3 contains sufficient water that the addition of additional water is typically not needed and indeed, our original procedure 9f shown in Scheme 7.2 does not include the addition of H2O. The addition of 3 equivalents of H2O to commercial B(OPh)3 in procedures IIB and IIIB was done to compensate for any variation in quality of commercial B(OPh)3. 557 Table 7.1 Protocol dependence of the multicomponent aziridination Ar (S)-VAPOL + A (5 mol%) B(OPh)3 B (15 mol%) Ar + + 4 Å MS O O NH2 C (100 mol%) a Ph + OEt H N2 D (105 mol%) E (120 mol%) toluene 25 °C, 24 h Ar Ar Ar Ar Ar N Ph OMe Ar2CH = MEDAM # Proc 1 I A+B+C 2 IIA A+B+C + CO2Et 114a NH (Ph)H Ph(H) 118a(119a) Yield 114a b (%) 3 IIB 4 IIIA A+B+C 1) toluene 2) D, 4Å MS 3) E 80 °C, 0.5 h 25 °C, 2 h 25 °C, 24 h 1) toluene 2) D, 4Å MS 80 °C, 0.5 h E, 25 °C, 24 h 1) toluene H2O (15 mol%) 2) C, toluene 80 °C, 0.5 h E, 25 °C, 24 h 1) toluene 2) D, 4Å MS 25 °C, 1 h E, 25 °C, 24 h 92 95 98 98 98 98 98 3) D, 4Å MS 80 °C, 1 h then 0.5 mm Hg 80 °C, 0.5 h ee 114a c (%) 97 Reaction protocol A+B CO2Et 558 Table 7.1 cont’d 5 IIIB 6 a IIIC 1) toluene H2O (15 mol%) A+B+C 3) C, toluene 3) D, 4Å MS 80 °C, 1 h then 0.5 mm Hg 80 °C, 0.5 h A+B 25 °C, 1 h E, 25 °C, 24 h 1) toluene 2) D*, 4Å MS 80 °C, 0.5 h E, 25 °C, 24 h * 60 mol% 94 98 <1 – Unless otherwise specified, all reactions were performed with 0.025 mmol (S)-VAPOL A (5 mol%), 0.075 mmol B(OPh)3 B (15 mol%), 0.50 mmol amine C (1.0 equiv), 0.525 mmol benzaldehyde D (1.05 equiv) and 0.60 mmol of EDA E (1.2 equiv) in 1.0 mL toluene (0.5 M in amine) at 25 °C for 24 h. In each case, 150 mg powdered 4Å MS was added immediately b preceding benzaldehyde. Isolated Yield. Analysis of the crude reaction mixture indicates >50:1 cis:trans selectivity for 114a. Determined by HPLC. 7.5.2 In each case <1% 118a and 119a are formed. c Catalyst loading, N-substituent and ligand screening The catalytic asymmetric synthesis of aziridines from imines and diazo compounds has been honed with both benzhydryl and bis-(3,5-dimethylanisyl)methyl (MEDAM) substituents on the imine nitrogen. 9 Thus, prior to the substrate scope, the multi-component aziridination was examined with both benzhydryl amine 126a and the MEDAM amine 126c and the results with benzaldehyde are shown in Table 7.2. In addition, the reactions of both amines were screened with both VANOL and VAPOL catalysts and the catalyst loading profile was explored as well. As was found for the reactions of the corresponding imines, 9c the multi-component aziridination of benzaldehyde with MEDAM amine 126c gives higher yields and asymmetric inductions than the benzhydryl amine 126a. Nonetheless, the aziridines from benzhydryl amines can in most cases be crystallized to ≥ 99% ee which is important to note upon considering that benzhydryl 559 amine 126a is commercially available while the MEDAM amine 126c is not. 9a,9i During this work, another current group member, namely Yong Guan, developed a new ligand (S)-tBuVANOL 198 which proved to be the optimal ligand for aziridination with benzhydryl imines 18 78. It was found that the multicomponent aziridination works well with this ligand giving results better than VAPOL and VANOL (Table 7.2, entry 8). However, as was observed with the corresponding imines, the multi-component aziridinations with VAPOL and VANOL catalysts are very similar with a slight edge in asymmetric induction to the VAPOL catalyst. 9a,9i The optimal catalyst loading for the reaction with the MEDAM amine is 3-5 mol%. This reaction does not go to completion in 24 h with 1 mol% of either the VANOL or VAPOL catalyst but both go to completion with a 3 mol% catalyst loading. The reaction is severely impeded by the absence of molecular sieves and gives only a 35% yield of the aziridine 114a along with a 52% yield of the unreacted imine 111a generated from amine 126c and benzaldehyde (entry 14). Finally, in the optimization studies it was noted that 4 Å molecular sieves was superior to 5 Å molecular sieves which gives more unknown side-products and a lower yield of the aziridine (entries 14 vs. 15). Table 7.2 Catalyst Loading, N-substituent and Ligand Screening PG NH2 (S)-Ligand (x mol%) B(OPh)3 (3x mol%) 1. PhCHO 127a 4 Å MS toluene 25 °C, 1 h 2. EDA 85 25 °C, 24 h 126a PG = CHPh2 126c PG = MEDAM a PG PG N Ph + CO2Et (Ph)H NH CO2Et Ph(H) 86a PG = CHPh2 87a(88a) PG = CHPh2 114a PG = MEDAM 118a(119a) PG = MEDAM 560 Table 7.2 cont’d # Ligand PG Cat. x mol% 1 (S)-VAPOL Bh 10 2 3 4 5 6 7 8 9 (R)-VANOL (S)-VAPOL (R)-VANOL (S)-VAPOL (R)-VANOL (S)-VAPOL (S)-tBu-VANOL (S)-VAPOL Bh Bh Bh Bh Bh Bh Bh MEDAM 10 10 10 5 5 5 5 10 (R)-VANOL MEDAM 10 11 (S)-VAPOL 10 MEDAM 5 f Yield 86a/114a b (%) 75 ee 86a/114a c (%) 92 78 85 77 77 72 f 77 80 90 f f d Enamines e (%) 33:1 7 –88 91 –88 92 91 86 97 98 g cis/trans 50:1 25:1 50:1 50:1 50:1 50:1 > 50:1 > 50:1 15 9 15 6 7 7 6 <1 93 –96 > 50:1 <1 f 97 98 > 50:1 <1 f 90 98 h,i (35) –96 98 – > 50:1 > 50:1 > 50:1 <1 <1 <1 12 13 14 (R)-VANOL (S)-VAPOL (S)-VAPOL MEDAM MEDAM MEDAM 5 5 5 15 16 17 18 19 20 21 22 (S)-VAPOL (S)-VANOL (S)-VAPOL (S)-VANOL (S)-VAPOL (R)-VANOL (S)-VAPOL MEDAM MEDAM MEDAM MEDAM MEDAM MEDAM MEDAM 5 5 3 3 1 1 1 70 95 92 94 (20) (31) g (48) 98 95 98 97 – – – > 50:1 > 50:1 > 50:1 > 50:1 > 50:1 > 50:1 > 50:1 2 <1 5 6 <1 <1 4 (R)-VANOL MEDAM 1 (29) – > 50:1 <1 j g a Unless otherwise specified, all reactions were performed with procedure IIIA in Table 7.1 with 0.50 mmol amine 126a or 126c (1.0 equiv, 0.5 M), 0.525 mmol benzaldehyde 127a (1.05 b equiv) and 0.60 mmol of EDA 85 (1.2 equiv) and went to 100% completion. Isolated Yield. 1 c Yield in parenthesis determined by H NMR spectra with Ph3CH as internal standard. d Determined by HPLC. Ratio determined by integration of the methine protons of cis- and 1 e trans-aziridine in the H NMR spectrum of the crude reaction mixture. Determined by integration of the NH signals of enamines relative to the methine proton of cis aziridine in the 1 f H NMR spectrum of the crude reaction mixture. Reaction performed with procedure IIA in Table 7.1. g 8 equiv EDA used. h Reaction performed without 4 Å MS. i 1 The H NMR spectra of the crude reaction mixture indicates the presence of 52% unreacted imine 111a. Reaction performed with 5 Å MS. 561 j 7.5.3 Substrate scope for aromatic aldehydes The general screen for the multi-component (MCAZ) was taken forward with the MEDAM amine 126c since it gives aziridines with both higher yields and asymmetric inductions (Table 7.2) and a 12-fold increased rate over reactions with pre-formed imines. 9b Likewise, the screen of the MCAZ reaction was pursued with VAPOL 58 since it gave small, but consistently higher inductions than VANOL 59 (Table 7.2). Excellent yields and asymmetric inductions were observed for a number of substituted benzaldehydes including those with both electronwithdrawing and electron-donating groups (Table 7.3). The reaction with benzaldehyde 127a 1 was complete in 1 h with 5 mol% catalyst as monitored by H NMR but no attempt was made to determine minimum reaction times with the other substrates. Excellent inductions could also be obtained with hetero-aryl aldehydes giving aziridines 114i – 114n in 90 – 97% ee. The yields for the reactions of 2-thiophenyl and 2-furyl carboxaldehydes 127k and 127l were moderate but this could be substantially improved by employing excess EDA. There was no attempt made to optimize the amount of EDA. However, the corresponding pyrrole-2-carboxaldehyde 127m did not give any aziridine (entry 20). It is interesting that pyridine-2-carboxaldehyde 127i was an effective substrate, 8a whereas, pyridine-3-carboxaldehyde 127j failed to give any aziridine (entry 9c 11). The results obtained from MCAZ were comparable to those obtained with imines. Table 7.3 Multicomponent aziridination of aryl and hetero-aryl aldehydes (S)-VAPOL (5 mol%) MEDAM NH2 B(OPh)3 (15 mol%) toluene 25 °C, 1 h 1. RCHO 127 2. EDA 85 25 °C, 24 h MEDAM MEDAM 4 Å MS + N CO2Et R 114 126c 562 a (R)H NH CO2Et R(H) 118(119) Table 7.3 cont’d series Yield 114 b (%) ee 114 c (%) cis/trans 1 g 2 a 98 f 97 98 g 98 50:1 g 50:1 <1 g <1 3 g 4 b 96 f 94 >99 g 99 50:1 g 50:1 3 g 4 c 96 >99 50:1 3 # R d Enamines e (%) Me 5 6 Me d 95 99 50:1 5 7 OMe e 78 98 20:1 5 f 92 99 50:1 3 i 96 f 90 90 g 94 >50:1 g >50:1 <1 g <1 j <1 – – – 52 g 88 93 g 97 12.5:1 g 25:1 <1 g <1 8 NO2 9 g 10 N 11 N 11 g 12 13 14 15 16 17 18 19 g g k S (19) g 51 g 65 g g g (62) l O 40 57 55 f f,h i g, i f, g, h j g, j 563 – – g g 94 95 96 89 95 g g g g g 9:1 50:1 8.3:1 8.5:1 8.3:1 9.3:1 7.0:1 g g g g g g g <1 <1 <1 <1 <1 1 3 g g g g g g g Table 7.3 cont’d 20 21 22 m N H g O g N n Me <1 97 98 – g, k g, k 97 96 – g > 50:1 g > 50:1 – g <1 g <1 g g a Unless otherwise specified, all reactions were performed with procedure IIIA in Table 7.1 with 0.50 mmol amine 126c (1.0 equiv, 0.5 M), 0.525 mmol aldehyde 127 (1.05 equiv) and 0.60 mmol of EDA 85 (1.2 equiv) and went to 100% completion. b Isolated Yield. Yield in 1 c parenthesis determined by H NMR spectra with Ph3CH as internal standard. Determined by HPLC. d Ratio determined by integration of the methine protons of cis- and trans1 aziridine in the H NMR spectrum of the crude reaction mixture. e Determined by integration 1 of the NH signals of enamines relative to the methine proton of cis aziridine in the H NMR spectrum of the crude reaction mixture. g h f Reaction performed with procedure IIA in Table i 7.1. 8 equiv EDA used. Reaction performed at –10 °C. The aldehyde was added at –10 °C followed by the addition of EDA at –10 °C and the mixture was stirred at –10 °C for 2 h j prior to warming to room temperature. The pre-formed and purified imine 111l, made from MEDAM-NH2 126c and aldehyde 126l, was used and EDA was added at –10 °C. The mixture was stirred at –10 °C for 2 h prior to warming to room temperature. Refer Scheme k 7.5. The aldehyde was added at –10 °C followed by the addition of EDA was carried out at –10 °C and the mixture was stirred at –10 °C for 15 min prior to warming to room temperature. The efficacy of the multicomponent reaction is shown in Scheme 7.5. We have compared the preparation of aziridine 114l by the MCAZ method described here with that of a two-step method involving the isolation of the imine from aldehyde 127l and amine 126c. Substantial material loss is encountered in the two-step method as a result of purification of the imine. Also, the asymmetric induction was found to drop by 6 percentage points (Table 7.3, entries 15 vs. 18 and Scheme 7.5). 564 Scheme 7.5 (A) Preparation of Imine 111l (B) Synthesis of aziridine 114l via two-step method A MeO MeO O O MgSO4 + H2N OMe CH2Cl2 N O 25 °C, 24 h 126c 127l OMe 111l 26% B B(OPh)3 (3 equiv) (S)-VAPOL (5 mol%) 0.1 mm Hg pre-catalyst toluene, 80 °C, 1 h 80 °C, 0.5 h OMe MeO O + MeO N O OEt N2 toluene, 25 °C, 24 h 85 111l 7.6 OMe pre-catalyst (5 mol%) N O CO2Et 114l 57% y, 89% ee Optimization and substrate scope of alkyl substrates in the MCAZ reaction Since the whole idea was envisioned to find a general solution for alkyl aziridination, we then decided to examine the MCAZ reaction with n-butanal 127o. However, the procedure optimized for aromatic substrates was found to be non-applicable and further optimization was then carried out and is described below. 565 7.6.1 Initial optimization using n-butanal and n-hexadecanal The problem of imine self-condensation was encountered in the MCAZ of n-butanal 127o. The aziridination of n-butanal with MEDAM amine 126c at room temperature with 5 mol% VANOL catalyst under the conditions in entry 1 of Table 7.4 gives only a 25% yield of aziridine 114o along with a 20% yield of the condensation product 386o as well as a 38% yield of the imine 111o which was generated in-situ but did not undergo complete reaction. The formation of the side-product 386o was found to be disfavored at lower temperatures. The same reaction with 5 mol% VANOL catalyst at 0 °C gives a 50% yield of 114o with only a 6% yield of 386o (Table 7.4, entry 2). The yield of the aziridine 114o increases to 80% for reaction at –10 °C with 10 mol% VANOL catalyst (entry 4) but the reaction slows at –30 °C and only gives 45% yield under the same conditions and goes to only 61% completion in 24 h (entry 6). With VAPOL catalyst, the yield of the reaction can be increased to 94% (96% ee) and at the same time the catalyst loading can be lowered to 5 mol% catalyst if 8 equiv of EDA is used and in this case no detectable amount of 386o was observed (Table 7.4, entry 9). Further optimization found that the reaction of n-butanal with only 3 mol% catalyst and 2 equiv of EDA can provide 2.4 g (6 mmol) of aziridine 114o in 92% yield and 96% ee (entry 12). Table 7.4 Optimization of the multicomponent aziridination reaction of n-butanal 2) 1) Ligand (x mol %) MEDAM B(OPh)3 (3x mol %) NH2 126c Toluene O H 127o 4 Å MS MEDAM MEDAM N N MEDAM N 3) EDA 85 T °C, 24 h + + CO2Et 114o 566 a 386o 111o Table 7.4 cont’d T (°C) Cat. Proc. x mol% Equiv 85 Yield 114o b (%) ee 114o c (%) Yield 386o d (%) Yield 111o e (%) # Ligand 1 (R)-VANOL IIIA 5 25 1.2 (25) – 20 38 2 (R)-VANOL IIIA 5 0 1.2 (50) – 6 21 3 (R)-VANOL IIA 5 0 1.2 (53) – 6 17 4 (R)-VANOL IIA 10 0 1.2 74 –95 2 <1 5 (R)-VANOL IIA 10 –10 1.2 80 –96 <1 <1 6 (R)-VANOL IIA 10 –30 1.2 45 –96 11 30 7 (S)-VAPOL IIA 10 –10 1.2 82 98 <1 <1 8 (S)-VAPOL IIA 5 –10 8 91 96 <1 <1 9 (S)-VAPOL IIIA 5 –10 8 94 96 <1 <1 10 (S)-VAPOL IIIA 5 –10 3 85 96 <1 <1 11 (S)-VAPOL IIIA 4 –10 6 97 g 95 <1 <1 h 96 <2 <2 12 (S)-VAPOL IIIA 3 –10 2 92 f a Unless otherwise specified, all reactions were performed with procedure IIIA or IIA in Table 7.1 with 0.50 mmol amine 126c (1.0 equiv, 0.5 M), 0.525 mmol n-butanal 127o (1.05 b equiv) and 0.60 mmol of EDA 85 (1.2 equiv) and went to 100% completion. Isolated Yield. 1 Yield in parenthesis determined by H NMR spectra with Ph3CH as internal standard. Determined by HPLC. 1 d 2 Determined by integration of the γ-sp -CH signals of vinyl imine in H NMR spectra with Ph3CH as internal standard. 1 e 2 Determined by integration of the sp -CH signals of the imine in H NMR spectra with Ph3CH as internal standard. 61% completion. g c Reaction on 2.5 mmol scale. h f Reaction went to Reaction on 6.0 mmol scale. The real advantage of the MCAZ over two-step method aziridination is shown in Table 7.5. It must be noted that this study was performed by another current group member namely, 19 Munmun Mukherjee (Entry 4 is part of this doctoral research work). When the reaction was performed with pre-formed imine 111p (derived from n-hexadecanal 127p) using traditional 567 method of aziridination, low yields and asymmetric inductions were observed (Table 7.5, entries 1-2). However, a significant increase in yield and ee was observed when MCAZ protocol was utilized (Table 7.5, entries 3-4). Another group member, Yubai Zhou found that the reaction gave ee up to 98% using (S)-tBu-VANOL 198 ligand (entry 8). 20 Table 7.5 Optimization of the multicomponent aziridination reaction of n-hexadecanal 127p O 2) H 13 127p 4 Å MS 1) Ligand (x mol %) MEDAM B(OPh)3 (3x mol %) NH2 Toluene, 80 °C, 0.5 h 126c 3) EDA 85 T °C, 24 h MEDAM N MEDAM N + CO2Et 13 3 4 5 6 7 8 118p(119p) Ligand Cat. x mol% T (°C) Equiv 85 Yield 114p b (%) ee 114p c (%) Yield 386p d (%) Yield 118p+119p e (%) f (S)-VAPOL 10 25 1.2 40 88 20 – g (S)-VAPOL 10 0 1.2 60 90 18 4 f (S)-VAPOL 10 0 1.2 70 95 6 15 h (S)-VAPOL 10 –10 1.2 82 96 <1 6 i (S)-VAPOL 10 –10 2.0 85 95 <1 3 i (S)-VAPOL 10 –10 2.0 90 95 <1 2 i (S)-VANOL 10 –10 2.0 85 95 <1 2 (S)-tBu-VANOL 10 –10 2.0 95 98 <1 <1 # 2 MEDAM NH (C15H31) H + CO2Et 13 (H) C15H31 13 386p 114p 1 a i,k j a Unless otherwise specified, all reactions were performed with procedure IIA in Table 7.1 with 0.50 mmol amine 126c (1.0 equiv, 0.5 M), 0.525 mmol n-hexadecanal 127p (1.05 equiv) b and 0.60 mmol of EDA 85 (1.2 equiv) and went to 100% completion. Isolated Yield. Yield 1 in parenthesis determined by H NMR spectra with Ph3CH as internal standard. by Chiral HPLC. d 2 c Determined Determined by integration of the γ-sp -CH signals of vinyl imine 386p 1 relative to the methine proton of cis-aziridine in the H NMR spectra of the crude reaction mixture. e Determined by integration of the NH signals of the enamines relative to the 1 methane proton of cis-aziridine in the H NMR spectra of the crude reaction mixture. 568 Table 7.5 cont’d f Reaction was performed with pre-formed imine 111p (derived from n-hexadecanal 127p). The imine was isolated and dried under high vacuum (~ 0.2 mmHg) for 0.5 h and the resulting oil was redissolved in toluene followed by its transfer to pre-catalyst (method C, Chapter 2). g Reaction was performed with pre-formed imine 111p (derived from n-hexadecanal 127p). The imine was not isolated and transferred directly to the pre-catalyst (method C, Chapter 2) h i using a filter syringe. This work. The concentration of the reaction = 0.2 M and aldehyde 127p was added as a solution in toluene. Yubai Zhou. 7.6.2 j Reaction on 4.5 mmol scale. k Data provided by Substrate scope for aliphatic aldehydes A series of nine aliphatic aldehydes were screened in the multi-component aziridination reaction (Table 7.6). Excellent asymmetric inductions were observed for the aziridination of a number of functionalized unbranched, α-branched and α,α-branched aliphatic aldehydes. These include a number of “problem” aldehydes that have failed to give aziridines via in-situ generated imines such as dihydrocinnamyl aldehyde 127t, phenyl acetaldehyde 127u and ethyl-5oxopentanoate 127r due to the problem pertaining to condensation product formation (Scheme 14 7.1). Even with the optimized MCAZ protocol, the aziridination of aldehyde 127t proceeds to give only a 24% yield of the aziridine 114t (entry 10). The yield of aziridine 114t can be increased to 96% if excess (8 equiv) of EDA is used and this is interpreted to mean that the imine undergoes aziridination before it can self condense (entry 11). A similar profile is noted with the phenyl acetaldehyde 127u (entries 13-15). The “problem” aldehyde 127r can be directly taken to the aziridine 114r in 70% yield and with excess EDA the yield can be increased to 82% of material with 97% ee optical purity (entry 6, 7). However, in both cases, no attempt was made to optimize the amount of EDA. The MCAZ is also readily scalable as aziridines 114p and 114o are obtained with essentially the same induction and in slightly higher yield when the scale is increased ten-fold (Table 7.6, entries 3 vs 4) and twelve-fold (Table 7.4, entries 9 vs 12). The 569 side-reactions noted for α-unbranched aldehydes are not as severe for other types of aliphatic aldehydes and for this reason their reactions can be run at room temperature. The multicomponent asymmetric catalytic aziridination of cyclohexane carboxaldehyde 127v at room temperature gives the aziridine 114v in 95% yield and 90% ee which is within experimental error of the results obtained from the aziridination of the cooresponding imine at either room temperature or at 0 °C. 9c Likewise the MCAZ of the α,α-branched pivaldehyde 127w gives the aziridine 114w in 89% yield and 94% ee at room temperature which is to be compared with 95% yield and 94% ee from the aziridination of the pre-formed imine at the same temperature. Table 7.6 Multicomponent aziridination of alkyl aldehydes NH2 (S)-VAPOL (x mol %) B(OPh)3 (3x mol %) R H 127 4 Å MS Toluene 126c a O O MEDAM 9c OEt N2 MEDAM N 85 –10 °C, 24 h R 114 CO2Et series Proc Cat. x mol% Equiv 85 Yield 114 b (%) ee 114 c (%) 1 2 o IIA IIIA 10 5 1.2 8 82 94 98 96 3 4 p IIA IIA 10 10 1.2 3 82 85 96 d 95 q IIA 10 1.2 80 98 r IIA IIIA 10 5 1.2 8 70 82 94 97 s IIA IIIA 10 5 1.2 8 55 50 93 90 # 5 6 7 8 9 R 12 4 OTBS O OEt 570 Table 7.6 cont’d 10 11 12 17 18 19 nd 97 96 e nd 98 98 t 1.2 8 8 24 96 91 IIA IIA IIIA 10 10 5 1.2 8 8 19 94 86 v IIIA 5 1.2 95 90 w f 10 10 5 u 13 14 15 16 e IIA IIA IIIA IIA IIIA IIIA 10 10 10 1.2 2 8 89 95 97 94 92 90 f f f a Unless otherwise specified, all reactions were performed with procedure IIA or IIIA in Table 7.1 with 0.50 mmol amine 126c (1.0 equiv, 0.5 M), 0.525 mmol aldehyde 127 (1.05 equiv) and 0.60 mmol of EDA 85 (1.2 equiv) and went to 100% completion with a cis/trans ratio of >50:1 for aziridine 114. Small amounts of enamine products were observed for some b c d reactions (<1 to 6%). Isolated Yield. Determined by HPLC. Reaction on 5.0 mmol scale. e determined. 7.7 1 Determined by H NMR spectra with Ph3CH as internal standard. f nd = not Reaction performed at 25 °C. Mechanistic study towards the five-component catalyst assembly/catalytic asymmetric aziridination While studying the mechanistic aspects involving the order of the addition of the various components, we have discovered that this reaction is actually a five-component process in which the catalyst is assembled by the amine from the ligand and B(OPh)3 and then the catalyst causes imine formation and then finally, aziridine formation (Figure 7.1C). 13 The possible combinations of all of the outcomes of all the different known reactions between the five species shown in Figure 7.1C would lead to a mixture of 10 different products (Figure 7.3) and yet a 571 solution of these five-species leads to the formation of the aziridine in very high yields and enantioselectivies. The purpose of the present work is to provide an insight to and support for the operation of this five-component catalyst assembly/catalytic asymmetric aziridination. Figure 7.3 Chemoselectivity in the five-component catalyst assembly/catalytic asymmetric aziridination Ar Ar Ar Ar NH R Ar NH CO2Et N2 Ar CO2Et R H Ar Ar N NH R R H R Ar Ar Ar N * O Ar OH OH NH2 B(OPh)3 * O OH O CO2Et R CO2Et H O OEt N2 OH O O R R OEt H CO2Et OH O R OH O OEt H N2 OEt R 572 OEt 7.7.1 Effects of the order of addition on the multicomponent cis-aziridination That the aziridination reaction of focus here is in fact a true multi-component reaction is indicated by the results shown by procedures V, VI and VII in Table 7.7. First of all, procedure IV reveals that all the components can be added followed by the addition of the solvent. Hence, 1 h of stirring is not required as in procedure IIIA. The successful aziridination from the reaction where the EDA (E) is added before the aldehyde (D) reveals that imine formation can occur in the presence of EDA (procedure V and VI). The VAPOL ligand is not alkylated by the EDA under these conditions (Table 7.7, procedures V and VI) as might have been expected from the results in Scheme 7.4A. This reveals that once the VAPOL boroxinate B3 catalyst 215b is generated, the VAPOL ligand is protected from alkylation. Table 7.7 Effect of order of addition on the multi-component aziridination reaction Ar + (S)-VAPOL A (5 mol%) B(OPh)3 + C (100 mol%) 4 Å MS O O + NH2 B (15 mol%) Ar Ar Ph a + OEt H N2 D (105 mol%) E (120 mol%) toluene 25 °C, 24 h Ar Ar Ar N OMe Ar2CH = MEDAM # 1 Procedure IIIA d Ar + Ph CO2Et 114a Reaction protocol A+B+C 1) toluene 2) D, 4Å MS 25 °C, 1 h E, 25 °C, 24 h 573 NH (Ph)H CO2Et Ph(H) 118a(119a) Yield 114a b (%) ee 114a c (%) 98 95 Table 7.7 cont’d e 2 IV 3 V 4 VI 5 VII f A+B+C g A+B+C h 6 VIII 7 a A+B+C IX A+B j A+B k A+B 1) E, toluene D, 4Å MS 25 °C, 24 h 1) E, toluene 2) D, 4Å MS 25 °C, 1 h 25 °C, 24 h E, toluene 1) D, 4Å MS 25 °C, 24 h D, 4Å MS 1) toluene E, then C 25 °C, 24 h 1) D, 4Å MS 25 °C, 24 h D, 4Å MS 1) E, toluene 98 94 98 94 98 2) C E, toluene 2 min 88 85 i 98 <1 25 °C, 24 h – _ _ Unless otherwise specified, all reactions were performed with procedure IIIA or IV-XI with 0.025 mmol (S)-VAPOL A (58), 0.075 mmol B(OPh)3 B (187a), 0.50 mmol amine C (126c) (1.0 equiv, 0.5 M), 0.525 mmol aldehyde D (127) (1.05 equiv) and 0.60 mmol of EDA E (85) (1.2 equiv) and went to 100% completion with a cis/trans ratio of >50:1 for aziridine 114. In each case, 150 mg powdered 4Å MS was added immediately preceding benzaldehyde. b c d e Isolated Yield. Determined by HPLC. See Table 7.1. A mixture of A, B, C, 4 Å MS, D, and E, added in that order, was dissolved in toluene and the resulting solution allowed to f stir for 24 h at 25 °C. The diazo compound E is added to a mixture of A, B and C and then toluene is added and the mixture stirred at 25 °C for 1 h after which powdered 4 Å MS and D g are added and the mixture stirred for 24 h at 25 °C. A mixture of A, B, C, E, 4 Å MS, and D, added in that order, was dissolved in toluene and the resulting solution allowed to stir for 24 h at 25 °C. h A mixture of A, B, 4 Å MS, D, E, and C, added in that order, was dissolved in toluene and the resulting solution allowed to stir for 24 h at 25 °C. i A 3% yield of j enamines 118a and 119a was observed. A mixture of A, B, 4 Å MS, D and E, added in that order, was dissolved in toluene and the resulting solution allowed to stir for 2 min at 25 °C before C was added and the resulting solution stirred for 24 h at 25 °C. The products of this k reaction are shown in Figure 7.4. Same as procedure VIII except that C was not added. The products from this reaction are 395a (5%), 396a (38%), 397a (11%), 398a (5%), 399a (<1%) and 230 (37%). 574 The results from procedure VII in Table 7.7 where the amine C is added last reveals that this is a five-component reaction where both the catalyst assembly and the aziridination reaction can be carried out simultaneously. Since the amine is added last, considerable concern arose from the results in Scheme 7.4A that suggest that the VAPOL ligand may be alkylated before the catalyst is generated. That is why in procedure VII all five of the components were added in the order shown without solvent, and at the end, solvent was added to effect dissolution. That this provides for a successful aziridination indicates that the amine, which is added last, can quickly assemble the catalyst such that the ligand is protected from alkylation by the EDA. The speed at which catalyst assembly occurs is indicated by procedure VIII in Table 7.7. When the first four components including EDA are dissolved in toluene and then 2 min later the amine is added, no aziridine formation is observed. A very complex reaction mixture is observed and the products are indicated in Figure 7.4 and include products from the reaction of EDA with both the aldehyde and the imine, however, no detectable amount of the aziridine 114a could be observed. The major product is the imine 111a (34%) and there is also a considerable amount of the unreacted amine 126c (40%). Since the aldehyde is partially consumed in the formation of the β-keto ester 396a (23%) and its tautomer 397a (5%), the presence of the unreacted amine 126c may lead to its selective binding to the catalyst thus preventing aziridination of the imine if indeed any boroxinate catalyst was formed at all in this reaction. As a control, the same reaction in which the amine is not added at all was also carried out (Table 7.7, procedure IX) and this gave a product mixture that was shown to have a very similar profile to the reaction of benzaldehyde 127a and ethyl diazoacetate 85 promoted by B(OPh)3 (Scheme 7.4B). The combined results from procedures VII and VIII in Table 7.7 make it clear that the assembly of the catalyst by the amine is exceedingly fast. The events that occur in the two minutes prior to 575 amine addition in procedure VIII are sufficient to completely thwart catalyst assembly and aziridination. Figure 7.4 Products from the reaction with procedure VIII in Table 7.7 MEDAM N Ph MEDAM + H CO2Et O CO2Et 395a <1% Ph NH N CO2Et + Ph Ph H 119a 4% O + 7.7.2 CO2Et + Ph 118a 10% 114a <1% Ph MEDAM NH 396a 23% Ph H + 126c 40% OH OH CO2Et + H 397a 5% H MEDAM NH2 111a 34% OH CO2Et + MEDAM CO2Et Ph 398a <1% CO2Et + Ph N2 399a <1% Mode of catalysis and sequence of the final steps in the five-component catalyst assembly/aziridination The simultaneous presence of the five chemical species shown in Figure 7.5A together in the same solution could have lead to several possible outcomes. There could have been reaction between the VAPOL ligand 58 and the EDA 85 mediated by B(OPh)3 to give the alkylated product 230 (Scheme 7.4A) or there could have been a reaction between the aldehyde 127 and EDA 85 mediated by B(OPh)3 to give the series of products indicated in Scheme 7.4B. The data in Table 7.7 indicates that instead there is a very rapid assembly of a boroxinate species from the VAPOL ligand and B(OPh)3 mediated by the amine 126a/126c which gives rise to the 576 AMINO- BOROX species 215a/215b. At this point the question arises as to the subsequent order of events. In one extreme, a small amount of imine 78/111 could be formed and then immediately converted to aziridine 86/114 before the rest of the imine is formed (Route I, C to E in Figure 7.5). This would suggest that the reaction is catalyzed by AMINO-BOROX species 215a/215b, thereby resulting in AMINO-BOROX catalysis as the mode of the catalysis. In the other extreme, the process could first proceed to give complete conversion of the amine and aldehyde to the imine 78/111 and only then does the imine 78/111 react with EDA 85 under the ageis of the IMINO-BOROX catalyst 188/190 to give the aziridine 86/114 (Route II, D to E in Figure 7.5). The last entry in Table 7.1 suggests that it is the latter since the presence of excess amine over aldehyde (0.6 equiv) results in the complete suppression of aziridine formation. This issue was further probed with additional experiments and the results are presented in Tables 7.8 and 7.9. Figure 7.5 Time course of events in the five-component catalyst assembly/aziridination reaction. (A) Time zero. (B) Assembly of AMINO-BOROX 215a/215b. (C) Start of formation of imine 78/111 (78a/111a when R = Ph) in presence of AMINO-BOROX 215a/215b. (D) Formation of IMINO-BOROX catalyst 188/190 (188a/190a when R = Ph). (E) Catalytic asymmetric aziridination. 577 Figure 7.5 cont’d A B O Ar OEt N2 OH * OH Ar O 58 R * Ar NH2 126a/c H 127 NH2 H 127 R D O OEt OPh N 2 85 O B O Ar Ar B O O O B NH2 OPh 215a/b O 126a/c H B(OPh)3 187a 85 Ar C Ar Ar O O Ar OEt N H N2 85 H R * Ar OPh Ar O B O N B O 78/111 O O B R OPh 188/190 * ? IMINO-BOROX Catalysis ? E Ar Route II Ar N R CO2Et 86/114 578 Ar NH2 OEt N2 85 OPh Ar Ar O B O N B O O O B 78/111 R OPh 215a/b O 127 H R AMINO-BOROX Catalysis Route I The multi-component aziridination of benzaldehyde 127a with benzhydryl amine 126a was examined with different amounts of benzaldehyde ranging from 0.6 to 1.0 equiv and the results are presented in Table 7.8. Just as with the reaction of the MEDAM amine 126c with 0.6 equiv of benzaldehyde (Table 7.1, entry 6), the reaction of benzhydryl amine 126a with 0.6 equiv of benzaldehyde results in essentially no formation of aziridine 86a (1%) even though benzaldehyde is essentially completely transformed into the imine 78a and 98% of this imine remains unreacted after 24 h (Table 7.8, entry 5). The amount of aziridine 86a formed with 0.9 equiv of benzaldehyde (entry 2) is nearly the same as with 1.0 equiv (entry 1). However, it should be noted that with 0.9 equiv, 8% of the imine 78a remains unreacted, whereas with 1.0 equiv of benzaldehyde, the imine 78a is nearly completely consumed (1% unreacted). This suggests there is an equilibrium between the boroxinate 215a containing a protonated amine and the boroxinate 188a containing a protonated imine (Scheme 7.6). Given the fact that imines are ~ 103 times less basic than amines, 21 even when the amount of excess amine is equal to the amount of catalyst (0.9 equiv 127a added, entry 2), there appears to be enough of the IMINO- BOROX catalytst 188a present in solution containing the activated imine to allow the reaction to proceed in 24 h. Table 7.8 Multicomponent aziridination with a deficiency of benzaldehyde (S)-VAPOL (10 mol%) Ph Ph NH2 B(OPh)3 (30 mol%) CHCl3 25 °C, 1 h 1. PhCHO 127a (x equiv) Ph Ph 4 Å MS 2. EDA 85 25 °C, 24 h a Ph + N CO2Et Ph 86a 126a 579 Ph NH (Ph)H CO2Et Ph(H) 87a(88a) Table 7.8 cont’d Yield 87a+88a f (%) Unreacted 78a b (%) 25:1 9 1 89 25:1 8 8 6 – 50:1 <1 94 0.7 4 – > 50:1 <1 96 0.6 1 – 50:1 <1 98 # 127a x equiv Yield 86a b,c (%) ee 86a d (%) 1 1.0 77 (78) 90 2 0.9 75 (73) 3 0.8 4 5 cis/trans e a Unless otherwise specified, all reactions were performed with procedure IIIA in Table 7.1 with 0.50 mmol amine 126a (1.0 equiv, 0.5 M), benzaldehyde 127a (x equiv) and 0.60 mmol b 1 of EDA 85 (1.2 equiv) and went to 100% completion. Determined by H NMR spectra of crude reaction mixture with Ph3CH as internal standard. isolation by silica gel chromatography. d c Yield in parentheses are after Determined by HPLC on purified aziridine. 1 e Ratio determined by integration of the methine protons of cis- and trans-aziridine in the H NMR spectrum of the crude reaction mixture. f Determined by integration of the NH signals of 1 enamines relative to the methine proton of cis aziridine in the H NMR spectrum of the crude reaction mixture. It should be pointed out that factors other than basicity may affect the equilibrium of AMINO-BOROX and IMINO-BOROX species (see below, Table 7.9). Even if the equilibrium between 215a and 188a is facile (Figure 7.5 and Scheme 7.6), the reaction greatly slows when equal amounts of amine 126a and imine 78a are present since the amount of unreacted imine 78a is 8% when the reaction with 10% excess amine 126a is stopped after 24 h (Table 7.8, entry 2). This suggests that the greater base strength of the amine 126a greatly favors the AMINO-BOROX species 215a over that of the imine are similar. IMINO-BOROX 188a when the concentrations of the amine and In the normal protocol for the multi-component catalytic asymmetric aziridination (Table 7.1), a slight excess of aldehyde (1.05 equiv) is typically used which assures 580 complete consumption of the amine and avoidance of a slow down during the end of the reaction. Scheme 7.6 An equilibrium between (A) AMINO-BOROX catalyst 215a/b and (B) IMINOBOROX catalyst 188/190 A B O Ar H * Ar NH2 Ar OEt N2 Ar N 85 H R OPh Ar Ar O B O N B O O O B 78/111 R OPh 215a/b O 127 H R OPh O B B O O O B 188/190 OPh O O * O R H OEt N2 85 Ar Ar NH2 126a/c 127 To futher examine the effect of the base strength of other species present in the reaction mixture, the aziridination of the pre-formed imine 78a was carried out in the presence of varying amounts of four different nitrogen bases and the results are presented in Table 7.9. In the absence of any added base, the reaction gives aziridine 86a in 85% isolated yield and 90% ee which is nearly the same as has been previously reported for this reaction in chloroform. 9a In these reactions, a boroxinate species is assembled by treating VAPOL and 3 equiv of B(OPh)3 with the base at room temperature for 1 h and then adding the imine 78a and the EDA to consummate the reaction. These conditions directly generate the situation indicated in Figure 7.5D where only the imine and EDA substrates are present. The difference is that the reaction in 581 Table 7.9 begins with an AMINO-BOROX catalyst rather than an IMINO-BOROX catalyst. The reaction in the presence of 10 mol% of benzhydryl amine 126a (Table 6, entry 5) gives nearly the same yield as the reaction without base, and this mirrors the result in entry 2 of Table 7.8. The only difference is that none of the imine 78a remains unreacted at the end in case of the reaction with the pre-formed imine. However, the reaction with 20 mol% of benzhydryl amine 126a slows the reaction dramatically and 86% of the imine 78a remains after 24 h. Similar results are seen with 10 mol% Et3N and 10 mol% benzhydryl amine 126a (entries 2 vs 5), however, with 20 mol% Et3N the reaction is completely stopped and no detectable amount of the aziridine is observed (entries 2 & 3). These results further suggest that an equilibrium is present between an AMINO-BOROX and an IMINO-BOROX species (Scheme 7.6). The fact that there is nearly complete reaction when 10 mol% Et3N or 10 mol% Ph2CHNH2 are added, suggests that at the point when the ratio of amine to imine is 1:1, there is still enough of the IMINO-BOROX species present such that the reaction can still go forward. a Table 7.9 Aziridination reaction of pre-formed imine 78a with added bases. (S)-VAPOL (10 mol%) B(OPh)3 (30 mol%) Base (x mol%) CHCl3 25 °C, 1 h Ph Ph Ph 1. PhCH=NBh 78a 2. EDA 85 25 °C, 24 h Ph + N (Ph)H CO2Et Ph # pKa 1 – Base none 87a(88a) f Yield 87a+88a g (%) Unreacted 78a c (%) 100:1 10 1 Base x mol% Yield 86a c,d (%) ee 86a e (%) cis/trans 0 83 (85) 90 582 CO2Et Ph(H) 86a b NH Table 7.9 cont’d 2 3 4 10.75 Et3N 10 20 40 71 (77) <1 <1 86 – – 25:1 – – 9 – – 6 89 92 5 6 10.60 BhNH2 10 20 77 (80) 10 89 – 27:1 12:1 10 2 <1 86 7 8 9.20 DMAP 10 20 <1 <1 – – – – – – 96 80 9 10 4.60 PhNH2 10 20 73 (78) 17 (20) 88 86 33:1 23:1 8 6 5 68 a Unless otherwise specified, the boroxinate catalyst 215 was prepared in CHCl3 from 10 mol% (S)-VAPOL, 30 mol% B(OPh)3 and x mol% of a base to induce the boroxinate formation. After 1 h at 25 °C, 100 mol% of imine 78a and 120 mol% EDA 85 were added to the catalyst and the aziridination reaction carried out with 1.0 mmol of imine (0.5 M) for 24 h b c 1 at 25 °C. All bases were purified by distillation or sublimation. Determined by H NMR spectra of crude reaction mixture with Ph3CH as internal standard. after isolation by silica gel chromatography. e d Yield in parentheses are Determined by HPLC on purified aziridine. f 1 Ratio determined by integration of the methine protons of cis- and trans-aziridine in the H NMR spectrum of the crude reaction mixture. g Determined by integration of the NH signals 1 of enamines relative to the methine proton of cis aziridine in the H NMR spectrum of the crude reaction mixture. Aniline is a weaker base than aliphatic amines and this can be correlated with its decreased ability to slow the reaction since even with 20 mol% aniline there is 32% conversion of the imine giving a 20% isolated yield of aziridine 86a (entry 10). The formation of aziridine in only 20% yield is surprising given the fact that aniline is a much weaker base than either the aliphatic amines or the imine 78a. This suggests that equilibrium is shifted towards AMINOBOROX species in spite of aniline being a weaker base. To this point, the reader’s attention should be brought to the fact that although these reactions were performed with 10 mol% 583 catalyst, the aziridination reaction with benzhydryl imines 78 can be effected under these conditions with as little as 0.25 mol% catalyst. 9a The ability of the amine to inhibit the reaction does correlate to some degree with the basicity of the amine, but there are obviously other factors that must contribute to the magnitude of the equilbrium constant indicated in Scheme 7.6. This is most clear in the reaction with added DMAP. Although less basic than aliphatic amines, DMAP completely stops the reaction upon addition of just 10 mol% (Table 7.9, entry 7). In this case, any equilibrium between the AMINOBOROX and IMINO-BOROX species may be determined by more than just the relative basicity of the amine and the imine. This equilibrium may be shifted to the AMINO-BOROX further than might be predicted from the basicity alone. The crystal structure of the AMINO-BOROX spieces containing DMAP reveals the presence of non-covalent interactions in addition to the H-bond between the protonated base and the boroxinate anion. 9e Specifically, there is a π-π stacking interaction between the pyridinium cation and one of the phenanthrene rings of the VAPOL ligand and there is a CH-π interaction between one of the ortho-hydrogen of the pyridinium cation and one of the phenoxy groups of the boroxinate core. 9e These results are consistent with the view that the catalytic cycle for the multi-component catalyst assembly/aziridination involves the complete (or nearly complete) formation of the imine before the aziridination reaction can commence (Route II, C to D then to E, Figure 7.5). 7.8 Multiplex diversity: evolution of a seven-component catalyst assembly/catalytic asymmetric aziridination As discussed earlier, the diversity in BOROX catalyst can be achieved by replacing B(OPh)3 with a combination of borane, water and different alcohols (Table 2.3, Chapter 2). 584 These variations would generate a large pool of catalyst and thereby provide new opportunities in asymmetric catalysis. Up to this point, we have only used these variations for aziridination reaction with imines. Hence, it was wondered that whether a seven-component catalyst assembly/catalytic asymmetric aziridination can be realized by using borane along with phenol and water. We have been able to achieve this goal by employing either BH3•Me2S or BH3•THF as the boron source and the results are described below. 7.8.1 Using BH3•Me2S as the boron source Considering the structure of the BOROX catalyst, the boroxinate catalyst can be assembled from a molecule of the ligand, three molecules of BH3•Me2S complex, three molecules of water and two molecules of a phenol or alcohol (Figure 2.5, Chapter 2). To start with, procedure Iʹ′ which is similar to procedure IIIA was used where a mixture of the ligand A (58/59), 2 equiv phenol B (194a), 20 equiv amine C (126a), 3 equiv BH3•Me2S D (192a), 3 equiv H2O E was stirred in toluene at 25 °C for 1 h (Scheme 7.7). This was followed by the addition of the 4 Å MS, benzaldehyde F (127a) and EDA G (85) in the given order. The resulting mixture was stirred at 25 °C for 24 h. Unfortunately, no aziridine 86a was observed (Table 7.10, entries 1-2). Procedure I was then examined which involved heating a mixture of A-E at 100 °C for 1 h (procedure I, Scheme 7.7) followed by the addition of 4Å MS, benzaldehyde F (127a) and EDA G (85) at 25 °C. The resulting mixture was stirred at 25 °C for 24 h to give aziridine 86a in 82% yield and 95% ee (Table 7.10, entry 3). While the VAPOL catalyst gave complete conversion with procedure I leading to aziridine in high yields in 24 h, the VANOL catalyst gave incomplete conversion (70%) under the same conditions (entry 4). 585 This is the first time that there was any significant difference observed between these ligands in the aziridination reaction. Surprisingly, a similar but larger trend was observed in case of the MEDAM amine 126c (Table 7.10, entries 5-6). Only a 17% conversion was observed in case of the reaction involving MEDAM amine 126c and VANOL catalyst (entry 6). The reason for the failure of procedure I with the VANOL catalyst is not known yet. However, essentially optically pure aziridine 114a was obtained with the VAPOL catalyst (entry 5). Scheme 7.7 Various protocols for multicomponent aziridination reaction using BH3•Me2S. Ligand + Ph Ar H O + Ar BH3•Me2S + NH2 A B C D (5 mol%) (10 mol%) (100 mol%) (15 mol%) O O H2O + + Ph H Ar N 4 Å MS toluene 25 °C, 24 h OEt Ar Ph 86a/114a N2 E F G (15 mol%) (105 mol%) (120 mol%) Procedure Iʹ′ A+B+C Procedure I A+B+C Procedure II A+B Procedure III A+B 1) toluene 3) F, 4Å MS 2) D + E 25 °C, 1 h G, 25 °C, 24 h 1) toluene 3) F, 4Å MS 2) D + E 100 °C, 1 h G, 25 °C, 24 h 1) toluene 3) C 4) F, 4Å MS 2) D + E 100 °C, 1 h 25 °C, 1 h G, 25 °C, 24 h 1) toluene 3) C 4) F, 4Å MS 2) D + E 100 °C, 1 h 0.5 mm Hg 100 °C, 0.5 h 25 °C, 1 h G, 25 °C, 24 h 586 CO2Et Table 7.10 Multicomponent aziridination using BH3•Me2S as the boron source + NH2 + Ph C (126a/126c) (100 mol%) PG O O PG a H F (127a) (105 mol%) OEt N2 G (85) (120 mol%) Procedure I'–III 4 Å MS, toluene 25 °C, 24 h N Ph CO2Et 86a/114a Ligand PG Yield azi b (%) Ee azi c (%) # Procedure catalyst x mol% 1 Iʹ′ 10 (S)-VAPOL Bh <1 – 2 Iʹ′ 10 (S)-VANOL Bh <1 – 3 I 10 (S)-VAPOL Bh 82 95 4 I 10 (S)-VANOL Bh 62 (70) 88 5 I 5 (S)-VAPOL MEDAM 99 6 I 5 (S)-VANOL MEDAM – (17) – 7 II 5 (S)-VAPOL MEDAM 90 97 8 II 5 (S)-VANOL MEDAM 85 95 9 III 5 (S)-VAPOL MEDAM 89 97 10 III 5 (S)-VANOL MEDAM 82 95 99.3 a Unless otherwise specified, all reactions were performed with procedures Iʹ′-III in Scheme 7.7 with 1 mmol of amine 126a/126c in toluene (0.5 M in imine) with 1.05 equiv of aldehyde 127a and 1.2 equiv of 85 and went to 100% completion and gave aziridine 86a/114a with cis/trans ratio of >50:1. Small amount of enamine side-products were observed for some b reactions (<1 to 9%). Isolated Yield. Number in parenthesis is the percent conversion. Percent conversion is determined by integration of the methine proton of cis-aziridine relative 2 1 to the sp -CH proton of the unreacted imine in the H NMR spectrum of the crude reaction mixture. c Determined by HPLC. In the process of further optimization, we tried to mimic the procedure that has been used for imines by replacing it with amine. Hence, the pre-catalyst was made by heating a mixture of 587 A, B, D and E at 100 °C for 1 h (procedure II, Scheme 7.7). This was followed by stirring the resulting mixture with amine 126c for 1 h at 25 °C. Subsequent addition of 4Å MS, benzaldehyde F (127a) and EDA G (85) followed by stirring the reaction mixture for 24 h at 25 °C afforded aziridine 114a in high yields and enantioselectivity (entries 7-8). Although a small drop in ee was encountered, the reaction seemed to have worked equally as well for the VANOL catalyst. In addition, no change in ee was observed when the pre-catalyst was kept under vacuum for 0.5 h at 100 °C prior to treatment with the amine 126c (procedure III, Table 7.10, entries 9-10). The results in Table 7.10 establish the feasibility of a higher order seven- component catalyst assembly/catalytic asymmetric aziridination reaction. Inspired by the procedure III of MCAZ, aza-Cope rearrangement was performed by Hong Ren, a current group member, using procedure III with a slight modification (heating of amine with the pre-catalyst 22 instead of stirring at room temperature). It must be noted that the aza-Cope rearrangement was already optimized with imines prior to the evolution of the procedure III of MCAZ. 7.8.2 Using BH3•THF as the boron source With the demonstration that the reaction with seven components can be successfully realized with BH3•Me2S, the focus was then shifted to the further simplification by removing the heating unit operation in the procedure. It was thought that this could be possible with BH3•THF D (192b) as it was reported earlier that it works very well with imines at room temperature (Table 2.1, entry 9 in Chapter 2). Procedure I was then employed where A-E were mixed and stirred for 1 h at 25 °C (Scheme 7.8). This was followed by the subsequent addition of 4Å MS, 588 benzaldehyde F (127a) and EDA G (85) and the resulting mixture was stirred for 24 h at 25 °C. Unexpectedly, both the VAPOL and VANOL catalysts gave incomplete conversions (78% for VAPOL and 46% for VANOL, Table 7.10, entries 1-2). In case of VAPOL, a 72% yield of aziridine 86a was isolated with 92% ee. Another current group member, Wynter Osminski was able to obtain nearly complete conversion by adding PhCO2H to the mixture (PhCO2H : ligand = 23 1 : 2) and using excess aldehyde (1.5 equiv) (entries 3-5). Scheme 7.8 Various protocols for multicomponent aziridination reaction using BH3•THF Ligand + Ph Ph H O + Ph BH3•THF + NH2 A B C D (5 mol%) (10 mol%) (100 mol%) (15 mol%) O O H2O + + Ph H Ph N 4 Å MS toluene 25 °C, 24 h OEt Ph Ph CO2Et 86a N2 E F G (15 mol%) (105 mol%) (120 mol%) Procedure I A+B+C Procedure II A+B Procedure III A+B 1) toluene 3) F, 4Å MS 2) D + E 25 °C, 1 h G, 25 °C, 24 h 1) toluene 3) C 4) F, 4Å MS 2) D + E 25 °C, 0.25 h 25 °C, 1 h G, 25 °C, 24 h 1) toluene 3) C 4) F, 4Å MS 2) D + E 25 °C, 0.25 h 0.5 mm Hg 25 °C, 0.5 h 25 °C, 1 h G, 25 °C, 24 h 589 Procedure II in Scheme 7.8 is analogous to the procedure II in Scheme 7.7 except that the mixture of A, B, D and E are stirred at room temperature rather than at 100 °C. After stirring a mixture of A, B, D and E at 25 °C for 15 min the amine C (126a) is added and the resulting mixture was stirred for 1 h at 25 °C (procedure II, Scheme 7.8). Then 4Å MS, benzaldehyde F (127a) and EDA G (85) are added and the reaction mixture was stirred for 24h at 25 °C. The aziridine 86a was obtained in 80% yield and 90% ee when VAPOL was used as the ligand (entry 6). Interestingly, complete conversion was also obtained with the VANOL catalyst using procedure II (entry 7). A slightly better result was obtained when the pre-catalyst was kept under vacuum for 0.5 h at 25 °C prior to treatment with the amine 126a (procedure III, Table 7.11, entries 8-9). Table 7.11 Multicomponent aziridination using BH3•THF as the boron source Ph Ph O NH2 + Ph C (126a) (100 mol%) Ph O + H F (127a) (105 mol%) OEt N2 G (85) (120 mol%) Procedure I–III 4 Å MS, toluene 25 °C, 24 h Ph Procedure Cat. loading Ligand 1 2 I I 10 10 (S)-VAPOL (S)-VANOL Yield 86a b (%) 72 (78) – (46) 3 I 10 (S)-VAPOL 94 (98) 5 6 7 8 9 I I II II III III 10 5 10 10 10 10 (S)-VANOL (S)-VAPOL (S)-VAPOL (S)-VANOL (S)-VAPOL (S)-VANOL 590 – (29) 88 (90) 80 75 85 82 Ph N # 4 a 86a CO2Et ee 86a c (%) 92 – d 95 d – d 96 90 87 91 89 Table 7.11 cont’d a Unless otherwise specified, all reactions were performed with procedures I-III in Scheme 7.8 with 1 mmol of amine 126a in toluene (0.5 M in imine) with 1.05 equiv of aldehyde 127a and 1.2 equiv of 85 and went to 100% completion and gave aziridine 86a with cis/trans ratio of >50:1. Small amount of enamine side-products were observed for some reactions (3 to 9%). All the reactions were performed with a new bottle of BH3•THF. The data represents the b average of two runs for each entry. Isolated Yield. Number in parenthesis is the percent conversion. Percent conversion is determined by integration of the methine proton of cis2 1 aziridine relative to the sp -CH proton of the unreacted imine 78a in the H NMR spectrum of the crude reaction mixture. c Determined by HPLC. d PhCO2H was used as an additive (PhCO2H : ligand = 1:2) during the stirring of A-E for 1 h at 25 °C. Also, 1.5 equiv of aldehyde 127a used. Data provided by Wynter Osminski. The results presented in Table 7.11 are the average of two runs using a new bottle of BH3•THF. However, it was found that the results did vary depending the quality of the BH3•THF used in the reaction. The quality of BH3•THF cannot be controlled as it decomposes over a period of time. Sometimes, the results were found to be unsatisfactory even if a new bottle of BH3•THF was used. 7.9 Initial attempts towards a multicomponent trans-aziridination reaction In the year 2010, our group reported the first examples of trans-aziridination using our IMINO-BOROX catalyst. 9g The evolution of the trans-aziridination has been a step towards the universal aziridination as our protocol now provides easy access to both cis- and trans-aziridines from the same catalyst and the same imine. After successful completion of the project related to the first multicomponent cis-aziridination, it was thought to extend the methodology by expanding to include the first multicomponent trans-aziridination. This reaction was to found to be extremely substrate specific. The results are presented in Table 7.12. 591 Table 7.12 Multicomponent trans-aziridination of aldehydes (S)-VANOL (10 mol%) MEDAM NH2 toluene 80 °C, 0.5 h O 1. B(OPh)3 (30 mol%) MEDAM R H 4 Å MS 2. 1 2 3 4 5 6 i e e NHX 123a (X = Ph) i 128a (X = Bu) i i 7 8 9 123a (X = Ph) CHO 12 Ph H3C 128b (X = Bn) 123a (X = Ph) CHO 128a (X = Bu) CHO 128a (X = Bu) Ph CHO 128a (X = Bu) 10 C5H11 CHO 128a (X = Bu) 11 TIPS CHO 128a (X = Bu) i N CONHX CONHX R 125 (X = Ph) 129 (X = Bu) 400 (X = Bn) Yield transazi b (%) Diazo 128a (X = Bu) Ph CHO + R N2 –20 °C, 24 h Aldehyde 127 MEDAM N O 126c # a 124 (X = Ph) 130 (X = Bu) 401 (X = Bn) ee transazi c (%) Yield cisazi b (%) ee cisazi c (%) t/c d i <1 f,g,h (20) – i nd – j (11) – i nd – i 1.8:1 i (43) nd (20) nd 2.2:1 i 65 i 50 i 35 f,i k,l 92 k,m 82 k,m 57 i i <1 i <1 i <1 j i i i – – – i i i i nd nd nd i i i i i <1 – <1 – – i <1 – <1 – – i 5 – 89 88 1:18 i <1 – 70 88 nd i <1 – 93 88 1:50 a Unless otherwise specified, all reactions were performed with procedure IIA in Table 7.1 with 0.5 mmol of amine 126c in toluene (0.2 M in imine) with 1.05 equiv of aldehyde 127 and 1.2 equiv of 123a (X = Ph) or 128a (X = Bu) or 128b (X = Bn) and went to 100% completion. b Small amount of enamine side-products were observed for some reactions (1 to 9%). 1 Isolated Yield. Yield in parentheses is determined by H NMR spectra of crude reaction mixture with Ph3CH as internal standard. c Determined by HPLC. 1 d Ratio determined by integration of the methine protons of cis- and trans-aziridine in the H NMR spectrum of the 592 Table 7.12 cont’d crude reaction mixture. e The amount of epoxide 426a, enamines and unreacted imine 111a are 9%, 16%, 43% and 9%, 2%, 3% for entry 2 and 3 respectively. B(OPh)3 and amine 126c was stirred at 25 °C for 1 h. catalyst loading and concentration = 0.3 M. i g f The mixture of ligand , Reaction temp = 0 °C. h 5 mol% The mixture containing the AMINO-BOROX 215b, aldehyde and 4Å MS was stirred for 1 h prior to the addition of diazoacetamide 123a. The opposite enantiomer of 124 was observed. k j The AMINO-BOROX specie 215b was prepared in 0.4 M. Aldehyde 127p was added as a solution in toluene. 93% ee was obtained when the reaction was performed at –10 ºC. Munmun Mukherjee. m l A 70% yield and Data provided by While the reaction between benzaldehyde 127a and diazoacetamide 128a (X = Bu) gave no aziridines, a 20% yield of trans-aziridine 125a was obtained when diazoacetamide 123a (X = Ph) was employed (Table 7.11, entries 1-2). Incomplete conversions and poor selectivities were obtained for the multicomponent trans-aziridination with benzaldehyde irrespective of the method used i.e. true multicomponent or sequential multicomponent reaction (entry 2 vs 3). Additionally, a small amount of epoxide 426a (9%) resulting from the reaction between benzaldehyde and diazoacetamide 123a was observed in both cases. To our delight and surprise, the same reaction between n-hexadecanal 127p and diazoacetamide 128a (X = Bu) yielded aziridine 129p in 65% yield and 92% ee (entry 4). The same reaction gave an yield of 70% and an ee of 93% at –10 ºC. Later on, another group member, Munmun Mukherjee found that the reaction with n-hexadecanal 127p is highly dependent on the kind of diazoacetamide used (entries 5-6). Since the reactions seemed to be highly dependent on the kind of substrate used, we decided to screen some alkenyl and alkynyl aldehydes. No reaction was obtained with cinnamaldehye or crotonaldehyde. It must be noted that it is also the case that no reaction was observed between the imines derived from these aldehydes and ethyl diazoacteate 85 (Chapter 593 6). Later, another current group member, Yong Guan, found that the aziridination reaction between imines derived from alkynyl aldehydes and diazoacetamide 123a afforded cis-aziridines 18 124 in high yields and ees (Chapter 1). More interestingly, the same reaction with the same enantiomer of the ligand afforded the opposite enantiomer of cis-aziridine 124 when ethyl 18 diazoacetate 85 was employed (Chapter 1). As a part of this doctoral research, we attempted theses reactions in a multicomponent fashion and we were able to obtain cis-aziridine 130 in high yields and ees when the reaction was performed with alkynyl aldehydes and diazoacetamide 128a (entries 9-11). Although, the multicomponent trans-aziridination works well with aliphatic aldehydes, there is obviously still work needed to optimize the reaction with aromatic aldehydes. 7.10 Determination of absolute stereochemistry of cis- and trans-aziridines using circular dichroism As a part of further understanding, we decided to determine the absolute chemistry of the cis-aziridines 124 and 130 and trans-aziridines 125, 125ʹ′, 129 and 400. In this regard, the absolute configuration was established by the excellent method developed by Borhan and coworkers using circular dichroism. 24 This work was done in collaboration with Carmin Burrell, a current graduate student in Borhan group. The method was applied to a number of aziridines as listed in Figure 7.6A and 7.7A. The absolute stereochemistry of the cis-aziridines was confirmed through evaluation by exciton coupled circular dichroism (ECCD). The sign of the observed ECCD curve is a reflection of the stereochemistry of the aziridines in that a pair of enantiomeric molecules will 594 exhibit ECCD signals with opposite sign. Each aziridine was titrated into a 1µM solution of the porphyrin tweezer, Zn-C5-TPFP-Tz, in hexanes at 0 °C. Below is a summary of the ECCD data and the mnemonic to explain the signs of the observed ECCD signals. Figure 7.6 Determination of absolute stereochemistry of cis-aziridines 124 and 130. (A) Observed ECCD amplitudes for chiral cis-aziridines. All measurements were performed with 1µM tweezer in hexanes at 0 ºC. (B) Proposed mnemonic explaining the signs of the observed ECCD signals. A MEDAM N H N MEDAM N nBu O TIPS MEDAM N H N nBu H N Ph O (S,S)-124a (98% ee) A = –1559, 60 equiv 595 nBu (R,R)-130b (88% ee) A = +888, 5 equiv MEDAM N Ph H N O C5H11 (S,S)-130c (88% ee) A = –269, 20 equiv MEDAM N Ph O (S,S)-130a (88% ee) A = –944, 15 equiv nBu O TIPS (R,R)-130c (88% ee) A = +520, 40 equiv H N MEDAM N Ph H N Ph O (R,R)-124z (21% ee) A = +119, 60 equiv Figure 7.6 cont’d B PG N HH H N R' R RR O Y N Y P1 PG Zn N H R N Zn N N N Zn Y O Zn-C5-TPFP-Tz (Y = C6F5 ) H P2 H N R' O Zn Y N O P2 PG N Y O P1 R N Y N H N O PG HH N H R' N S S R O R' P1 PG Zn H N H N R H R' Zn P2 P1 O P2 O The host-guest, aziridine-tweezer, complex is formed by coordination of the nitrogen and the oxygen of the amide carbonyl to the zinc centers of the porphyrin tweezer. In the case of cisaziridines, it is believed that the protecting group of the cis-aziridine nitrogen (PG) will reside opposite of the cis-aziridine substituents. Therefore, as shown in Figure 7.6B, the front porphyrin P1 binds to the cis-aziridine to the same face as the substituents and remains essentially static. The rear porphyrin P2 binds to the carbonyl of the amide and rotates away from the cis-aziridine. Hence, a positive ECCD signal is expected for the (R,R)-aziridines and a negative signal for the (S,S)-aziridines. It was delightful to observe the correct prediction of the absolute stereochemistry of cis-aziridines when compared to the already established absolute 18 stereochemistry of (S,S)-124a 9g and (R,R)-124z 596 via chemical derivatization. In the case of trans-aziridines, the shown absolute configuration (Figure 7.7A) is based on a hypothetical mnemonic that will require conformation by other means. It is conjectured that for the trans-azridines, when bound to the porphyrin tweezer, the nitrogen is pyramidalized such that the lone pair electrons of the nitrogen are opposite to the amide functionality. As shown in Figure 7.7B, the rear porphyrin P2 binds to the nitrogen and rotates away from the R group. The front porphyrin P1 binds to the carbonyl of the amide and rotates toward the hydrogen. Therefore, substrates with an (S,R) configuration are expected to give a positive ECCD signal and a negative signal would be observed for the substrates with an (S,R) configuration. Figure 7.7 Determination of absolute stereochemistry of trans-aziridines 125, 125ʹ′, 129 and 400. (A) Observed ECCD amplitudes for chiral trans-aziridines. All measurements were performed with 1µM tweezer in hexanes at 0 ºC. (B) Proposed mnemonic explaining the signs of the observed ECCD signals. A BUDAM N BUDAM N H N O BUDAM N H N O (S,R)-125'x (83% ee) A = +21, 400 equiv MEDAM N Ph O (R,S)-125'z (88% ee) A = –41, 200 equiv (R,S)-125'w (89% ee) A = –22, 60 equiv MEDAM N H N Ph H N O O (R,S)-400a (94% ee) A = –94, 20 equiv (R,S)-129a (98% ee) A = +80, 5 equiv 597 H N Figure 7.7 cont’d MEDAM N MEDAM N H N C14H29 C14H29 O MEDAM N H N C14H29 O (R,S)-129p (87% ee) A = –160, 20 equiv H N O (S,R)-125p (80% ee) A = +343, 20 equiv (R,S)-400p (82% ee) A = –114, 20 equiv B P2 Zn PG H R N H N R' H PG N HH R O N R' Zn H SR O P1 Y Y N N Zn N N Y Y Y O O N N Zn N N Zn-C5-TPFP-Tz (Y = C6F5 ) O O Y PG P2 HH N R PG N SR Zn R' H HH N R O N H PG R' N H O Zn N R' R RS O P1 P1 P2 P2 P1 The absolute stereochemistry of (S,R)-125a (R = Ph, Rʹ′ = Ph, Figure 7.7B, aziridine not shown here) was established via chemical derivatization. 9g The same stereochemistry has been assumed for other trans-aziridines prepared from same enantiomer of the ligand. It was delightful to observe the correct prediction of the absolute stereochemistry of trans-aziridines when compared to the already established absolute stereochemistry of (S,R)-125a (not shown 598 here). Unfortunately, the proposed mnemonic for the three aziridines (R,S)-125ʹ′z, (R,S)-125p and (R,S)-129a did not match to the experimental results (shown in red color in Figure 7.7A). It must be noted that the absolute stereochemistry of these substrates was not determined by any other means and the stereochemistry indicated in the Figure 7.7A is based on the expected configuration from the ligand employed for their synthesis. In these cases, the ECCD sign is opposite to what is predicted by proposed mnemonic. The result obtained from ECCD indicates either these three particular substrates behave differently with ligands or the substrate-tweezer complex favors a different conformation for these substrates, which is affecting the outcome of ECCD. Hence, to determine the cause of the incorrect ECCD sign, the stereochemistry of these substrates should be confirmed by other means and a screen of ECCD conditions should be conducted. Further probe is underway during the time of the writing of this dissertation. 7.11 Gram scale catalysis and large scale synthesis The real application of any methodology lies in its easy adaption towards the large-scale synthesis. The multicomponent aziridination was easily applicable to gram scale without any detrimental effect on the yields or ee (Scheme 7.9). Scheme 7.9 Gram scale asymmetric catalysis MEDAM NH2 + 126c 6 mmol scale O O + H 127o OEt (S)-VAPOL boroxinate catalyst (3 mol %) MEDAM N toluene, –10 °C, 24 h N2 CO2Et 114o 85 92 % yield (2.4 g) (1.8 g) 96 % ee 599 Scheme 7.9 cont’d MEDAM NH2 O O + + 12 126c H OEt toluene, –10 °C, 24 h N2 127p (S)-VAPOL boroxinate catalyst (10 mol %) MEDAM N CO2Et 12 114p 85 5 mmol scale 85 % yield (2.6 g) (1.5 g) 95 % ee The tetra-methyldianisylmethyl (MEDAM) amine 126c is the optimal protecting group in the case of the Wulff catalytic asymmetric cis- 9c and trans-aziridination 9g reaction. Unfortunately, the MEDAM amine 126c is not commercially available. Hence, we decided to develop an easy and economic route to prepare amine 126c from the commercially available starting materials. The synthesis of tetra-methyldianisylmethyl (MEDAM) amine 126c shown in Scheme 7.10 follows that previously reported and was scaled up to 58 mmol on the 9c commercially available bromide 403. The nitrile 404 can be obtained from the bromide 403 by the Shechter modification of the Rosenmund-Van Braun reaction. 25 The key step in the synthesis of amine 126c involves the reaction of the nitrile 404 with the in-situ generated Grignard reagent 405. The subsequent in-situ reduction of the resulting imine intermediate 405ʹ′ provides the amine 126c in 66% yield from the nitrile 404. The entire process of preparation of MEDAM amine 126 was carried out efficiently without the use of any column chromatography purification. It must be noted that this project was initiated by Munmun Mukherjee. The modifications that were made in the reaction sequence are as follows: a) commercially available bromide 403 was used, b) the nitrle 404 was used in the Grignard reaction without any 600 purification and c) MEDAM amine•HCl salt was made using dry HCl gas instead of a 12 M HCl solution during the purification of final product 126c. Scheme 7.10 Large scale synthesis of MEDAM amine 126c OMe OMe OMe CuCN, DMF reflux, 12 h 95% yield (8.93 g, crude) Br 403 58.3 mmol scale (12.54 g) Commerically avaliable BrMg 405 OMe MeO THF, reflux, 7 h NH CN 404 53 mmol scale (8.54 g) isolated, not purified OMe MeO MEDAM amine 66% yield (10.50 g) 405' NH2 126c LiAlH4 THF reflux, 20 h crystallization 7.12 Application of multicomponent aziridination reaction in organic synthesis The real advantage of any methodology lies in its practical application in the field of organic synthesis. Henceforth, we decided to apply the newly developed multicomponent aziridination reaction in organic synthesis. It must be pointed out that another current group member Munmun Mukherjee has done the following work shown in Scheme 7.11A-C. Following the MCAZ protocol, we have been able to accomplish the synthesis of all four diastereomers of sphinganines in good yield in four steps from amine 126c (Scheme 7.11B). 19 Also, the MCAZ reaction has been found to be useful in the diastereoselective aziridination of chiral aldehydes (Scheme 7.11A). 26 Further, we have been able to perform a direct 601 transformation of benzaldehyde 127a to β-hydroxy-α-amino ester 408 and α-amino ester 409 in 12 a one-pot fashion (Scheme 7.11C). Last, but not the least, a direct access to β-lactam 411 from 27 aldehydes was possible in 58% overall yield as shown in Scheme 7.11D. Scheme 7.11 Application of MCAZ reaction in organic synthesis A Studies towards enantioselective synthesis of phytosphingosines OH MEDAM O H OTBS 406 12 MEDAM N (R)-VAPOL-B3 (10 mol% ) O + OH OH NH2 L-lyxo-phytosphingosine 12 NH2 126c OEt 12 4Å MS, toluene OEt –10 ºC, 24 h N2 85 OH OTBS O 407 OH 12 OH NH2 L-arabino-phytosphingosine 92% y, dr >99:1 B Enantioselective synthesis of sphinganines 5 mol% (S)-VAPOL-B3 MEDAMNH2 OH MEDAM 4 steps N CO2Et 114p 85% yield, 97% ee 12 OEt N2 MeO O OH 12 O OH NH2 OH 12 NH2 392 391 L-threo-sphinganine D-erythro-sphinganine (safingol) (sphinganine) OMe H 12 127p MEDAM O MEDAM OEt N N2 5 mol% (R)-VAPOL-B3 MEDAMNH2 OH 4 steps OH 12 CO2Et ent-114p 86% yield, 97% ee 12 OH NH2 393 OH 12 NH2 394 L-erythro-sphinganine D-threo-sphinganine 602 Scheme 7.11 cont’d C One-pot synthesis of β-hydroxy-α-amino ester 408 and α-amino ester 409 NHBoc 1) TfOH 2) H2O MEDAM NH2 126c O O + OEt H Ph 4Å MS, toluene 25 ºC, 3 h N2 N 408 60% y, 98% ee CO2Et 114a not purified Ph 85 127a CO2Et OH 3) Boc2O NaHCO3 MEDAM (S)-VAPOL-B3 (5 mol% ) Ph Pd(OH)2 MeOH NHBoc Ph Boc2O H2 (1 atm) CO2Et 409 70% y, 98% ee D One-pot synthesis of β-lactam 410 MEDAM MEDAM NH2 126c O nPr + H 127a (S)-VAPOL-B3 (5 mol% ) N O 1) aq KOH MEDAM 4Å MS, toluene nPr CO2Et 2) [Me2N=CHCl]Cl OEt –10 ºC, 24 h 114o N2 not purified 85 N O nPr Cl 410 58% y, 96% ee 7.13 Future applications: multicomponent intra-molecular aziridination reaction The Wulff group has been working on intra-molecular aziridination for quite a while. The initial idea is presented in Scheme 7.12A. However, the synthesis and stability of imine 411 was not known. Also, the possibility of self-condensation of the imine 411 under traditional aziridination conditions cannot be ruled out. The development of MCAZ protocol has taken the idea one step further. Hence, the stability of the imine and the possibility of aldol-adduct would not be a problem in the case of proposed multicomponent intra-molecular aziridination reaction (Scheme 7.12B). However, there is the daunting task of making the aldehyde 413. It is an 603 unknown compound and might be highly unstable due to the presence of the diazo component. It was then envisioned that this problem could be solved by using compounds like 417 and 418 (Scheme 7.12B). The 2-(2-pyridyl)Propane-1,3-diol 416 is a mild protecting group and can be easily deprotected under mild basic conditions. 28 Although, we were able to make diol 416, several attempts towards the generation of 417 and 418 were not successful and are not presented here. However, based on the information obtained from the multicomponent aziridination reaction described in this work, it is reasonable to expect that the intra-molecular aziridination reaction will be accomplished in the near future provided that the compounds 417 and 418 are available. Scheme 7.12 Proposed intramolecular aziridination reaction via (A) Traditional aziridination (B) Multicomponent aziridination reaction. A Ar N O Ar Ar (R)-VAPOL + B(OPh)3 (10 mol% ) (30 mol% ) [pre-catalyst] N2 Ar N 411 O toluene, 25 ºC, 24 h 412 B O O Ar H N2 Ar Ar NH2 (S)-VAPOL (x mol %) B(OPh)3 (3x mol %) N 413 4Å MS, toluene -10 ºC, 24 h N2 O toluene, 25ºC, 1 h O 412 Ar O 126 Ar O Ar N 414 4Å MS, toluene 25 ºC, 24 h 604 O O 415 Scheme 7.12 cont’d N N N O OH OH O N2 417 416 O H O O N2 O O 418 7.14 Conclusions The practicing chemist now has at one’s avail a multi-component asymmetric catalytic method for the preparation of aziridines directly from aldehydes, an amine and a diazo compound. 12 The chiral catalyst for this reaction has a boroxinate core comprised of a chiral polyborate that is assembled in-situ from a vaulted biaryl ligand (VANOL or VAPOL) and three equivalents of B(OPh)3 by the amine substrate. The present work shows that this is actually a rather unique five-component process involving both catalyst assembly and a catalytic asymmetric aziridination reaction. 13 A solution of these five components has the potential to create a chaotic array of products and yet there is order since aziridines are formed in very high yields, diastereoselectivities and enantioselectivities. This order is imposed by the amine in causing an exceedingly fast assembly of the boroxinate catalyst from the ligand and B(OPh)3. Once the catalyst is assembled, it is protected from alkylation by the diazo compound and since the B(OPh)3 is consumed, the epoxidation reaction of the diazo compound and the aldehyde is thwarted. This then permits the formation of an imine from the aldehyde and amine and the 605 resulting imine binds in its protonated form to the boroxinate catalyst. This is followed by binding of the diazo compound to the chiral boroxinate catalyst in such proximity to the bound iminium that an aziridine is formed with high diastereo- and enantioselection. 9h In addition, a seven-component catalyst assembly/catalytic asymmetric aziridination was also realized. Further, the methodology was used as the key step in the enantioselective synthesis of the 19 sphinganine family of biologically important compounds. In the synthesis of phytosphingosines, a diastereoselective aziridination was performed as the key step following the MCAZ protocol. 26 All in all, the MCAZ reaction incorporates a very simplified protocol and it provides an effective solution to the catalytic asymmetric syntheses of alkyl-substituted aziridines which have remained elusive until now. Also, it is quite general for a wide range of aldehydes bearing a variety of functional groups. More recently, the practical viability of this methodology has been highlighted in reputed magazines and journals. 606 29 APPENDIX 607 7.15 Experimental 7.15.1 General Information ..................................................................................................... 609 7.15.2 Synthesis of amine 126c, imines 78a, and diazoacetamides 123a, 128a and 128b .... 609 7.15.3 Attempt to make imine 111t from aldehyde 127t (Scheme 7.1) .................................. 616 7.15.4 Possible complications for the five-component catalyst assembly/aziridination (Scheme 7.4) ............................................................................................................................... 617 7.15.5 Different protocols for MCAZ: procedures (I, IIA-B, IIIA-C) (Table 7.1) ................. 621 7.15.6 Synthesis of aryl and heteroaryl MEDAM aziridines 114a-n (via Procedure IIIA, Table 7.3) ............................................................................................................................... 630 7.15.7 Synthesis of alkyl MEDAM aziridines 114o-w (via Procedure IIIA, Table 7.6) ........ 642 7.15.8 Synthesis of MEDAM imine 111l and aziridine 114l (aziridination with preformed imine, Scheme 7.5) ....................................................................................................... 653 7.15.9 Mechanistic study of MCAZ ....................................................................................... 656 7.15.10 MCAZ using BH3•Me2S as the boron source: Procedures (Iʹ′-III) (Table 7.10) ......... 668 7.15.11 MCAZ using BH3•THF as the boron source: Procedures (I-III) (Table 7.11) ............ 673 7.15.12 Initial attempts towards multi-component trans-aziridination (Table 7.12) ................ 675 608 7.15.1 General Information Same as Chapter 2 7.15.2 Synthesis of amine 126c, imines 78a, and diazoacetamides 123a, 128a and 128b a) Large scale synthesis of MEDAM amine 126c OMe OMe OMe CuCN, DMF reflux, 12 h 95% yield (8.93 g, crude) Br 403 58.3 mmol scale (12.54 g) Commerically avaliable BrMg 405 OMe MeO THF, reflux, 7 h NH CN 404 53 mmol scale (8.54 g) isolated, not purified OMe MeO MEDAM amine 66% yield (10.50 g) 405' NH2 126c LiAlH4 THF reflux, 20 h crystallization 4-methoxy-3,5-dimethylbenzonitrile 404: A 500-mL three-necked round-bottomed flask, sealed with rubber septums at two necks and equipped with a big stir bar and a 24/40 vacuum adapter at the middle neck, was flame-dried and cooled under nitrogen. To this flask was added CuCN (6.27 g, 70 mmol, 1.2 equiv.) through one of the necks. During addition, a continuous flow of nitrogen was maintained at the middle neck via vacuum adapter along with an outlet of nitrogen (in the form of a bubbler) at the other neck. It was followed by the addition of 5-bromo2-methoxy-1,3-dimethylbenzene 403 (9.3 mL, 12.54 g, 58.3 mmol) and anhydrous DMF (125 mL, freshly distilled and stored over 4Å MS) using 10 mL syringe and 60 mL syringe 609 respectively. The vacuum adapter, on the middle neck, was then replaced by a rubber septum with a nitrogen-filled balloon. Thereafter, the reaction mixture was purged with nitrogen under the surface of the solution for next 15 min via left neck of the flask utilizing the long metal needle attached directly to the nitrogen source. During purging, an outlet of nitrogen (in the form of a bubbler) was maintained through the other (right) neck. Immediately, an oven-dried Vigreux air condenser (25 mm × 350 mm) followed by an oven-dried water condenser (17 mm × 220 mm) was placed on the middle neck along with a Teflon sleeve at the joint. The source of nitrogen was then changed to a nitrogen-filled balloon on the top of the condenser through a rubber septum stopper. Thereafter, the rubber septums, at the other two necks, were replaced by teflon stoppers and all the necks were further sealed by Teflon tape. The mixture was then heated to reflux in an oil bath (178 ºC) for 12 h (the reaction was followed by TLC until the disappearance of the starting material). During the refluxing, the solid CuCN dissolved after approximately 15 min and a light green precipitate of CuBr was observed which further dissolves to give a brown colored solution in due course of time. The reaction mixture was then cooled gradually to room temperature and after cooling down, it was a dark green solution with little light green precipitate of copper salt at the bottom of the flask. Beyond this point, all the operations were carried out under the hood. The reaction mixture was then slowly poured into a 2 L Erlenmeyer flask containing an aqueous solution of ethylenediamine (25 mL ethylene diamine in 620 mL water) along with a big stir bar at 0 ºC (ice-bath). During addition, a continuous stirring was maintained. The three-neck round-bottomed flask was washed with 20 mL of an aqueous solution of ethylene diamine (25 mL ethylene diamine in 620 mL water). The resulting purple colored reaction mixture was then allowed to warm gradually to room temperature. It was then followed by the addition of benzene (200 mL) and the resulting mixture 610 was stirred vigorously at room temperature for 20 min and then transferred directly into a 2 L separatory funnel. The top organic layer (mud colored) was separated. The purple colored aqueous layer was then extracted with benzene (80 mL × 4). The combined organic layer was washed with 1.22 M NaCN solution (100 mL) and a change in color from mud to murky white was observed. The resulting solution was then washed with water (110 mL × 2), dried over MgSO4 and filtered (washed with benzene (50 mL × 2)) to a 1 L round bottom flask. The yellow solution was then subjected to rotary evaporation (25 °C, 20 mmHg) to afford the crude product 2 as pale yellow oil, which became a murky white solid (8.93 g, 95% crude yield) on being kept under vacuum overnight. It was used in next step without any further purification. Bis-(2,6-di-methyl-4-methoxyphenyl)methineamine 126c: A 500-mL three-necked roundbottomed flask, sealed with rubber septums at two necks and equipped with a big stir bar and a 24/40 vacuum adapter at the middle neck, was flame-dried and cooled under nitrogen. To this flask was added magnesium (3.6 g, 148.4 mmol, 2.8 equiv, 20 mesh) through one of the necks utilizing powder funnel. Next, anhydrous THF (125 mL, freshly distilled) and a few crystals of iodine (2 crystals, 92 mg) were added. During addition, a continuous flow of nitrogen was maintained at the middle neck via vacuum adapter. The vacuum adapter, on the middle neck, was then replaced by an oven-dried water condenser (33 mm × 470 mm) placed on the middle neck along with a Teflon sleeve at the joint and sealed with Teflon Tape. The source of nitrogen was then changed to a nitrogen-filled balloon on the top of the condenser through a rubber septum stopper. It was followed by the addition of 4-bromo-2,6-dimethylanisole 403 (9.3 mL, 12.54 g, 58.3 mmol, 1.1 equiv) using 10 mL syringe. During addition a continuous stirring was maintained Thereafter, the rubber septums, at the other two necks, were replaced by teflon stoppers and all the necks were further sealed by Teflon tape. The red color mixture was then 611 heated to reflux in an oil bath (78 ºC) for 4 h. The resulting clear grey solution was allowed to cool down to room temperature. One of the Teflon stoppers was then replaced by a rubber septum. Meanwhile, to a flame-dried 250 mL round-bottomed flask, filled with nitrogen, was added 4-methoxy-3,5-dimethylbenzonitrile 404 (8.54 g, 53 mmol, 1.0 equiv) and THF (100 mL, freshly distilled). This yellowish orange solution was then transferred (dropwise) via cannula to the 500 mL three-necked round-bottomed flask containing the freshly prepared Grignard reagent 405 over a period of 20 min at room temperature. The flask containing 4-methoxy-3,5dimethylbenzonitrile 404 was then rinsed with THF (10 mL, freshly distilled) and the rinse was transferred to the flask containing Grignard reagent 405. The resulting mixture was heated to reflux in an oil bath (78 ºC) for 7 h under nitrogen. A reddish brown colored solution was obtained and then allowed to cool down to room temperature, and then to 0 ºC (ice-bath). Meanwhile, a suspension of LiAlH4 (2.2 g, 58.3 mmol, 1.1 equiv) in THF (55 mL, freshly distilled) was prepared in a flame-dried 1 L round-bottomed flask filled with nitrogen and precooled at 0 ºC. Next, the in-situ generated imine 405ʹ′ was transferred to 1 L round-bottomed flask containing LAH suspension via cannula at 0 ºC. The flask containing in-situ generated imine 405ʹ′ was then rinsed with THF (10 mL, freshly distilled) and the rinse was transferred to the flask containing LiAlH4 suspension. The ice bath was then removed and the same water condenser (along with the Teflon sleeve), utilized in the synthesis of Grignard reagent, was placed on the 1 L round-bottomed flask containing the reaction mixture. The joint was further sealed by Teflon tape. Thereafter, the resulting greenish yellow reaction mixture was heated to reflux in an oil bath (78 ºC) for 20 h under nitrogen. The reaction flask was cooled down to room temperature and then to 0 ºC, and carefully quenched (under hood) by the slow addition of water (2.2 mL), then 3.75 M NaOH solution (2.2 mL), and water (6.6 mL) over a period of 10 min. The 612 resulting green colored suspension was filtered through a Celite (503) pad into a 1 L roundbottomed flask and washed with ether (100 mL). The remaining filter cake was then transferred to a 1 L beaker along with a big stir bar. Thereafter, ether (150 mL) was added to it. The resulting suspension was stirred vigorously for 10 min. The top of the beaker was covered with aluminum foil during stirring. Meanwhile, the filtrate, after first washing, was concentrated using rotatory evaporation (25 °C, 20 mm Hg). The suspension, in 1 L beaker, was then filtered to 1 L round-bottomed flask containing the crude product. The beaker was then washed with ether (50 mL) and then filtered through the same Celite pad. The above process was repeated eight times using ether ((150 + 50) mL × 8). Subsequently, the filter cake was washed with ether (100 mL × 3) during the last filtration process. The color of the filter cake changed from grey to white. The filtrate was concentrated by rotary evaporation (25 °C, 20 mm Hg) to afford yellow solid (18.87 g, 119% crude yield) on being kept under vacuum overnight. The light yellow solid was then dissolved in EtOAc (100 mL) and stirred for 30 min. Further, the flask was cooled to 0 °C. A stream of in-situ generated dry HCl gas was gradually passed into the Erlenmeyer flask containing the amine until the pH ~ 2 (determined by pH paper) resulting in the appearance of yellowish white precipitate. It takes 20 min approximately. During the addition, a continuous stirring was maintained. After addition, the mixture was stirred for 10 min at room temperature. Thereafter, it was allowed to stand still for 1 h at room temperature. The flask was covered with aluminum foil during this period. The resulting yellow colored suspension was filtered through a Buchner Funnel into a 250 mL round-bottomed flask and washed with hexanes (50 mL × 2). The obtained filter cake (amine salt) was then transferred back to a 100 mL beaker with a big stir bar. To this beaker was added EtOAc (40 mL) and the resulting suspension was stirred for 10 min at 0 °C. The resulting yellow colored suspension was filtered through a Buchner Funnel into 613 the same 250 mL round-bottomed flask and washed with hexanes (50 mL). The above procedure was repeated once more. The resulting off-white cake (amine salt) was transferred to preweighed 500 mL round bottom flask and was dried overnight at 0.01 mmHg to provide amine salt as an off-white solid (14.67 g). The filtrate was subjected to rotary evaporation (30 °C, 20 mm Hg) to afford an orange solid (2.55 g) on being kept under vacuum overnight. Meanwhile, a stir bar was added to flask containing amine salt (14.67 g) followed by the addition of the ether (125 mL) and the resulting mixture was cooled to 0 °C. To this solution was added pre-cooled (0 ºC) 6 M NaOH (50 mL) was added portion-wise (~ 5 mL each time) till the pH (water layer) ~ 13. A continuous stirring should be maintained during the addition of the base. The flask was covered with aluminum foil before addtion of base. After pH ~ 13, the mixture was stirred under nitrogen for 0.5-1 h so as to dissolve the entire solid. The reaction mixture was then transferred to 250 mL separatory funnel. The flask was washed with ether (30 mL) and the washing was transferred to the separatory funnel. The organic layer was separated and aqueous layer was washed with ether (60 mL × 4), dried over MgSO4, filtered (washed with ether (50 mL × 3) into a 1 L round-bottom flask. The resulting filtrate was reduced to approximately 100 mL by rotary evaporation (25 °C, 20 mm Hg). It was then transferred to a pre-weighed 250 mL round-bottom flask and concentrated to afford a pale yellow solid (12.71 g, 80.09 % crude yield) on being kept under vacuum overnight. Purification: The crude amine 126c was purified by crystallization. A sample of crude product (~ 5 mg) was saved to use as the seeding crystals later on. The 250 mL round-bottomed flask containing the crude solid (12.71 g) was then equipped with reflux condenser sealed with rubber septum having a nitrogen balloon at the top. The solid was then dissolved in hot hexanes (12 mL, 70 °C) and left to cool to room temperature. Thereafter, it was seeded by the sample of crude 614 product (~ 2 mg) and left overnight at room temperature under nitrogen. Thereafter, the mother liquor was decanted to another pre-weighed 100 mL round-bottomed flask using a 12 inch long pipette. The pipette was washed with hexanes (3 mL) directly into the same pre-weighed 100 mL round-bottomed flask. Now, to the flask containing the resulting pale yellow crystals was added ice-cold hexanes (2 mL × 2) and was decanted to the flask containing the mother liquor. The color of the crystals was changed to off-white. The crystals were dried overnight at 0.01 mmHg to provide 126c as an off-white crystalline solid in 22.1 % yield (3.500 g, 11.66 mmol, first crop, mp. 60-61 ºC). The mother liquor along with the washings was then subjected to rotary evaporation (25 °C, 20 mmHg) to afford the crude product as a yellow solid (8.90 g). The resulting crude product was then subjected to re-crystallization using hot hexanes (8 mL, 70 °C) as discussed above. Likewise earlier, the mother liquor was decanted to another pre-weighed 100 mL round-bottomed flask using a 12 inch long pipette. The pipette was washed with hexanes (3 mL) directly into the same pre-weighed 100 mL round-bottomed flask. Now, to the flask containing the resulting pale yellow crystals was added ice-cold hexanes (3 mL × 1 and 2 mL × 2) and was decanted to the flask containing the mother liquor. The color of the crystals was changed to off-white. The crystals were dried overnight at 0.01 mmHg to provide 126c as an offwhite crystalline solid in 25.2 % yield (4.000 g, 13.36 mmol, second crop, mp. 59-60 ºC). The crude product (4.80 g) obtained after rotary evaporation (25 °C, 20 mmHg) was subjected to recrystallization using hot hexanes (5 mL, 70 °C). Following the above discussed procedure, an 18.9 % yield (3.000 g, 10.02 mmol, third crop, mp. 59-61 ºC) of 126c was obtained after the washing with ice-cold hexanes (3 mL × 1 and 2 mL × 2). The resulting crude product (1.8 g, dark red) was not further purified. After three crystallizations, the combined yield of 126c was 66.2% (10.50 g, 35.04 mmol). 615 1 Spectral Data for 126c: Rf = 0.3 (5:1:0.2 EtOAc/Hexanes/MeOH). H-NMR (CDCl3, 300 MHz) δ 1.73 (s, 2H), 2.26 (s, 12H), 3.69 (s, 6H), 5.00 (s, 1H), 7.01 (s, 4H); 13 C-NMR (CDCl3, 75 MHz) δ 16.10, 58.77, 59.50, 126.96, 130.56, 140.88, 155.65; IR (thin film) 3376m, 3306m, -1 + 2943vs, 1493s cm ; Mass spectrum: m/z (% rel intensity) 299 M (35), 298 (54), 283 (47), 268 (94), 163 (100); Anal calcd for C19H25NO2: C, 76.22; H, 8.42; N, 4.68. Found: C, 75.89; H, 8.54; N, 4.62. These spectral data match those previously reported for this compound. 9c b) Synthesis of imine 78a: see chapter 2 (experimental) c) Synthesis of diazoacetamides 123a, 128a and 128b: see Chapter 8 (experimental) 7.15.3 Attempt to make imine 111t from aldehyde 127t (Scheme 7.1) Ar H Ph 127t Hb Ar H2N H a 126c O 4 Å MS toluene, 25 °C, t h Hf Ar Ar Ph N H c + Hd Ar Ar N H e Ph Ph 111t 386t Ar + Ar H2N H a 126c To a 5 mL flame-dried single-necked round bottom flask, equipped with a stir bar, filled with argon was added MEDAM amine 126c (59.9 mg, 0.200 mmol), 4Å MS (50 mg, freshly dried) and dry toluene (1 mL). After stirring for 10 min, aldehyde 127t (28.2 mg, 0.210 mmol, 1.05 equiv) was added. The reaction mixture was stirred at room temperature. The crude reaction 616 1 mixture was then monitored at different time intervals by H NMR. The result is described in the chapter. 7.15.4 Possible complications for the five-component catalyst assembly/aziridination (Scheme 7.4) A) Alkylation of the ligand: O OEt Ph Ph Hb OH OH N2 + B(OPh)3 (3 equiv) 85 (2 equiv) CDCl3 25 °C, 10 min Hb Ph Ph O OH O Hb' OEt 80% 230 mono-alkylated (S)-VAPOL derivative δ = 9.56 ppm and 9.83 ppm (Hb and Hb') (S)-VAPOL 58 δ = 9.77 ppm (Hb) To a 10 mL flame-dried round bottom flask, equipped with a stir bar and a rubber septum and filled with argon was added (S)-VAPOL 58 (54 mg, 0.10 mmol, 1.0 equiv), B(OPh)3 (87 mg, 0.30 mmol, 3.0 equiv), ethyl diazoacetate 85 (0.20 mmol, 2.0 equiv.), Ph3CH (12.2 mg, 0.500 mmol) and CDCl3 (1 mL). The resultant mixture was stirred for 10 min at room temperature. The resulting solution was then directly transferred to a quartz NMR tube (freshly flame-dried) and was subjected to NMR analysis. The reaction furnished the mono-alkylated adduct 230 in 617 80% yield as determined by integration against an internal standard (Ph3CH) and with the aid of the spectral data previously published for this compound. 9a,30 B) NMR analysis of a mixture of PhCHO 127a and EDA 85 in different reaction conditions: As discussed in the chapter, benzaldehyde and ethyl diazoacetate react with each other in presence of Lewis acids and Brønsted acids resulting in the formation of several products. It was thought to examine the possibility of these products under the reaction conditions of a possible multicomponent aziridination (MCAZ). (a) with B(OPh)3: Ph B(OPh)3 O O H + (14 mol%) OEt 127a Ph CDCl3 25 °C, 10 min N2 85 (1.14 equiv) + CO2Et 395a 3% Ph Ph CO2Et + H H 397a 8% CO2Et 396a 47% OH OH + O O OH CO2Et CO2Et + Ph Ph N2 398a 1% 399a 2% To a 10 mL flame-dried single-necked round bottom flask, equipped with a stir bar and a rubber septum and filled with argon was added B(OPh)3 (22 mg, 0.075 mmol, 0.14 equiv), benzaldehyde 127a (52.0 µL, 0.525 mmol, 1.00 equiv), ethyl diazoacetate 85 (62.0 µL, 0.600 mmoL, 1.14 equiv), Ph3CH (12.2 mg, 0.500 mmol) and CDCl3 (1 mL). The resultant mixture was stirred for 24 h at room temperature. The resulting solution was then directly transferred to a NMR tube and was then subjected to NMR analysis. Several products were observed as shown 618 in the reaction. The presence of each product was confirmed by characteristic peaks (δ 3.83 31 17h 395a , δ 5.91 399a 17j , δ 12.20 398a 32 17j , δ 12.61 397a , δ 3.98 396a 1 ) in the H NMR previously published for these compounds and the amount of each was quantified by integration against an internal standard (Ph3CH). There was also 5% of unreacted benzaldehyde 127a. (b) with (S)-VAPOL: CO2Et O N2 Ph H 127a 1.0 equiv 1.14 equiv CDCl3 4.8 mol% (S)-VAPOL 25 °C, 24 h 85 No Reaction To a 10 mL flame-dried single-necked round bottom flask, equipped with a stir bar and a rubber septum and filled with argon was added (S)-VAPOL 58 (14 mg, 0.025 mmol, 0.048 equiv), benzaldehyde 127a (52.0 µL, 0.525 mmol, 1.00 equiv), ethyl diazoacetate 85 (62.0 µL, 0.600 mmoL, 1.14 equiv), Ph3CH (12.2 mg, 0.500 mmol) and CDCl3 (1 mL). The resultant mixture was stirred for 24 h at room temperature. The resulting solution was then directly transferred to a NMR tube and was then subjected to NMR analysis. The crude NMR revealed the presence of unreacted starting materials. (c) with 4 Å Molecular Seives : CO2Et O 4 Å MS (150 mg) N2 Ph H 127a 1.0 equiv 1.14 equiv CDCl3 25 °C, 24 h 85 No Reaction 619 To a 10 mL flame-dried single-necked round bottom flask, equipped with a stir bar and a rubber septum and filled with argon was added 4Å Molecular Seives (150 mg, freshly flame-dried), benzaldehyde 127a (52.0 µL, 0.525 mmol, 1.00 equiv.), ethyl diazoacetate 85 (62.0 µL, 0.600 mmoL, 1.14 equiv), Ph3CH (12.2 mg, 0.500 mmol) and CDCl3 (1 mL). The resultant mixture was stirred for 24 h at room temperature. The resulting solution was then directly transferred to a NMR tube utilizing a filter syringe (Corning® syringe filters, Aldrich) to remove the 4Å 1 Molecular Sieves. It was then subjected to NMR analysis. The H NMR of the crude reaction mixture revealed the presence of unreacted starting materials. (d) without any catalyst/additive: CO2Et N2 85 O 1.14 equiv Ph H 127a 1.0 equiv CDCl3 No Reaction 25 °C, 24 h To a 10 mL flame-dried single-necked round bottom flask, equipped with a stir bar and a rubber septum and filled with argon was added benzaldehyde 127a (52.0 µL, 0.525 mmol, 1.00 equiv.), ethyl diazoacetate 85 (62.0 µL, 0.600 mmoL, 1.14 equiv), Ph3CH (12.2 mg, 0.500 mmol) and CDCl3 (1 mL). The resultant mixture was stirred for 24 h at room temperature. The resulting solution was then directly transferred to a NMR tube and was then subjected to NMR analysis. 1 The H NMR of the crude reaction mixture revealed the presence of unreacted starting materials. 620 7.15.5 Different protocols for MCAZ: procedures (I, IIA-B, IIIA-C) (Table 7.1) Procedure I: Catalyst @ 80 °C, 0.5 h and EDA 85 added after 2 h after the addition of aldehyde 127a. MeO 1. 4 Å MS (p) 2. O H2N 5 mol% (S)-VAPOL OMe 126c 15 mol% B(OPh)3 toluene, 80 °C, 0.5 h H 127a 1.05 equiv 25 °C, 2 h O MeO OMe OEt N2 85 1.2 equiv 25 °C, 24 h N CO2Et 114a (2R,3R)-ethyl-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-phenylaziridine-2carboxylate 114a: To a 10 mL flame-dried home-made Schlenk flask, prepared from a singlenecked 25 mL pear-shaped flask that had its 14/20 glass joint replaced with a high vacuum threaded Teflon valve, equipped with a stir bar and filled with argon was added (S)-VAPOL (14 mg, 0.025 mmol), B(OPh)3 (22 mg, 0.075 mmol) and amine 126c (149.7 mg, 0.5000 mmol). Under an argon flow through the side-arm of the Schlenk flask, dry toluene (2 mL) was added. The flask was sealed by closing the Teflon valve, and then placed in an oil bath (80 ºC) for 0.5 h. The flask was then allowed to cool to room temperature and open to argon through side-arm of the Schlenk flask. To the flask containing the catalyst was added the 4Å Molecular Sieves (150 mg, freshly flame-dried) and aldehyde 127a (52.0 µL, 0.525 mmoL, 1.05 equiv). The resulting mixture was allowed to stir for 2 h at ambient temperature. Thereafter, ethyl diazoacetate (EDA) 85 (62 µL, 0.60 mmoL, 1.2 equiv) was added. The resulting mixture was stirred for 24 h at room temperature. The reaction was dilluted by addition of hexane (6 mL). The reaction mixture was 621 then filtered through a Celite pad to a 100 mL round bottom flask. The reaction flask was rinsed with EtOAc (3 mL × 3) and the rinse was filtered through the same Celite pad. The resulting solution was then concentrated in vacuo followed by exposure to high vacuum (0.05 mm Hg) for 1 h to afford the crude aziridine as an off-white solid. 1 The cis/trans ratio was determined by comparing the H NMR integration of the ring methine protons for each aziridine in the crude reaction mixture. The cis (J = 7-8 Hz) and the trans (J = 2-3 Hz) coupling constants were used to differentiate the two isomers. The yields of 1 the acyclic enamine side products 118a and 119a were determined by H NMR analysis of the crude reaction mixture by integration of the N-H proton relative to the that of the cis-aziridine methine protons with the aid of the isolated yield of the cis-aziridine. Purification of the crude aziridine by silica gel chromatography (30 mm × 300 mm column, 9:1 hexanes/EtOAc as eluent, gravity column) afforded pure cis-aziridine 114a as a white solid (mp 107-108 ºC on 99.8% ee material) in 92% isolated yield (218 mg, 0.460 mmol); cis/trans: >50:1. Enamine side products: <1 % yield of 118a and <1% yield of 119a. The optical purity of 114a was determined to be 95% ee by HPLC analysis (CHIRALCEL OD-H column, 99:1 hexane/2-propanol at 226nm, flow-rate: 0.7 mL/min): retention times; Rt = 9.26 min (major enantiomer, 114a) and Rt = 12.52 min (minor enantiomer, ent-114a). 9c 1 Spectral data for 114a: Rf = 0.42 (1:9 EtOAc/hexane); H NMR (CDCl3, 500 MHz) δ 0.98 (t, 3H, J = 7.1 Hz), 2.18 (s, 6H), 2.24 (s, 6H), 2.55 (d, 1H, J = 6.8 Hz), 3.10 (d, 1H, J = 6.6 Hz), 3.62 (s, 3H), 3.66 (s, 1H), 3.68 (s, 3H) 3.87-3.97 (m, 2H), 7.09 (s, 2H), 7.18 (s, 2H), 7.21-7.24 (m, 3H), 7.36 (d, 2H, J = 7.3 Hz); 13 C (CDCl3, 125 MHz) δ 14.01, 16.16, 16.22, 46.26, 48.20, 622 59.52, 59.58, 60.47, 77.04, 127.21, 127.41, 127.70, 127.80,127.85, 130.59, 130.60, 135.33, -1 137.79, 137.96, 155.95, 156.10, 168.01; IR (thin film) 2961 vs, 1750 vs, 1414 vs, 1202 vs cm ; Mass spectrum: m/z (% rel intensity) 473 M+ (0.27), 284(78), 283 (100), 268 (34), 253 (20), 237 (11), 210(10), 117 (18), 89 (11); Anal calcd for C30H35NO4: C, 76.08; H, 7.45; N, 2.96. Found: C, 76.31; H, 7.28; N, 2.82; [α ]23 +41.3 (c 1.0, EtOAc) on 99% ee material (HPLC). These D spectral data match those previously reported for this compound. Procedure IIA: Catalyst @ 80 °C, 0.5 h and EDA 85 added immediately after the addition of the aldehyde 127a. MeO 1. 4 Å MS (p) 2. O H2N 5 mol% (S)-VAPOL 127a 1.05 equiv OEt N2 85 1.2 equiv 25 °C 25 °C, 24 h H OMe 126c 15 mol% B(OPh)3 toluene, 80 °C, 0.5 h O MeO OMe N CO2Et 114a (2R,3R)-ethyl-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-phenylaziridine-2carboxylate 114a: To a 10 mL flame-dried home-made Schlenk flask, prepared from a singlenecked 25 mL pear-shaped flask that had its 14/20 glass joint replaced with a high vacuum threaded Teflon valve, equipped with a stir bar and filled with argon was added (S)-VAPOL (14 mg, 0.025 mmol), B(OPh)3 (22 mg, 0.075 mmol) and amine 126c (149.7 mg, 0.5000 mmol). Under an argon flow through the side-arm of the Schlenk flask, dry toluene (2 mL) was added. 623 The flask was sealed by closing the Teflon valve, and then placed in an oil bath (80 ºC) for 0.5 h. The flask was then allowed to cool to room temperature and open to argon through side-arm of the Schlenk flask. To the flask containing the catalyst was added the 4Å Molecular Sieves (150 mg, freshly flame-dried) and aldehyde 127a (52.0 µL, 0.525 mmoL, 1.05 equiv). To this solution was rapidly added ethyl diazoacetate (EDA) 85 (62 µL, 0.60 mmoL, 1.2 equiv). The resulting mixture was stirred for 24 h at room temperature. The reaction was dilluted by addition of hexane (6 mL). The reaction mixture was then filtered through a Celite pad to a 100 mL round bottom flask. The reaction flask was rinsed with EtOAc (3 mL × 3) and the rinse was filtered through the same Celite pad. The resulting solution was then concentrated in vacuo followed by exposure to high vacuum (0.05 mm Hg) for 1 h to afford the crude aziridine as an off-white solid. Purification of the crude aziridine by silica gel chromatography (30 mm × 300 mm column, 9:1 hexanes/EtOAc as eluent, gravity column) afforded pure cis-aziridine 114a as a white solid (mp 107-108 ºC on 99.8% ee material) in 97% isolated yield (230 mg, 0.485 mmol); cis/trans: >50:1. Enamine side products: <1% yield of 118a and <1% yield of 119a. The optical purity of 114a was determined to be 98% ee by HPLC analysis (CHIRALCEL OD-H column, 99:1 hexane/2-propanol at 226nm, flow-rate: 0.7 mL/min): retention times; Rt = 9.26 min (major enantiomer, 114a) and Rt = 12.52 min (minor enantiomer, ent-114a). Procedure IIB: Pre-catalyst followed by the addition of amine 6 and stirring @ 80 °C, 0.5 h and then EDA 2 added immediately after the addition of the aldehyde 7a. 3 equiv B(OPh)3 3 equiv H2O (S)-VAPOL 5 mol % toluene, 80 °C, 1 h 624 0.1 mm Hg 80 °C, 0.5 h pre-catalyst MeO 1. 4 Å MS (p) 2. O H2N pre-catalyst 127a 1.05 equiv OEt N2 85 1.2 equiv 25 °C 25 °C, 24 h H OMe 126c toluene, 80 °C, 0.5 h O MeO OMe N CO2Et 114a (2R,3R)-ethyl-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-phenylaziridine-2carboxylate 114a: To a 10 mL flame-dried home-made Schlenk flask, prepared from a singlenecked 25 mL pear-shaped flask that had its 14/20 glass joint replaced with a high vacuum threaded Teflon valve, equipped with a stir bar and filled with argon was added (S)-VAPOL (14 mg, 0.025 mmol), B(OPh)3 (22 mg, 0.075 mmol). Under an argon flow through the side-arm of the Schlenk flask, dry toluene (2 mL) was added through the top of the Teflon valve to dissolve the two reagents and this was followed by the addition of water (1.4 µL, 0.075 mmol). The flask was sealed by closing the Teflon valve, and then placed in an 80 ºC (oil bath) for 1 h. After 1 h, a vacuum (0.5 mm Hg) was carefully applied by slightly opening the Teflon valve to remove the volatiles. After the volatiles are removed completely, a full vacuum is applied and is maintained for a period of 30 min at a temperature of 80 ºC (oil bath). The flask was then allowed to cool to room temperature and opened to argon through the side-arm of the Schlenk flask. To the flask containing the pre-catalyst was added the amine 126c (149.7 mg, 0.5000 mmol) and then dry toluene (1 mL) under an argon flow through side-arm of the Schlenk flask. The flask was sealed by closing the Teflon valve, and then placed in an oil bath (80 ºC) for 0.5 h. The flask was then allowed to cool to room temperature and open to argon through side-arm of the Schlenk flask. To 625 the flask containing the pre-catalyst was added the 4Å Molecular Sieves (150 mg, freshly flamedried) and aldehyde 127a (52.0 µL, 0.525 mmoL, 1.05 equiv). To this solution was rapidly added ethyl diazoacetate (EDA) 85 (62 µL, 0.60 mmoL, 1.2 equiv). The resulting mixture was stirred for 24 h at room temperature. The reaction was dilluted by addition of hexane (6 mL). The reaction mixture was then filtered through a Celite pad to a 100 mL round bottom flask. The reaction flask was rinsed with EtOAc (3 mL × 3) and the rinse was filtered through the same Celite pad. The resulting solution was then concentrated in vacuo followed by exposure to high vacuum (0.05 mm Hg) for 1 h to afford the crude aziridine as an off-white solid. Purification of the crude aziridine by silica gel chromatography (30 mm × 300 mm column, 9:1 hexanes/EtOAc as eluent, gravity column) afforded pure cis-aziridine 114a as a white solid (mp 107-108 ºC on 99.8% ee material) in 98% isolated yield (232 mg, 0.490 mmol); cis/trans: >50:1. Enamine side products: <1% yield of 118a and <1% yield of 119a. The optical purity of 114a was determined to be 98 % ee by HPLC analysis (CHIRALCEL OD-H column, 99:1 hexane/2-propanol at 226nm, flow-rate: 0.7 mL/min): retention times; Rt = 9.26 min (major enantiomer, 114a) and Rt = 12.52 min (minor enantiomer, ent-114a). Procedure IIIA: Catalyst @ 25 °C, 1 h and EDA 85 added immediately after the addition of the aldehyde 127a. MeO 1. 4 Å MS (p) 2. O H2N 5 mol% (S)-VAPOL 127a 1.05 equiv OEt N2 85 1.2 equiv 25 °C 15 mol% B(OPh)3 toluene, 25 °C, 1 h MeO OMe 25 °C, 24 h H OMe 126c O N CO2Et 114a 626 (2R,3R)-ethyl-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-phenylaziridine-2carboxylate 114a: To a 10 mL flame-dried single-necked round bottom flask equipped with a stir bar and filled with argon was added (S)-VAPOL (14 mg, 0.025 mmol), B(OPh)3 (22 mg, 0.075 mmol) and amine 126c (149.7 mg, 0.5000 mmol). Dry toluene (1 mL) was added under an argon atmosphere to dissolve the reagents. The flask was fitted with a rubber septum and a nitrogen balloon. The reaction mixture was stirred at room temperature for 1 h. Thereafter, 4Å Molecular Sieves (150 mg, freshly flame-dried) was added followed by the addition of the aldehyde 127a (52.0 µL, 0.525 mmoL, 1.05 equiv). To this solution was rapidly added ethyl diazoacetate (EDA) 85 (62 µL, 0.60 mmoL, 1.2 equiv). The resulting mixture was stirred for 24 h at room temperature. The reaction was dilluted by addition of hexane (6 mL). The reaction mixture was then filtered through a Celite pad to a 100 mL round bottom flask. The reaction flask was rinsed with EtOAc (3 mL × 3) and the rinse was filtered through the same Celite pad. The resulting solution was then concentrated in vacuo followed by exposure to high vacuum (0.05 mm Hg) for 1 h to afford the crude aziridine as an off-white solid. Purification of the crude aziridine by silica gel chromatography (30 mm × 300 mm column, 9:1 hexanes/EtOAc as eluent, gravity column) afforded pure cis-aziridine 114a as a white solid (mp 107-108 ºC on 99.8% ee material) in 97% isolated yield (230 mg, 0.490 mmol); cis/trans: >50:1. Enamine side products: <1% yield of 118a and <1% yield of 119a. The optical purity of 114a was determined to be 98% ee by HPLC analysis (CHIRALCEL OD-H column, 99:1 hexane/2-propanol at 226nm, flow-rate: 0.7 mL/min): retention times; Rt = 9.26 min (major enantiomer, 114a) and Rt = 12.52 min (minor enantiomer, ent-114a). 627 Procedure IIIB: Pre-catalyst followed by the addition of amine 126c and stirring @ 25 °C, 1 h and then EDA 85 added immediately after the addition of the aldehyde 127a. 3 equiv B(OPh)3 3 equiv H2O 0.1 mm Hg (S)-VAPOL 5 mol % toluene, 80 °C, 1 h 80 °C, 0.5 h pre-catalyst MeO 1. 4 Å MS (p) 2. O H2N pre-catalyst 127a 1.05 equiv OEt N2 85 1.2 equiv 25 °C toluene, 25 °C, 1 h MeO OMe 25 °C, 24 h H OMe 126c O N CO2Et 114a (2R,3R)-ethyl-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-phenylaziridine-2carboxylate 114a: To a 10 mL flame-dried home-made Schlenk flask, prepared from a singlenecked 25 mL pear-shaped flask that had its 14/20 glass joint replaced with a high vacuum threaded Teflon valve, equipped with a stir bar and filled with argon was added (S)-VAPOL (14 mg, 0.025 mmol), B(OPh)3 (22 mg, 0.075 mmol). Under an argon flow through the side-arm of the Schlenk flask, dry toluene (2 mL) was added through the top of the Teflon valve to dissolve the two reagents and this was followed by the addition of water (1.4 µL, 0.075 mmol). The flask was sealed by closing the Teflon valve, and then placed in an 80 ºC (oil bath) for 1 h. After 1 h, a vacuum (0.5 mm Hg) was carefully applied by slightly opening the Teflon valve to remove the volatiles. After the volatiles are removed completely, a full vacuum is applied and is maintained for a period of 30 min at a temperature of 80 ºC (oil bath). The flask was then allowed to cool to room temperature and opened to argon through the side-arm of the Schlenk flask. To the flask 628 containing the pre-catalyst was added the amine 126c (149.7 mg, 0.5000 mmol) and then dry toluene (1 mL) under an argon flow through side-arm of the Schlenk flask. The flask was sealed by closing the Teflon valve, and then the resulting mixture was allowed to stir at room temperature for 1 h. The flask was then open to argon through side-arm of the Schlenk flask. To the flask containing the catalyst was added the 4Å Molecular Sieves (150 mg, freshly flamedried) and aldehyde 127a (52.0 µL, 0.525 mmoL, 1.05 equiv). To this solution was rapidly added ethyl diazoacetate (EDA) 85 (62 µL, 0.60 mmoL, 1.2 equiv). The resulting mixture was stirred for 24 h at room temperature. The reaction was dilluted by addition of hexane (6 mL). The reaction mixture was then filtered through a Celite pad to a 100 mL round bottom flask. The reaction flask was rinsed with EtOAc (3 mL × 3) and the rinse was filtered through the same Celite pad. The resulting solution was then concentrated in vacuo followed by exposure to high vacuum (0.05 mm Hg) for 1 h to afford the crude aziridine as an off-white solid. Purification of the crude aziridine by silica gel chromatography (30 mm × 300 mm column, 9:1 hexanes/EtOAc as eluent, gravity column) afforded pure cis-aziridine 114a as a white solid (mp 107-108 ºC on 99.8% ee material) in 94% isolated yield (223 mg, 0.470 mmol); cis/trans: >50:1. Enamine side products: <1% yield of 118a and <1% yield of 119a. The optical purity of 114a was determined to be 98% ee by HPLC analysis (CHIRALCEL OD-H column, 99:1 hexane/2-propanol at 226nm, flow-rate: 0.7 mL/min): retention times; Rt = 9.26 min (major enantiomer, 114a) and Rt = 12.52 min (minor enantiomer, ent-114a). Procedure IIIC: Catalyst @ 25 °C, 1 h and EDA 85 added immediately after the addition of the aldehyde 127a (0.6 equiv with respect to amine 126c). 629 MeO 1. 4 Å MS (p) 2. O H2N 5 mol% (S)-VAPOL O 127a 0.6 equiv 15 mol% B(OPh)3 toluene, 25 °C, 1 h 25 °C OMe OEt N2 85 1.2 equiv 25 °C, 24 h H OMe 126c MeO N CO2Et 114a (2R,3R)-ethyl-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-phenylaziridine-2carboxylate 114a: The procedure is exactly similar to procedure IIIA except that 0.6 equiv of 1 benzaldehyde 127a was added. No aziridine 114a was observed from the H NMR analysis of crude reaction mixture. 7.15.6 Synthesis of aryl and heteroaryl MEDAM aziridines 114a-n (via Procedure IIIA, Table 7.3) MeO 1. 4 Å MS (p) 2. O H2N 5 mol% (S)-VAPOL 127a 1.05 equiv OEt N2 85 1.2 equiv 25 °C 15 mol% B(OPh)3 toluene, 25 °C, 1 h MeO OMe 25 °C, 24 h H OMe 126c O N CO2Et 114a (2R,3R)-ethyl-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-phenylaziridine-2carboxylate 114a: Aldehyde 127a (52.0 µL, 0.525 mmol) was reacted according to the general Procedure IIIA described above with (S)-VAPOL as ligand. Purification of the crude aziridine 630 by silica gel chromatography (30 mm × 300 mm column, 9:1 hexanes/EtOAc as eluent, gravity column) afforded pure cis-aziridine 114a as a white solid (mp 107-108 ºC on 99.8% ee material) in 98% isolated yield (232 mg, 0.490 mmol); cis/trans: >50:1. Enamine side products: <1% yield of 118a and <1 % yield of 119a. The optical purity of 114a was determined to be 98% ee by HPLC analysis (CHIRALCEL OD-H column, 99:1 hexane/2-propanol at 226nm, flow-rate: 0.7 mL/min): retention times; Rt = 9.26 min (major enantiomer, 114a) and Rt = 12.52 min (minor enantiomer, ent-114a). This reaction was repeated and monitored by 1 H NMR Spectroscopy that revealed that the reaction had gone to completion in 1 h. Also, it gave 70 % yield of 114a and 98% ee when the same reaction was carried out utilizing 5Å MS instead of 4Å MS. 1 Spectral data for 114a: Rf = 0.42 (1:9 EtOAc/hexane); H NMR (CDCl3, 500 MHz) δ 0.98 (t, 3H, J = 7.1 Hz), 2.18 (s, 6H), 2.24 (s, 6H), 2.55 (d, 1H, J = 6.8 Hz), 3.10 (d, 1H, J = 6.6 Hz), 3.62 (s, 3H), 3.66 (s, 1H), 3.68 (s, 3H) 3.87-3.97 (m, 2H), 7.09 (s, 2H), 7.18 (s, 2H), 7.21-7.24 (m, 3H), 7.36 (d, 2H, J = 7.3 Hz); 13 C (CDCl3, 125 MHz) δ 14.01, 16.16, 16.22, 46.26, 48.20, 59.52, 59.58, 60.47, 77.04, 127.21, 127.41, 127.70, 127.80,127.85, 130.59, 130.60, 135.33, -1 137.79, 137.96, 155.95, 156.10, 168.01; IR (thin film) 2961 vs, 1750 vs, 1414 vs, 1202 vs cm ; Mass spectrum: m/z (% rel intensity) 473 M+ (0.27), 284(78), 283 (100), 268 (34), 253 (20), 237 (11), 210(10), 117 (18), 89 (11); Anal calcd for C30H35NO4: C, 76.08; H, 7.45; N, 2.96. Found: C, 76.31; H, 7.28; N, 2.82; [α ]23 +41.3 (c 1.0, EtOAc) on 99% ee material (HPLC). These D spectral data match those previously reported for this compound. 631 9c MeO (2R,3R)-ethyl-1-(bis(4-methoxy-3,5-dimethylphenyl) OMe methyl)-3-(naphthalene-1-yl)aziridine-2-carboxylate 114b: Aldehyde 127b (71.0 µL, 0.525 mmol) was reacted according N CO2Et 114b to the general Procedure IIIA described above with (S)VAPOL as ligand. Purification of the crude aziridine by silica gel chromatography (30 mm × 300 mm column, 9:1 hexanes/EtOAc) afforded pure cisaziridine 114b as a white solid (mp 79-80 ºC on 99% ee material) in 96% isolated yield (251 mg, 0.480 mmol); cis/trans: 50:1. Enamine side products: 2.9% yield of 118b and <1% yield of 119b. The optical purity of 114b was determined to be 99.3% ee by HPLC analysis (CHIRALCEL OD-H column, 99:1 hexane/2-propanol at 226 nm, flow-rate: 0.7 mL/min): retention times; Rt = 8.15 min (major enantiomer, 114b) and Rt = 16.15 min (minor enantiomer, ent-114b). 1 Spectral data for 114b: Rf = 0.25 (9:1 hexanes/EtOAc); H NMR (CDCl3, 600 MHz) δ 0.65 (t, 3H, J = 7.1 Hz), 2.22 (s, 6H), 2.26 (s, 6H), 2.81 (d, 1H, J = 6.8 Hz), 3.58 (d, 1H, J = 6.8 Hz), 3.63 (s, 3H), 3.69 (s, 3H), 3.69-3.76 (m, 2H), 3.79 (s, 1H), 7.17 (s, 2H), 7.23 (s, 2H), 7.36 (dd, 1H, J = 7.8, 7.6 Hz), 7.40-7.46 (m, 2H), 7.67-7.69 (m, 2H), 7.78 (d, 1H, J = 7.8 Hz), 8.06 (d, 1H, J = 7.6 Hz); 13 C NMR (CDCl3, 150 MHz) δ 13.67, 16.18, 16.24, 45.98, 46.63, 59.55, 59.62, 60.33, 77.47, 123.06, 125.31, 125.42, 125.83, 126.61, 127.36, 127.52, 128.12, 128.50, 130.68, 130.71, 130.85, 131.49, 133.08, 137.69, 137.95, 155.95, 156.26, 168.02; IR (thin film) 2942vs, -1 + 1748s, 1484s, 1221s, 1186s, 1017m cm ; HRMS (ESI-TOF) m/z 524.2807 [(M+H ); calcd. for C34H38NO4 : 524.2801]; [α ]20 –19.3 (c 1.0, EtOAc) on 99 % ee material (HPLC) of ent-114b. D 632 MeO (2R,3R)-ethyl-1-(bis(4-methoxy-3,5-dimethylphenyl) OMe methyl)-3-(o-tolyl)aziridine-2-carboxylate 114c: Aldehyde 127c (61.0 µL, 0.525 mmol) was reacted according to the N CO2Et 114c general Procedure IIIA described above with (S)-VAPOL as ligand. Purification of the crude aziridine by silica gel chromatography (30 mm × 300 mm column, 9:1 hexanes/EtOAc as eluent, gravity column) afforded pure cis-aziridine 114c as a white solid (mp 174-175 ºC on 99.7% ee material) in 96% isolated yield (234 mg, 0.480 mmol); cis/trans: 50:1. Enamine side products: 1.9% yield of 118c and 1.0% yield of 119c. The optical purity of 114c was determined to be >99% ee by HPLC analysis (CHIRALCEL OD-H column, 99:1 hexane/2-propanol at 226 nm, flow-rate: 0.7 mL/min): retention times; Rt = 9.45 min (major enantiomer, 114c) and Rt = 12.21 min (minor enantiomer, ent-114c). 1 Spectral data for 114c: Rf = 0.38 (1:9 EtOAc/hexane); H NMR (CDCl3, 500 MHz) δ 0.89 (t, 3H, J = 7.1 Hz), 2.20 (s, 6H), 2.24 (s, 6H), 2.26 (s, 3H), 2.61 (d, 1H, J = 6.8 Hz), 3.08 (d, 1H, J = 6.6 Hz), 3.62 (s, 3H), 3.66 (s, 1H), 3.68 (s, 3H), 3.88 (q, 2H, J = 7.1 Hz), 7.01 (d, 1H, J = 6.6 Hz), 7.06-7.09 (m, 2H), 7.13 (s, 2H), 7.18 (s, 2H), 7.53 (d, 1H, J = 6.3 Hz); 13 C (CDCl3, 125 MHz) δ 13.90, 16.16, 16.22, 18.76, 45.55, 47.15, 59.53, 59.59, 60.36, 77.34, 125.28, 127.05, 127.33, 127.95, 128.62, 129.08, 130.61, 130.63, 133.45, 136.03, 137.85, 138.01, 155.92, 156.18, 168.16; -1 IR (thin film) 2937vs, 1749s, 1485s, 1221s, 1192vs cm ;HRMS (ESI-TOF) m/z + 488.2801 [(M+H ); calcd. for C31H38NO4 : 488.2801]; [α ]23 +46.4 (c 1.0, EtOAc) on 97% ee D material (HPLC). These spectral data match those previously reported for this compound. 633 9c MeO (2R,3R)-ethyl-1-(bis(4-methoxy-3,5-dimethylphenyl) OMe methyl)-3-(p-tolyl)aziridine-2-carboxylate 114d: Aldehyde 127d (61.0 µL, 0.525 mmol) was reacted according to the N CO2Et 114d general Procedure IIIA described above with (S)-VAPOL as ligand. Purification of the crude aziridine by silica gel chromatography (30 mm × 300 mm column, 9:1 hexanes/EtOAc as eluent, gravity column) afforded pure cis-aziridine 114d as a white solid (mp 116-117 ºC on 99.5% ee material) in 95 % isolated yield (232 mg, 0.480 mmol); cis/trans: 50:1. Enamine side products: 3.8% yield of 118d and 1.0% yield of 119d. The optical purity of 114d was determined to be >99% ee by HPLC analysis (CHIRALCEL OD-H column, 99:1 hexane/2-propanol at 226 nm, flow-rate: 0.7 mL/min): retention times; Rt = 9.22 min (major enantiomer, 114d) and Rt = 11.62 min (minor enantiomer, ent-114d). 1 Spectral data for 114d: Rf = 0.30 (1:9 EtOAc/hexanes); H NMR (CDCl3, 500 MHz) δ 1.01 (t, 3H, J = 7.1 Hz), 2.18 (s, 6H), 2.24 (s, 6H), 2.26 (s, 3H), 2.52 (d, 1H, J = 6.6 Hz), 3.07 (d, 1H, J = 6.8 Hz), 3.62 (s, 3H), 3.64 (s, 1H), 3.68 (s, 3H) 3.93 (dq, 2H, J = 3.2 Hz, 7.1 Hz), 7.02 (d, 2H, J = 7.8 Hz), 7.08 (s, 2H), 7.17 (s, 2H), 7.24 (d, 2H, J = 8.0 Hz); 13 C (CDCl3, 125 MHz) δ 14.05, 16.16, 16.22, 21.11, 46.20, 48.21, 59.52, 59.58, 60.44, 77.11, 127.43, 127.72, 127.81, 128.41, 130.54, 130.57, 132.28, 136.78, 137.86, 138.00, 155.93, 156.08, 168.10; IR (thin film) 2978vs, -1 + 1748s, 1483s, 1221s, 1190vs cm ; HRMS (ESI-TOF) m/z 488.2806 [(M+H ); calcd. for C31H38NO4 : 488.2801]; [α ]23 +29.4 (c 1.0, EtOAc) on 99.8% ee material (HPLC). These D spectral data match those previously reported for this compound. 634 9c MeO OMe (2R,3R)-ethyl-1-(bis(4-methoxy-3,5-dimethylphenyl) methyl)-3-(4-methoxyphenyl)aziridine-2-carboxylate 114e: Aldehyde 127e (64.0 µL, 0.525 mmol) was reacted N CO2Et MeO 114e according to the general Procedure IIIA described above with (S)-VAPOL as ligand. Purification of the crude aziridine by silica gel chromatography (30 mm × 300 mm column, 9:1 hexanes/EtOAc with 1% Et3N as eluent, gravity column; the column was set up by making a slurry of silica gel in hexanes with 2 % Et3N) afforded pure cis-aziridine 114e as a white solid (mp 56-57 ºC on 98% ee material) in 78% isolated yield (196 mg, 0.390 mmol); cis/trans: 20:1. Enamine side products: <1% yield of 118e and 4.7% yield of 119e. The optical purity of 114e was determined to be 98% ee by HPLC analysis (CHIRALCEL OD-H column, 99:1 hexane/2-propanol at 226 nm, flow-rate: 0.7 mL/min): retention times; Rt = 12.07 min (major enantiomer, 114e) and Rt = 19.20 min (minor enantiomer, ent-114e). 1 Spectral data for 114e: Rf = 0.28 (1:9 EtOAc/hexane); H NMR (CDCl3, 500 MHz) δ 1.02 (t, 3H, J = 7.1 Hz), 2.19 (s, 6H), 2.24 (s, 6H), 2.51 (d, 1H, J = 6.8 Hz), 3.06 (d, 1H, J = 6.8 Hz), 3.63 (s, 3H), 3.65 (s, 1H), 3.68 (s, 3H), 3.74 (s, 3H), 3.89-3.99 (m, 2H), 6.77 (d, 2H, J = 9.5 Hz), 7.09 (s, 2H), 7.18 (s, 2H), 7.29 (d, 2H, J = 8.8 Hz); 13 C (CDCl3, 125 MHz) δ 14.08, 16.16, 16.21, 46.20, 47.89, 55.19, 59.52, 59.57, 60.45, 77.05, 113.18, 127.43, 127.79, 128.93, 130.55, 2 130.57, 137.83, 138.01, 155.93, 156.07, 158.86, 168.14 (one sp carbon not located); IR (thin -1 + film) 2942vs, 1743s, 1514s, 1250s, 1180vs cm ; HRMS (ESI-TOF) m/z 504.2744 [(M+H ); 635 calcd. for C31H38NO5 : 504.2750]; [α ]23 +25 (c 1.0, EtOAc) on 96% ee material (HPLC). D These spectral data match those previously reported for this compound. MeO 9c (2R,3R)-ethyl-1-(bis(4-methoxy-3,5-dimethylphenyl) OMe methyl)-3-(4-nitrophenyl)aziridine-2-carboxylate Aldehyde 127f (79.3 mg, 0.525 mmol) was reacted N CO2Et O2N 114f 114f: according to the general Procedure IIIA described above with (S)-VAPOL as ligand. Purification of the crude aziridine by silica gel chromatography (30 mm × 300 mm column, 9:1 hexanes/EtOAc) afforded pure cis-aziridine 114f as a white solid (mp 174-175 ºC on 99.7% ee material) in 92% isolated yield (239 mg, 0.460 mmol); cis/trans: 50:1. Enamine side products: <1% yield of 118o and 2.8% yield of 119o. The optical purity of 114f was determined to be 99% ee by HPLC analysis (CHIRALCEL OD-H column, 99:1 hexane/2-propanol at 226 nm, flow-rate: 0.7 mL/min): retention times; Rt = 17.12 min (major enantiomer, 114f) and Rt = 27.13 min (minor enantiomer, ent-114f). 1 Spectral data for 114f: Rf = 0.30 (1:9 EtOAc/hexane); H NMR (CDCl3, 500 MHz) δ 1.02 (t, 3H, J = 7.1 Hz), 2.18 (s, 6H), 2.25 (s, 6H), 2.68 (d, 1H, J = 6.8 Hz), 3.15 (d, 1H, J = 6.8 Hz), 3.62 (s, 3H), 3.68 (s, 3H), 3.71 (s, 1H), 3.93 (dq, 2H, J = 2.2, 7.1 Hz), 7.06 (s, 2H), 7.16 (s, 2H), 7.57 (d, 2H, J = 8.8 Hz), 8.10 (d, 2H, J = 8.8 Hz); 13 C (CDCl3, 125 MHz) δ 14.08, 16.19, 16.24, 46.81, 47.26, 59.55, 59.59, 60.85, 76.89, 122.98, 127.26, 127.59, 128.81, 130.81, 130.86, 137.25, 137.48, 142.82, 147.28, 156.13, 156.28, 167.20; IR (thin film) 2984 vs, 1745 vs, 1603 s, 1522 vs, 636 -1 + 1221 vs cm ; HRMS (ESI-TOF) m/z 519.2505 [(M+H ); calcd. for C30H35N2O6 : 519.2495]; [α ]23 –4.8 (c 1.0, EtOAc) on 99.8% ee material (HPLC). These spectral data match those D previously reported for this compound. MeO OMe 9c (2R,3S)-ethyl-1-(bis(4-methoxy-3,5-dimethylphenyl) methyl)-3-(pyridin-2-yl)aziridine-2-carboxylate Aldehyde 127i (50.0 µL, 0.525 mmol) was reacted according N N CO2Et 114i 114i: to the general Procedure IIIA described above with (S)VAPOL as ligand. Purification of the crude aziridine by silica gel chromatography (30 mm × 300 mm column, 4:1 hexanes/EtOAc with 1% Et3N followed by 2:1 hexanes/EtOAc with 1% Et3N as eluent, gravity column; the column was set up by making a slurry of silica gel in hexanes with 2 % Et3N) afforded pure cis-aziridine 114i as a white solid (mp 60-61 ºC on 90.2% ee material) in 96% isolated yield (456 mg, 0.480 mmol); cis/trans: >50:1. Enamine side products: not observed. The optical purity of 114i was determined to be 90% ee by HPLC analysis (CHIRALCEL OD-H column, 99:1 hexane/2propanol at 226 nm, flow-rate: 0.7 mL/min): retention times; Rt = 16.90 min (major enantiomer, 114i) and Rt = 31.83 min (minor enantiomer, ent-114i). 1 Spectral data for 114i: Rf = 0.27 (2:1 hexanes/EtOAc); H NMR (CDCl3, 600 MHz) δ 1.01 (t, 3H, J = 7.1 Hz), 2.18 (s, 6H), 2.24 (s, 6H), 2.66 (d, 1H, J = 6.8 Hz), 3.27 (d, 1H, J = 6.8 Hz), 3.62 (s, 3H), 3.68 (s, 3H), 3.73 (s, 1H), 3.91-3.96 (m, 2H), 7.08 (s, 2H), 7.09-7.11 (m, 1H), 7.16 637 (s, 2H), 7.59-7.60 (m, 2H), 8.42 (td, 1H, J = 1.4, 4.6 Hz); 13 C NMR (CDCl3, 150 MHz) δ 14.00, 16.16, 16.23, 45.91, 49.45, 59.54, 59.60, 60.63, 122.29, 122.83, 127.36, 127.79, 130.65, 130.68, 3 135.87, 137.56, 137.78, 148.57, 155.48, 155.99, 156.12, 167.75 (one sp carbon not located); IR -1 (thin film) 2984s, 1746s, 1591, 1482s, 1221s, 1184s, 1015m cm ; HRMS (ESI-TOF) m/z + 475.2607 [(M+H ); calcd. for C29H35N2O4 : 475.2597]; [α ]20 +40.2 (c 1.0, EtOAc) on 90% ee D material (HPLC). MeO OMe (2R,3S)-ethyl-1-(bis(4-methoxy-3,5-dimethylphenyl) methyl)-3-(thiophen-2-yl)aziridine-2-carboxylate Aldehyde 127k (48.0 µL, 0.525 mmol) was reacted according N S CO2Et 114k 114k: to the general Procedure IIIA described above with (S)VAPOL as ligand except that an excess of EDA 85 (415 µL, 4.0 mmoL, 8 equiv) was used. Purification of the crude aziridine by silica gel chromatography (30 mm × 300 mm column, 9:1 hexanes/EtOAc with 1% Et3N as eluent, gravity column; the column was set up by making a slurry of silica gel in hexanes with 2% Et3N) afforded pure cisaziridine 114k as a white solid (mp 55-56 ºC on 97% ee material) in 88% isolated yield (211 mg, 0.440 mmol); cis/trans: 25:1. Enamine side products: not observed. The optical purity of 114k was determined to be 97% ee by HPLC analysis (CHIRALCEL OD-H column, 99:1 hexane/2propanol at 226 nm, flow-rate: 0.7 mL/min): retention times; Rt = 10.54 min (major enantiomer, 114k) and Rt = 15.27 min (minor enantiomer, ent-114k). 638 1 Spectral data for 114k: Rf = 0.21 (9:1 hexanes/EtOAc); H NMR (CDCl3, 600 MHz) δ 1.08 (t, 3H, J = 7.1 Hz), 2.21 (s, 6H), 2.24 (s, 6H), 2.58 (d, 1H, J = 6.6 Hz), 3.21 (d, 1H, J = 6.6 Hz), 3.64 (s, 3H), 3.66 (s, 1H), 3.67 (s, 3H), 3.96-4.06 (m, 2H), 6.86 (dd, 1H, J = 3.4, 4.9 Hz), 6.956.96 (m, 1H), 7.11 (dd, 1H, J = 1.2, 4.9 Hz), 7.14 (s, 2H), 7.16 (s, 2H); 13 C NMR (CDCl3, 150 MHz) δ 14.00, 16.12, 16.17, 43.76, 46.65, 59.51, 59.53, 60.70, 76.93, 124.49, 125.74, 126.38, 127.34, 127.71, 130.59, 130.62, 137.50, 137.63, 139.00, 155.94, 156.07, 167.77; IR (thin film) -1 + 2942s, 1748s, 1484s, 1221s, 1190s, 1015m cm ; HRMS (ESI-TOF) m/z 480.2216 [(M+H ); calcd. for C28H34NO4S : 480.2209]; [α ]20 +30.2 (c 1.0, EtOAc) on 97% ee material (HPLC). D MeO OMe (2R,3S)-ethyl-1-(bis(4-methoxy-3,5-dimethylphenyl) methyl)-3-(furan-2-yl)aziridine-2-carboxylate Aldehyde 127l (44.0 µL, 0.525 mmol) was reacted according N O CO2Et 114l 114l: to the general Procedure IIIA described above with (S)VAPOL as ligand except that the addition of aldehyde 127l was carried out at –10 °C followed by the addition of EDA 85 (415 µL, 4.0 mmoL, 8 equiv) at the same temperature. The reaction was stirred for 2 h at –10 °C prior to warming it to room temperature. Purification of the crude aziridine by silica gel chromatography (30 mm × 300 mm column, 15:1 hexanes/EtOAc with 1% Et3N as eluent, gravity column; the column was set up by making a slurry of silica gel in hexanes with 2% Et3N) afforded pure cis-aziridine 114l as a white solid (mp 45-46 ºC on 94% ee material) in 65% isolated yield (151 mg, 0.325 mmol); cis/trans: 8.3:1. Enamine side products: not observed. 639 The optical purity of 114l was determined to be 95% ee by HPLC analysis (CHIRALCEL OD-H column, 99.5:0.5 hexane/2propanol at 226 nm, flow-rate: 0.7 mL/min): retention times; Rt = 23.6 min (major enantiomer, 114l) and Rt = 39.1 min (minor enantiomer, ent-114l). 1 Spectral data for 114l: Rf = 0.21 (15:1 hexanes/EtOAc); H NMR (CDCl3, 600 MHz) δ 1.14 (t, 3H, J = 7.1 Hz), 2.21 (s, 6H), 2.24 (s, 6H), 2.60 (d, 1H, J = 6.6 Hz), 3.03 (d, 1H, J = 6.6 Hz), 3.65 (s, 3H), 3.67 (s, 1H), 3.68 (s, 3H), 4.03-4.13 (m, 2H), 6.28-6.29 (m, 1H), 6.29-6.30 (m, 1H), 7.09 (s, 2H), 7.14 (s, 2H), 7.26-7.27 (m, 1H); 13 C NMR (CDCl3, 150 MHz) δ 14.05, 16.11, 16.15, 41.73, 45.27, 59.50, 59.52, 60.76, 76.84, 107.97, 110.32, 127.49, 127.64, 130.53, 130.61, 137.34, 137.44, 141.80, 149.77, 156.01, 156.04, 167.70; IR (thin film) 2940s, 1750s, 1485s, -1 + 1221s, 1179s, 1013m cm ; HRMS (ESI-TOF) m/z 464.2441 [(M+H ); calcd. for C28H34NO5 : 464.2437]; [α ]20 –8.2 (c 1.0, EtOAc) on 94% ee material (HPLC) of ent-114l. D MeO OMe (2R,3S)-ethyl-1-(bis(4-methoxy-3,5-dimethylphenyl) methyl)-3-(2-methyloxazol-4-yl)aziridine-2-carboxylate 114n: Aldehyde 127n (59.0 mg, 0.525 mmol) was reacted N N O CO2Et 114n according to the general Procedure IIIA described above with (S)-VAPOL as ligand except except that the addition of aldehyde 127n was carried out at –10 °C followed by the addition of EDA 85 (415 µL, 4.0 mmoL, 8 equiv) at the same temperature. The reaction was stirred for 15 min at –10 °C prior to warming it to room temperature. Purification of the crude aziridine by silica gel chromatography 640 (30 mm × 300 mm column, 3:1 hexanes/EtOAc with 1% Et3N as eluent, gravity column; the column was set up by making a slurry of silica gel in hexanes with 2% Et3N) afforded pure cisaziridine 114n as a white solid (mp 58-59 ºC on 96% ee material) in 98% isolated yield (235 mg, 0.490 mmol); cis/trans: >50:1. Enamine side products: not observed. The optical purity of 114n was determined to be 97% ee by HPLC analysis (CHIRALPAK AS column, 93:7 hexane/2propanol at 226 nm, flow-rate: 0.7 mL/min): retention times; Rt = 7.7 min (major enantiomer, 114n) and Rt = 10.55 min (minor enantiomer, ent-114n). 1 Spectral data for 114n: Rf = 0.19 (3:1 hexanes/EtOAc); H NMR (CDCl3, 600 MHz) δ 1.13 (t, 3H, J = 7.2 Hz), 2.19 (s, 6H), 2.23 (s, 6H), 2.35 (s, 3H), 2.57 (d, 1H, J = 6.6 Hz), 2.94 (d, 1H, J = 6.0 Hz), 3.64 (s, 4H), 3.67 (s, 3H), 4.05 (q, 2H, J = 7.2 Hz), 7.03 (s, 2H), 7.09 (s, 2H), 7.49 (s, 1H); 13 C NMR (CDCl3, 150 MHz) δ 13.85, 14.12, 16.18, 16.20, 41.75, 45.28, 59.55, 59.58, 60.69, 76.83, 127.40, 127.64, 130.57, 130.64, 135.90, 136.52, 137.44, 137.64, 155.99, 156.08, -1 160.79, 167.64; IR (thin film) 2936vs, 1746s, 1582s, 1484s, 1223s, 1194s, 1015m cm ; HRMS + (ESI-TOF) m/z 479.2547 [(M+H ); calcd. for C28H35N2O5 : 479.2546]; [α ]20 –33.3.0 (c 1.0, D EtOAc) on 96% ee material (HPLC) of ent-114n. 641 7.15.7 Synthesis of alkyl MEDAM aziridines 114o-w (via Procedure IIIA, Table 7.6) MeO 1. 4 Å MS (p) 2. O H2N 5 mol% (S)-VAPOL OMe 126c 15 mol% B(OPh)3 toluene, 25 °C, 1 h O H 127o 1.05 equiv OEt N2 85 8 equiv –10 °C MeO –10 °C, 24 h OMe N CO2Et 114o (2R,3R)-ethyl-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-propylaziridine-2carboxylate 114o: Aldehyde 127o (46.0 µL, 38.0 mg, 0.525 mmol) was reacted according to the general Procedure IIIA described above with (S)-VAPOL as ligand except that the addition of aldehyde 127o was carried out at –10 °C followed by the addition of EDA 85 (415 µL, 4.00 mmoL, 8.00 equiv) at the same temperature. The reaction was stirred at –10 °C for 24 h. Purification of the crude aziridine by silica gel chromatography (20 mm × 250 mm column, 4:2:0.1 hexanes/CH2Cl2/EtOAc, gravity column) afforded pure cis-aziridine 114o as a yellow oil in 94% isolated yield (207 mg, 0.490 mmol); cis/trans: not determined. Enamine side products: not observed. The optical purity of 114o was determined to be 96% ee by HPLC analysis (CHIRALCEL OD-H column, 99:1 hexane/2-propanol at 226 nm, flow-rate: 0.7 mL/min): retention times; Rt = 4.73 min (major enantiomer, 114o) and Rt = 5.68 min (minor enantiomer, ent-114o). 1 Spectral data for 114o: Rf = 0.28 (4:2:0.1 hexanes/CH2Cl2/EtOAc); H NMR (CDCl3, 500 MHz) δ 0.72 (t, 3H, J = 7.6 Hz), 0.98-1.08 (m, 1H), 1.11-1.20 (m, 1H), 1.23 (t, 3H, J = 7.1 Hz), 1.38-1.45 (m, 1H), 1.49-1.55 (m, 1H), 1.95 (q, 1H, J = 6.6 Hz), 2.18 (d, 1H, J = 6.8 Hz) 2.22 (s, 642 12H), 3.39 (s, 1H), 3.65 (s, 3H), 3.67 (s, 3H), 4.12-4.23 (m, 2H), 6.99 (s, 2H), 7.07 (s, 2H); 13 C NMR (CDCl3, 125 MHz) δ 13.57, 14.33, 16.09, 16.16, 20.33 29.93, 43.53, 46.76, 59.56, 59.60, 60.64, 77.32, 127.41, 128.07, 130.44, 130.47, 137.75, 138.18, 155.81, 156.12, 169.69; IR (thin -1 + film) 2957vs, 1744s, 1483s, 1221s, 1182vs cm ; HRMS (ESI-TOF) m/z 440.2817 [(M+H ); calcd. for C27H38NO4 : 440.2801]; [α ]23 +95.3 (c 1.0, EtOAc) on 97% ee material (HPLC). D These spectral data match those previously reported for this compound. MeO OMe 9c (2R,3R)-ethyl-1-(bis(4-methoxy-3,5-dimethylphenyl) methyl)-3-pentadecylaziridine-2-carboxylate Aldehyde 127p (126 mg, 0.525 mmol) was reacted according N 12 CO2Et 114p 114p: to the general Procedure IIA described above with (S)VAPOL as ligand except the following differences : 1) the addition of aldehyde 127p was carried out at –10 °C followed by the addition of EDA 85 (62 µL, 0.60 mmoL, 1.2 equiv) at the same temperature; 2) the catalyst loading was 10 mol%. The reaction was stirred at –10 °C for 24 h. Purification of the crude aziridine by neutral alumina chromatography (20 mm × 250 mm column, 2:1:0.1 hexanes/CH2Cl2/Et2O, gravity column) afforded pure cis-aziridine 114p as a white solid (mp 41-42 ºC on 95% ee material) in 80% isolated yield (243 mg, 0.400 mmol); cis/trans: not determined. Enamine side products: 6% yield of 118p and 4% yield of 119p. The optical purity of 114p was determined to be 96% ee by HPLC analysis (PIRKLE COVALENT (R, R) WHELK-O 1 column, 99.5:0.5 hexane/2-propanol 643 at 226 nm, flow-rate: 0.7 mL/min): retention times; Rt = 18.26 min (major enantiomer, 114p) and Rt = 33.43 min (minor enantiomer, ent-114p). 1 Spectral data for 114p: Rf = 0.31 (2:1:0.2 hexanes/CH2Cl2/Et2O); H NMR (CDCl3, 500 MHz) δ 0.86 (t, 3H, J = 7.0 Hz), 1.14-1.28 (m, 1H), 1.43-1.50 (m, 26H), 1.93 (q, 1H, J = 6.5 Hz), 2.18 (d, 1H, J = 6.5 Hz) 2.22 (s, 12H), 3.38 (s, 1H), 3.65 (s, 3H), 3.67 (s, 3H), 4.12-4.23 (m, 2H), 6.99 (s, 2H), 7.07 (s, 2H); 13 C NMR (CDCl3, 125 MHz) δ 14.09, 14.34, 16.11, 16.16, 22.68, 27.24, 27.96, 29.18, 29.35, 29.51, 29.61, 29.62, 29.65, 29.68, 31.92, 43.56, 47.01, 59.57, 59.58, 60.64, 3 77.35, 127.41, 128.10, 130.42, 130.47, 137.78, 138.18, 155.81, 156.15, 169.69 (3 sp carbon not -1 located); IR (thin film) 2925vs, 1746s, 1484s, 1221s, 1183vs cm ; HRMS (ESI-TOF) m/z + 608.4683 [(M+H ); calcd. for C39H62NO4 : 608.4679]; [α ]20 +57.9 (c 1.0, EtOAc) on 95% ee D material (HPLC). MeO OMe (2R,3R)-ethyl-1-(bis(4-methoxy-3,5-dimethylphenyl) methyl)-3-(7- aziridine-2-carboxylate 114q: N TBSO 7 114q ((tert-butyldimethylsilyl) CO2Et oxy)heptyl) Aldehyde 127q (136 mg, 0.525 mmol) was reacted according to the general Procedure IIA described above with (S)-VAPOL as ligand except that the addition of aldehyde 127q was carried out at –10 °C followed by the addition of EDA 85 (62 µL, 0.60 mmoL, 1.2 equiv) at the same temperature and the catalyst loading was 10 mol%. The 644 reaction was stirred at –10 °C for 24 h. Purification of the crude aziridine by silica gel chromatography (30 mm × 300 mm column, 1:15 EtOAc/hexanes, gravity column) afforded pure cis-aziridine 114q as a yellow oil in 80% isolated yield (250 mg, 0.400 mmol); cis/trans: not determined. Enamine side products: <1% yield of 118q and 2.8% yield of 119q. The optical purity of 114q was determined to be 98% ee by HPLC analysis (CHIRALCEL OD-H column, 99.5:0.5 hexane/2-propanol at 226 nm, flow-rate: 0.7 mL/min): retention times; Rt = 5.33 min (major enantiomer, 114q) and Rt = 7.26 min (minor enantiomer, ent-114q). 1 Spectral data for 114q: Rf = 0.28 (12:1 hexanes/EtOAc); H NMR (CDCl3, 500 MHz) δ 0.02 (s, 6H), 0.87 (s, 9H), 1.11-1.21 (m, 8H), 1.24 (t, 3H, J = 7.1 Hz), 1.40-1.50 (m, 4H), 1.94 (q, 1H, J = 6.6 Hz), 2.19 (d, 1H, J = 6.8 Hz) 2.22 (s, 12H), 3.39 (s, 1H), 3.55 (t, 2H, J = 6.8 Hz), 3.65 (s, 3H), 3.67 (s, 3H), 4.12-4.22 (m, 2H), 6.99 (s, 2H), 7.08 (s, 2H); 13 C NMR (CDCl3, 125 MHz) δ -5.31, 14.31, 16.08, 16.12, 18.32, 25.62, 25.94, 27.17, 27.88, 29.12, 29.38, 32.80, 43.52, 46.92, 59.51, 59.52, 60.59, 63..22, 77.32, 127.37, 128.07, 130.38, 130.43, 137.74, 138.16, 155.79, -1 156.13, 169.63; IR (thin film) 2930s, 1746s, 1483s, 1221s, 1183vs cm ; HRMS (ESI-TOF) m/z + 626.4243 [(M+H ); calcd. for C37H60NO5Si : 626.4241]; [α ]20 +54.5 (c 1.0, EtOAc) on 98% ee D material (HPLC). (2R,3R)-ethyl-1-(bis(4-methoxy-3,5-dimethylphenyl) MeO OMe 114r: Aldehyde 127r (72.0 µL, 76.0 mg, 0.525 mmol) was N EtO2C 3 114r methyl)-3-(4-ethoxy-4-oxobutyl)aziridine-2-carboxylate CO2Et reacted according to the general Procedure IIIA described 645 above with (S)-VAPOL as ligand except that the addition of aldehyde 127r was carried out at – 10 °C followed by the addition of EDA 85 (415 µL, 4.0 mmoL, 8 equiv) at the same temperature. The reaction was stirred at –10 °C for 24 h. Purification of the crude aziridine by silica gel chromatography (30 mm × 300 mm column, 1:40 Et2O/CH2Cl2; 1:30 Et2O/CH2Cl2; 1:20 Et2O/CH2Cl2, gravity column) afforded pure cis-aziridine 114r as a semi solid in 82% isolated yield (210 mg, 0.410 mmol); cis/trans: not determined. Enamine side products: not observed. The optical purity of 114r was determined to be 97% ee by HPLC analysis (CHIRALCEL OD-H column, 99:1 hexane/2-propanol at 226 nm, flow-rate: 0.7 mL/min): retention times; Rt = 11.56 min (major enantiomer, 114r) and Rt = 12.86 min (minor enantiomer, ent-114r). 1 Spectral data for 114r: Rf = 0.31 (20:1 Et2O/CH2Cl2); H NMR (CDCl3, 500 MHz) δ 1.19 (t, 3H, J = 7.1 Hz), 1.24 (t, 3H, J = 7.1 Hz), 1.31-1.38 (m, 1H), 1.40-1.48 (m, 1H), 1.48-1.56 (m, 2H), 1.95 (q, 1H, J = 6.1 Hz), 2.07 (t, 2H, J = 7.6 Hz), 2.20 (d, 1H, J = 6.8 Hz), 2.22 (s, 12H), 3.39 (s, 1H), 3.65 (s, 3H), 3.66 (s, 3H), 4.04 (q, 2H, J = 7.1 Hz), 4.12-4.21 (m, 2H), 6.98 (s, 2H), 7.07 (s, 2H); 13 C NMR (CDCl3, 125 MHz) δ 14.16, 14.28, 16.08, 16.15, 22.51, 27.28, 33.53, 43.43, 46.22, 59.55, 60.12, 60.73, 77.26, 127.31, 128.02, 130.49, 130.57, 137.61, 138.01, 155.81, 3 156.21, 169.48, 173.21 (one sp carbon not located) ; IR (thin film) 2940vs, 1738s, 1483s, -1 + 1221s, 1183vs cm ; HRMS (ESI-TOF) m/z 512.3015 [(M+H ); calcd. for C30H42NO6 : 512.3012]; [α ]20 –68.5 (c 1.0, EtOAc) on 97% ee material (HPLC) of ent-114r. D 646 MeO OMe (2R,3R)-ethyl-1-(bis(4-methoxy-3,5-dimethylphenyl) methyl)-3-(3-phenylpropyl)aziridine-2-carboxylate Aldehyde 127s (75.0 µL, 78.0 mg, 0.525 mmol) was reacted N Ph 3 114s 114s: CO2Et according to the general Procedure IIIA described above with (S)-VAPOL as ligand except that the addition of aldehyde 127s was carried out at –10 °C followed by the addition of EDA 85 (415 µL, 4.0 mmoL, 8 equiv) at the same temperature. The reaction was stirred at –10 °C for 24 h. Purification of the crude aziridine by silica gel chromatography (30 mm × 300 mm column, 1:9 EtOAc/hexanes, gravity column) afforded pure cis-aziridine 114s as a yellow oil in 50% isolated yield (129 mg, 0.250 mmol); cis/trans: not determined. Enamine side products: not observed. The optical purity of 114s was determined to be 90% ee by HPLC analysis (CHIRALCEL OD-H column, 99:1 hexane/2-propanol at 226 nm, flow-rate: 0.7 mL/min): retention times; Rt = 7.47 min (major enantiomer, 114s) and Rt = 9.52 min (minor enantiomer, ent-114s). 1 Spectral data for 114s: Rf = 0.30 (1:9 hexanes/EtOAc); H NMR (CDCl3, 500 MHz) δ 1.23 (t, 3H, J = 7.1 Hz), 1.27-1.35 (m, 1H), 1.40-1.48 (m, 1H), 1.50-1.61 (m, 2H), 1.97 (q, 1H, J = 7.1 Hz), 2.19 (s, 6H), 2.21 (d, 1H, J = 6.8 Hz) 2.23 (s, 6H), 2.42 (t, 2H, J = 8.1 Hz), 3.40 (s, 1H), 3.54 (s, 3H), 3.67 (s, 3H), 4.11-4.21 (m, 2H), 6.99-7.00 (m, 4H), 7.09 (s, 2H) 7.10-7.13 (m, 1H), 7.19-7.21 (m, 2H); 13 C NMR (CDCl3, 125 MHz) δ 14.32, 16.08, 16.15, 27.69, 29.11, 35.38, 43.60, 46.61, 59.49, 59.56, 60.70, 77.36, 125.58, 127.33, 128.11, 128.16, 128.18, 130.49, 130.50, 137.67, 138.08, 142.30, 155.79, 156.24, 169.61; IR (thin film) 2930vs, 1744s, 1483s, 1221s, 647 -1 + 1184vs cm ; HRMS (ESI-TOF) m/z 516.3115 [(M+H ); calcd. for C33H42NO4 : 516.3114]; [α ]20 +61.7 (c 1.0, EtOAc) on 93% ee material (HPLC). D MeO OMe (2R,3R)-ethyl-1-(bis(4-methoxy-3,5-dimethylphenyl) methyl)-3-phenethylaziridine-2-carboxylate Aldehyde 127t (70.0 µL, 70.0 mg, 0.525 mmol) was reacted N Ph 2 114t 114t: CO2Et according to the general Procedure IIIA described above with (S)-VAPOL as ligand except that the addition of aldehyde 127t was carried out at –10 °C followed by the addition of EDA 85 (415 µL, 4.0 mmoL, 8 equiv) at the same temperature. The reaction was stirred at –10 °C for 24 h. Purification of the crude aziridine by silica gel chromatography (30 mm × 300 mm column, 1:12 EtOAc/hexanes, gravity column) afforded pure cis-aziridine 114t as a semi solid in 91% isolated yield (228 mg, 0.460 mmol); cis/trans: not determined. Enamine side products: <1% yield of 118t and 1.8 % yield of 119t. The optical purity of 114t was determined to be 96% ee by HPLC analysis (CHIRALCEL OD-H column, 99:1 hexane/2-propanol at 226 nm, flow-rate: 0.5 mL/min): retention times; Rt = 11.33 min (major enantiomer, 114t) and Rt = 12.80 min (minor enantiomer, ent-114t). 1 Spectral data for 114t: Rf = 0.20 (12:1 hexanes/EtOAc); H NMR (CDCl3, 500 MHz) δ 1.24 (t, 3H, J = 7.1 Hz), 1.80-1.92 (m, 2H), 1.96 (q, 1H, J = 7.1 Hz), 2.21 (d, 1H, J = 6.8 Hz) 2.24 (s, 6H), 2.27 (s, 6H), 2.29-2.34 (m, 1H), 2.48-2.53 (m, 1H), 3.41 (s, 1H), 3.67 (s, 3H), 3.68 (s, 3H), 4.12-4.20 (m, 2H), 6.91 (d, 2H, J = 7.3 Hz), 7.01 (s, 2H), 7.10 (s, 2H), 7.13 (d, 1H, J = 7.3 Hz), 648 7.19 (t, 2H, J = 7.3 Hz); 13 C NMR (CDCl3, 125 MHz) δ 14.29, 16.12, 16.15, 29.59, 33.25, 43.34, 46.13, 59.54, 59.60, 60.71, 77.22, 125.70, 127.26, 128.06, 128.15, 128.36, 130.50, 130.58, 137.77, 138.30, 141.35, 155.80, 156.22, 169.54; IR (thin film) 2934s, 1744s, 1484s, 1221s, -1 + 1182vs cm ; HRMS (ESI-TOF) m/z 502.2962 [(M+H ); calcd. for C32H40NO4 : 502.2957]; [α ]20 –62.3 (c 1.0, EtOAc) on 96% ee material (HPLC) of ent-114t. D MeO OMe (2R,3R)-ethyl-3-benzyl-1-(bis(4-methoxy-3,5-dimethyl phenyl)methyl)aziridine-2-carboxylate 114u: 127u (59.0 µL, 63.0 mg, 0.525 mmol) was reacted according N Ph 114u Aldehyde CO2Et to the general Procedure IIIA described above with (S)VAPOL as ligand except that the addition of aldehyde 127u was carried out at –10 °C followed by the addition of EDA 85 (415 µL, 4.0 mmoL, 8 equiv) at the same temperature. The reaction was stirred at –10 °C for 24 h. Purification of the crude aziridine by silica gel chromatography (30 mm × 300 mm column, 1:12 EtOAc/hexanes, gravity column) afforded pure cis-aziridine 114u as a semi solid in 86% isolated yield (209 mg, 0.430 mmol); cis/trans: not determined. Enamine side products: not observed. The optical purity of 114u was determined to be 98% ee by HPLC analysis (PIRKLE COVALENT (R, R) WHELK-O 1 column, 95:5 hexane/2-propanol at 226 nm, flow-rate: 0.7 mL/min): retention times; Rt = 11.53 min (major enantiomer, 114u) and Rt = 16.34 min (minor enantiomer, ent-114u). 649 1 Spectral data for 114u: Rf = 0.30 (12:1 hexanes/EtOAc); H NMR (CDCl3, 500 MHz) δ 1.25 (t, 3H, J = 7.2 Hz), 2.20 (s, 6H), 2.24 (s, 6H), 2.25-2.28 (m, 2H), 2.85 (dd, 1H, J = 6.1, 14.7 Hz), 2.94 (dd, 1H, J = 5.6, 14.9 Hz), 3.45 (s, 1H), 3.68 (s, 3H), 3.69 (s, 3H), 4.16-4.25 (m, 2H), 6.96 (s, 2H), 6.98-6.99 (m, 2H), 7.09 (s, 2H), 7.10-7.15 (m, 3H); 13 C NMR (CDCl3, 125 MHz) δ 14.26, 16.09, 16.13, 34.23, 43.04, 47.79, 59.49, 59.52, 60.78, 77.18, 126.01, 127.33, 127.95, 128.08, 128.53, 130.41, 130.49, 137.65, 137.86, 138.58, 155.80, 155.99, 169.59; IR (thin film) -1 + 2937s, 1742vs, 1484s, 1221s, 1182vs cm ; HRMS (ESI-TOF) m/z 440.2808 [(M+H ); calcd. for C31H38NO4 : 488.2801]; [α ]20 –54.2 (c 1.0, EtOAc) on 98% ee material (HPLC) of entD 114u. MeO OMe (2R,3R)-ethyl-1-(bis(4-methoxy-3,5-dimethyl phenyl)methyl)-3-cyclohexylaziridine-2-carboxylate 114v: Aldehyde 127v (63.0 µL, 59.0 mg, 0.525 mmol) was reacted N CO2Et 114v according to the general Procedure IIIA described above with (S)-VAPOL as ligand. Purification of the crude aziridine by silica gel chromatography (30 mm × 300 mm column, 4:2:0.1 hexanes/CH2Cl2/Et2O, gravity column) afforded pure cis-aziridine 114v as a semi solid in 95% isolated yield (229 mg, 0.480 mmol); cis/trans: > 50:1. Enamine side products: <1% yield of 118v and 1.9% yield of 119v. The optical purity of 114v was determined to be 90% ee by HPLC analysis (CHIRALCEL OD 650 column, 99:1 hexane/2-propanol at 223 nm, flow-rate: 0.7 mL/min): retention times; Rt = 10.06 min (major enantiomer, 114v) and Rt = 12.37 min (minor enantiomer, ent-114v). 1 Spectral data for 114v: Rf = 0.21 (2:1 hexane/CH2Cl2); H NMR (CDCl3, 300 MHz) δ 0.460.57 (m, 1H), 0.87-1.19 (m, 4H), 1.21 (t, 3H, J = 7.1 Hz), 1.22-1.32 (m, 2H), 1.40-1.60 (m, 4H), 1.71-1.76 (m, 1H), 2.16 (m, 1H), 2.19 (s, 6H), 2.20 (s, 6H), 3.35 (s, 1H), 3.60 (s, 3H), 3.63 (s, 3H), 4.10-4.25 (m, 2H), 6.95 (s, 2H), 7.10 (s, 2H); 13 C NMR (CDCl3, 75 MHz) δ 13.85, 15.56, 15.67, 24.91, 25.09, 25.73, 29.65, 30.38, 35.88, 42.97, 51.76, 59.01, 59.07, 60.12, 77.01, 126.90, 128.10, 129.84, 129.95, 137.16, 137.71, 155.31, 155.83, 169.30; IR (thin film) 2928vs, 1744s, -1 1483s, 1221s, 1181s, 1017m cm ; Mass spectrum: m/z (% rel intensity) 479 M+ (0.7), 283 (100), 268 (25), 253 (12), 237 (7), 210 (7), 195 (9), 141 (8), 95 (10), 67 (16), 55 (10), 41 (16); [α ]23 +107.9 (c 1.0, CH2Cl2) on 90% ee material (HPLC). These spectral data match those D previously reported for this compound. 9c OMe (2R,3R)-ethyl-1-(bis(4-methoxy-3,5-dimethyl phenyl) methyl)-3-(tert-butyl)aziridine-2-carboxylate MeO 114w: Aldehyde 127w (58.0 µL, 45.0 mg, 0.525 mmol) was reacted N CO2Et 114w according to the general Procedure IIIA described above with (S)-VAPOL as ligand except that 2 equiv of EDA 85 was used. Purification of the crude aziridine by silica gel chromatography (30 mm × 300 mm column, 4:2:0.1 hexanes/CH2Cl2/Et2O and then 2:1:0.1 hexanes/CH2Cl2/Et2O, gravity column) 651 afforded pure cis-aziridine 114w as a semi solid in 95% isolated yield (216 mg, 0.480 mmol); cis/trans: >50:1. Enamine side products: <1% yield of 118w and <1% yield of 119w. The optical purity of 114w was determined to be 92% ee by HPLC by HPLC analysis (CHIRALCEL OD column, 99:1 hexane/2-propanol at 226 nm, flow-rate: 1.0 mL/min): retention times; Rt = 6.8 min (major enantiomer, 114w) and Rt = 10.55 min (minor enantiomer, ent-114w). 1 Spectral data for 114w: Rf = 0.28 (1:2 hexane/CH2Cl2); H NMR (CDCl3, 300 MHz) δ 0.72 (s, 9H), 1.29 (t, 3H, J = 7.1 Hz), 1.70 (d, 1H, J = 7.3 Hz), 2.11 (d, 1H, J = 7.2 Hz), 2.24 (s, 6H), 2.26 (s, 6H), 3.38 (s, 1H), 3.63 (s, 3H), 3.66 (s, 3H), 4.05-4.26 (m, 2H), 7.04 (s, 2H), 7.30 (s, 2H); 13 C NMR (CDCl3, 75 MHz) δ 13.92, 15.84, 15.96, 27.24, 31.39, 43.16, 55.94, 59.20, 2 59.27, 60.24, 78.20, 127.30, 128.18, 130.01, 137.77, 138.74, 155.51, 155.98, 169.66 (one sp -1 carbon not located); IR (thin film) 2953vs, 1747s, 1481s, 1221s, 1181s, 1017m cm ; Mass spectrum: m/z (% rel intensity) 453 M+ (1), 283 (100), 268 (45), 253 (26), 237 (17), 225 (11), 210 (13), 195 (17), 164 (9) 141 (26), 132 (11), 127 (12), 91 (11), 69 (18), 55 (37), 41 (55); [α ]23 D +110.0 (c 1.0, CH2Cl2) on 94% ee material (HPLC). These spectral data match those previously reported for this compound. 9c 652 7.15.8 Synthesis of MEDAM imine 111l and aziridine 114l (aziridination with preformed imine, Scheme 7.5) MeO MeO O O MgSO4 + H2N OMe CH2Cl2 O OMe 25 °C, 24 h 126c 127l N 111l 26% (E)-N-(furan-2-ylmethylene)-1,1-bis(4-methoxy-3,5-dimethylphenyl)methanamine 111l: To a 25 mL flame-dried round bottom flask, equipped with a stir bar, filled with argon was added MEDAM amine 126c (598.8 g, 2.000 mmol), MgSO4 (500 mg, freshly flame-dried) and dry CH2Cl2 (6 mL). After stirring for 10 min, aldehyde 127l (174 µL, 2.10 mmol, 1.05 equiv) was added. The reaction mixture was stirred at room temperature for 24 h. The reaction mixture was filtered through Celite and the Celite bed was washed with CH2Cl2 (3 mL × 3) and then the filtrate was concentrated by rotary evaporation to give the crude imine as an off-white solid. Crystallization (1:25 CH2Cl2 / hexanes) and collection of the first crop afforded 111l as a white solid (mp 116-117 ºC) in 26% isolated yield (200 mg, 0.520 mmol). 1 Spectral data for 111l: H NMR (CDCl3, 600 MHz) δ 2.23 (s, 12H), 3.67 (s, 6H), 5.31 (s, 1H), 6.45 (dd, 1H, J = 1.7, 3.4 Hz), 6.77 (d, 1H, J = 3.4 Hz), 6.97 (s, 4H), 7.51 (d, 1H, J = 1.7 Hz), 8.13 (s, 1H); 13 C NMR (CDCl3, 150 MHz) δ 16.16, 59.60, 77.71, 111.60, 114.46, 127.94, 653 -1 130.66, 138.74, 144.77, 149.19, 151.73, 155.90; IR (thin film) 2944w, 1646s, 1484s, 1221 cm ; + HRMS (ESI-TOF) m/z 378.2075 [(M+H ); calcd. for C24H28NO3 : 378.2069] B(OPh)3 (3 equiv) (S)-VAPOL (5 mol%) 0.1 mm Hg pre-catalyst toluene, 80 °C, 1 h 80 °C, 0.5 h OMe MeO O + MeO N O OMe pre-catalyst (5 mol%) OEt toluene, 25 °C, 24 h N2 85 111l N O CO2Et 114l 57% y, 89% ee (2R,3S)-ethyl-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-(furan-2-yl)aziridine-2carboxylate 114l: To a 25 mL flame-dried home-made Schlenk flask , prepared from a singlenecked 25 mL pear-shaped flask that had its 14/20 glass joint replaced with a high vacuum threaded Teflon valve, equipped with a stir bar and flushed with argon was added (S)-VAPOL (7.00 mg, 0.0125 mmol) and B(OPh)3 (11.0 mg, 0.0375 mmol). Under an argon flow through the side-arm of the Schlenk flask, dry toluene (1 mL) was added through the top of the Teflon valve to dissolve the two reagents. The flask was sealed by closing the Teflon valve, and then placed in an 80 ºC oil bath for 1 h. After 1 h, a vacuum (0.5 mm Hg) was carefully applied by slightly opening the Teflon valve to remove the volatiles. After the volatiles were removed completely, a full vacuum was applied and maintained for a period of 30 min at a temperature of 654 80 ºC (oil bath). The flask was then allowed to cool to room temperature and opened to argon through the side-arm of the Schlenk flask. To the flask containing the pre-catalyst was first added the aldimine 111l (94.4 mg, 0.250 mmol) and then dry toluene (0.5 mL) under an argon flow through side-arm of the Schlenk flask. The reaction mixture was stirred for 5 min to give a light orange solution. The flask was then cooled to –10 °C. To this solution was rapidly added ethyl diazoacetate (EDA) 85 (31 µL, 0.30 mmol) followed by closing the Teflon valve. The resulting mixture was stirred for 2 h at –10 °C It was then warmed to room temperature and stirred for 24 h at room temperature. The reaction was dilluted by addition of hexane (6 mL). The reaction mixture was then transferred to a 50 mL round bottom flask. The reaction flask was rinsed with dichloromethane (3 mL × 2) and the rinse was added to the 50 mL round bottom flask. The resulting solution was then concentrated in vacuo followed by exposure to high vacuum (0.05 mm Hg) for 1 h to afford the crude aziridine as an off-white solid. Purification of the crude aziridine by silica gel chromatography (30 mm × 300 mm column, 15:1 hexanes/EtOAc with 1% Et3N as eluent, gravity column; the column was set up by making a slurry of silica gel in hexanes with 2% Et3N) afforded pure cisaziridine 114l as a white solid (mp 45-46 ºC on 94% ee material) in 57% isolated yield (66.0 mg, 0.143 mmol); cis/trans: 9.3:1. Enamine side products: 1.3% yield of 118l and 1% yield of 119l. The optical purity of 114l was determined to be 89% ee by HPLC analysis (CHIRALCEL OD-H column, 99.5:0.5 hexane/2-propanol at 226 nm, flow-rate: 0.7 mL/min): retention times; Rt = 23.6 min (major enantiomer, 114l) and Rt = 39.1 min (minor enantiomer, ent-114l). The spectral data of 114l matched to those reported above. 655 7.15.9 Mechanistic study of MCAZ (A) Different order of addition of reagents in MCAZ: Procedures (IV-IX) Procedure IV: Catalyst + 4Å MS + 127a + EDA 85 @ 25 °C, 24 h MeO 1. 4 Å MS (p) 2. O H2N 5 mol% (S)-VAPOL H OMe 126c 15 mol% B(OPh)3 25 °C 127a 1.05 equiv 25 °C O MeO OMe OEt N2 85 1.2 equiv toluene 25 °C, 24 h N CO2Et 114a (2R,3R)-ethyl-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-phenylaziridine-2carboxylate 114a: To a 10 mL flame-dried single-necked round bottom flask equipped with a stir bar and filled with argon was added in the following order (S)-VAPOL (14 mg, 0.025 mmol), B(OPh)3 (22 mg, 0.075 mmol), amine 126c (149.7 mg, 0.5000 mmol), 4Å Molecular Sieves (150 mg, freshly flame-dried), aldehyde 127a (52.0 µL, 0.525 mmoL, 1.05 equiv) and ethyl diazoacetate (EDA) 85 (62 µL, 0.60 mmoL, 1.2 equiv). Dry toluene (1 mL) was added under an argon atmosphere to dissolve the reagents. The flask was fitted with a rubber septum and a nitrogen balloon. The reaction mixture was stirred at room temperature for 24 h. The reaction was dilluted by addition of hexane (6 mL). The reaction mixture was then filtered through a Celite pad to a 100 mL round bottom flask. The reaction flask was rinsed with EtOAc (3 mL × 3) and the rinse was filtered through the same Celite pad. The resulting solution was then concentrated in vacuo followed by exposure to high vacuum (0.05 mm Hg) for 1 h to afford 656 the crude aziridine as an off-white solid. Purification of the crude aziridine by silica gel chromatography (30 mm × 300 mm column, 9:1 hexanes/EtOAc as eluent, gravity column) afforded pure cis-aziridine 114a as a white solid (mp 107-108 ºC on 99.8% ee material) in 88% isolated yield (208 mg, 0.44 mmol); cis/trans: >50:1. Enamine side products: <1 % yield of 118a and <1 % yield of 119a. The optical purity of 114a was determined to be 98% ee by HPLC analysis (CHIRALCEL OD-H column, 99:1 hexane/2-propanol at 226nm, flow-rate: 0.7 mL/min): retention times; Rt = 9.26 min (major enantiomer, 114a) and Rt = 12.52 min (minor enantiomer, ent-114a). Procedure V: Catalyst + EDA 85 @ 25 °C, 1 h and then addition of the aldehyde 127a. MeO 1. 4 Å MS (p) 2. O O H2N 5 mol% (S)-VAPOL OMe 126c 15 mol% B(OPh)3 OEt N2 85 1.2 equiv toluene 25 °C, 1 h MeO OMe H 127a 1.05 equiv 25 °C, 24 h N CO2Et 114a (2R,3R)-ethyl-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-phenylaziridine-2carboxylate 114a: To a 10 mL flame-dried single-necked round bottom flask equipped with a stir bar and filled with argon was added in the following order (S)-VAPOL (14 mg, 0.025 mmol), B(OPh)3 (22 mg, 0.075 mmol), amine 126c (149.7 mg, 0.5000 mmol) and ethyl diazoacetate (EDA) 85 (62 µL, 0.60 mmoL, 1.2 equiv). Dry toluene (1 mL) was added under an argon atmosphere to dissolve the reagents. The flask was fitted with a rubber septum and a 657 nitrogen balloon. The reaction mixture was stirred at room temperature for 1 h. Thereafter, 4Å Molecular Sieves (150 mg, freshly flame-dried) was added followed by the addition of the aldehyde 127a (52.0 µL, 0.525 mmoL, 1.05 equiv). The resulting mixture was stirred for 24 h at room temperature. The reaction was dilluted by addition of hexane (6 mL). The reaction mixture was then filtered through a Celite pad to a 100 mL round bottom flask. The reaction flask was rinsed with EtOAc (3 mL × 3) and the rinse was filtered through the same Celite pad. The resulting solution was then concentrated in vacuo followed by exposure to high vacuum (0.05 mm Hg) for 1 h to afford the crude aziridine as an off-white solid. Purification of the crude aziridine by silica gel chromatography (30 mm × 300 mm column, 9:1 hexanes/EtOAc as eluent, gravity column) afforded pure cis-aziridine 114a as a white solid (mp 107-108 ºC on 99.8% ee material) in 94% isolated yield (223 mg, 0.47 mmol); cis/trans: >50:1. Enamine side products: <1% yield of 118a and <1% yield of 119a. The optical purity of 114a was determined to be 98% ee by HPLC analysis (CHIRALCEL OD-H column, 99:1 hexane/2-propanol at 226nm, flow-rate: 0.7 mL/min): retention times; Rt = 9.26 min (major enantiomer, 114a) and Rt = 12.52 min (minor enantiomer, ent-114a). Procedure VI: Catalyst + EDA 85 + 4Å MS + 127a @ 25 °C, 24 h MeO 1. 4 Å MS (p) 2. O O H2N 5 mol% (S)-VAPOL OMe 126c 15 mol% B(OPh)3 OEt N2 85 1.2 equiv toluene 25 °C MeO OMe H 127a 1.05 equiv 25 °C, 24 h N CO2Et 114a 658 (2R,3R)-ethyl-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-phenylaziridine-2carboxylate 114a: To a 10 mL flame-dried single-necked round bottom flask equipped with a stir bar and filled with argon was added in the following order (S)-VAPOL (14 mg, 0.025 mmol), B(OPh)3 (22 mg, 0.075 mmol), amine 126c (149.7 mg, 0.5000 mmol) and ethyl diazoacetate (EDA) 85 (62 µL, 0.60 mmoL, 1.2 equiv). Dry toluene (1 mL) was added under an argon atmosphere to dissolve the reagents. The flask was fitted with a rubber septum and a nitrogen balloon. Thereafter, 4Å Molecular Sieves (150 mg, freshly flame-dried) was added followed by the addition of the aldehyde 127a (52.0 µL, 0.525 mmoL, 1.05 equiv). The resulting mixture was stirred for 24 h at room temperature. The reaction was dilluted by addition of hexane (6 mL). The reaction mixture was then filtered through a Celite pad to a 100 mL round bottom flask. The reaction flask was rinsed with EtOAc (3 mL × 3) and the rinse was filtered through the same Celite pad. The resulting solution was then concentrated in vacuo followed by exposure to high vacuum (0.05 mm Hg) for 1 h to afford the crude aziridine as an off-white solid. Purification of the crude aziridine by silica gel chromatography (30 mm × 300 mm column, 9:1 hexanes/EtOAc as eluent, gravity column) afforded pure cis-aziridine 114a as a white solid (mp 107-108 ºC on 99.8% ee material) in 94% isolated yield (223 mg, 0.47 mmol); cis/trans: >50:1. Enamine side products: <1% yield of 118a and <1% yield of 119a. The optical purity of 114a was determined to be 98% ee by HPLC analysis (CHIRALCEL OD-H column, 99:1 hexane/2-propanol at 226nm, flow-rate: 0.7 mL/min): retention times; Rt = 9.26 min (major enantiomer, 114a) and Rt = 12.52 min (minor enantiomer, ent-114a). 659 Procedure VII: Amine 126c added at the end prior to the addition of toluene. MeO 1. 15 mol% B(OPh)3 2. 4 Å MS (p) 3. O H 127a 1.05 equiv 5 mol% (S)-VAPOL 25 °C O MeO OEt N2 85 1.2 equiv H2N OMe OMe 126c toluene, 25 °C, 24 h N CO2Et 114a (2R,3R)-ethyl-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-phenylaziridine-2carboxylate 114a: To a 10 mL flame-dried single-necked round bottom flask equipped with a stir bar and filled with argon was added in following order (S)-VAPOL (14 mg, 0.025 mmol), B(OPh)3 (22 mg, 0.075 mmol), 4Å Molecular Sieves (150 mg, freshly flame-dried), aldehyde 127a (52.0 µL, 0.525 mmoL, 1.05 equiv), ethyl diazoacetate (EDA) 85 (62 µL, 0.60 mmoL, 1.2 equiv) and amine 126c (149.7 mg, 0.5000 mmol). Dry toluene (1 mL) was added under an argon atmosphere to dissolve the reagents. The flask was fitted with a rubber septum and a nitrogen balloon. The reaction mixture was stirred for 24 h at room temperature. The reaction was dilluted by addition of hexane (6 mL). The reaction mixture was then filtered through a Celite pad to a 100 mL round bottom flask. The reaction flask was rinsed with EtOAc (3 mL × 3) and the rinse was filtered through the same Celite pad. The resulting solution was then concentrated in vacuo followed by exposure to high vacuum (0.05 mm Hg) for 1 h to afford the crude aziridine as an off-white solid. Purification of the crude aziridine by silica gel chromatography (30 mm × 300 mm column, 9:1 hexanes/EtOAc as eluent, gravity column) afforded pure cisaziridine 114a as a white solid (mp 107-108 ºC on 99.8% ee material) in 85% isolated yield (201 mg, 0.430 mmol); cis/trans: >50:1. Enamine side products: 2% yield of 118a and 1% yield of 660 119a. The optical purity of 114a was determined to be 98% ee by HPLC analysis (CHIRALCEL OD-H column, 99:1 hexane/2-propanol at 226nm, flow-rate: 0.7 mL/min): retention times; Rt = 9.26 min (major enantiomer, 114a) and Rt = 12.52 min (minor enantiomer, ent-114a). A repeat 1 of this reaction also gave 114a in 85% yield. This is the H NMR yield determined by integration against an internal standard (Ph3CH). Procedure VIII: Amine 126c added at the end after 2 min stirring of a mixture of VAPOL 58, B(OPh)3, aldehyde 127a and EDA 85 in toluene. 1. 4 Å MS (p) 2. O 5 mol% 15 mol% (S)-VAPOL + B(OPh)3 MEDAM N Ph MEDAM + H CO2Et O toluene, rt 2 min MEDAM NH CO2Et + + 395a <1% Ph N CO2Et + Ph H 119a 4% 396a 23% Ph NH2 126c Products 25 °C, 24 h MEDAM H + 126c 40% OH OH CO2Et + H 397a 5% H MEDAM NH2 111a 34% OH CO2Et + MEDAM NH Ph O CO2Et N2 85 1.2 equiv Ph H 127a 1.05 equiv Ph 118a 10% 114a <1% Ph CO2Et CO2Et Ph 398a <1% + Ph CO2Et N2 399a <1% To a 10 mL flame-dried single-necked round bottom flask equipped with a stir bar and filled with argon was added in the following order (S)-VAPOL (14 mg, 0.025 mmol), B(OPh)3 (22 mg, 0.075 mmol), 4Å Molecular Sieves (150 mg, freshly flame-dried), aldehyde 127a (52.0 µL, 0.525 mmoL, 1.05 equiv), ethyl diazoacetate (EDA) 85 (62 µL, 0.60 mmoL, 1.2 equiv). Dry 661 toluene (1 mL) was added under an argon atmosphere to dissolve the reagents. The flask was fitted with a rubber septum and a nitrogen balloon. The mixture was stirred for 2 min followed by the addition of amine 126c (149.7 mg, 0.5000 mmol). The reaction mixture was stirred for 24 h at room temperature. The reaction was dilluted by addition of hexane (6 mL). The reaction mixture was then filtered through a Celite pad to a 100 mL round bottom flask. The reaction flask was rinsed with EtOAc (3 mL × 3) and the rinse was filtered through the same Celite pad. The resulting solution was then concentrated in vacuo followed by exposure to high vacuum (0.05 mm Hg) for 1 h to afford the crude mixture. An internal standard Ph3CH (12.2 mg, 0.500 1 mmol) was added and subjected to NMR analysis. The H NMR of crude reaction mixture revealed the presence of several products as shown in the reaction scheme. The presence of each 1 product was confirmed by characteristic peaks (as discussed earlier) in the H NMR previously published for these compounds and the amount of each was quantified by integration against an internal standard (Ph3CH). Procedure IX: Same as Procedure VIII except that amine 126c is not added. 1. 4 Å MS (p) 2. O 5 mol% 15 mol% (S)-VAPOL + B(OPh)3 O Ph CO2Et 395a 5% Ph N2 85 1.2 equiv Ph H 127a 1.05 equiv OH CO2Et + 396a 38% Products toluene, 25 °C, 24 h O + CO2Et Ph OH OH CO2Et + H 397a 11% 662 H CO2Et Ph 398a 5% + Ph CO2Et N2 399a <1% To a 10 mL flame-dried single-necked round bottom flask equipped with a stir bar and filled with argon was added in the following order (S)-VAPOL (14 mg, 0.025 mmol), B(OPh)3 (22 mg, 0.075 mmol), 4Å Molecular Sieves (150 mg, freshly flame-dried), aldehyde 127a (52.0 µL, 0.525 mmoL, 1.05 equiv), ethyl diazoacetate (EDA) 85 (62 µL, 0.60 mmoL, 1.2 equiv). Dry toluene (1 mL) was added under an argon atmosphere to dissolve the reagents. The flask was fitted with a rubber septum and a nitrogen balloon. The resulting mixture was stirred for 24 h at room temperature. The reaction was dilluted by addition of hexane (6 mL). The reaction mixture was then filtered through a Celite pad to a 100 mL round bottom flask. The reaction flask was rinsed with EtOAc (3 mL × 3) and the rinse was filtered through the same Celite pad. The resulting solution was then concentrated in vacuo followed by exposure to high vacuum (0.05 mm Hg) for 1 h to afford the crude mixture. An internal standard Ph3CH (12.2 mg, 0.500 1 mmol) was added and subjected to NMR analysis. The H NMR of the crude reaction mixture revealed the presence of several products as shown in the reaction scheme. The presence of each 1 product was confirmed by characteristic peaks (as discussed earlier) in the H NMR previously published for these compounds. There was also mono-alkylated (S)-VAPOL derivative 230 in 37% yield (with respect to (S)-VAPOL). Procedure VIII in CDCl3 : Amine 126c added at the end after 2 min stirring of a mixture of VAPOL 58, B(OPh)3, aldehyde 127a and EDA 2 in CDCl3. This reaction was run in CDCl3 because the crude reaction mixture in toluene was stripped of 1 volatiles before the H NMR was taken and some of the products many have been lost. 663 1. 4 Å MS (p) 2. O 5 mol% 15 mol% (S)-VAPOL + B(OPh)3 MEDAM N Ph MEDAM + H CO2Et O CDCl3, rt 2 min MEDAM NH CO2Et + + 395a <1% Ph N CO2Et + Ph H 119a 1% Ph Products MEDAM H + CO2Et + 111a 67% H MEDAM NH2 126c 18% OH OH H 397a 4% 396a 39% NH2 126c 25 °C, 24 h OH CO2Et + MEDAM NH Ph O CO2Et N2 85 1.2 equiv Ph H 127a 1.05 equiv Ph 118a 4% 114a <1% Ph CO2Et CO2Et Ph 398a <1% + Ph CO2Et N2 399a <1% To a 10 mL flame-dried single-necked round bottom flask equipped with a stir bar and filled with argon was added (S)-VAPOL in the following order (14 mg, 0.025 mmol), B(OPh)3 (22 mg, 0.075 mmol), 4Å Molecular Sieves (150 mg, freshly flame-dried), aldehyde 127a (52.0 µL, 0.525 mmoL, 1.05 equiv), ethyl diazoacetate (EDA) 85 (62 µL, 0.60 mmoL, 1.2 equiv). Dry CDCl3 (1 mL) was added under an argon atmosphere to dissolve the reagents. The flask was fitted with a rubber septum and a nitrogen balloon. The mixture was stirred for 2 min followed by the addition of amine 126c (149.7 mg, 0.5000 mmol). The reaction mixture was stirred for 24 h at room temperature. After 24 h, an internal standard Ph3CH (12.2 mg, 0.500 mmol) was added. The resulting solution was then directly transferred to a NMR tube utilizing a filter syringe (Corning® syringe filters, Aldrich) to remove the 4Å Molecular Sieves. It was then 1 subjected to NMR analysis. The H NMR of crude reaction mixture revealed the presence of 664 several products as shown in the reaction scheme. The presence of each product was confirmed 1 by characteristic peaks (as discussed earlier) in the H NMR previously published for these compounds. There was also mono-alkylated (S)-VAPOL derivative 230 in 28% yield (with respect to (S)-VAPOL). Procedure IX in CDCl3: Same as Procedure VIII except that amine 126c is not added (in CDCl3). This reaction was run in CDCl3 because the crude reaction mixture in toluene was stripped of 1 volatiles before the H NMR was taken and some of the products many have been lost. 1. 4 Å MS (p) 2. O 5 mol% 15 mol% (S)-VAPOL + B(OPh)3 O Ph CO2Et 395a 3% Ph N2 85 1.2 equiv Ph H 127a 1.05 equiv OH CO2Et + 396a 37% Products CDCl3, 25 °C, 24 h O + CO2Et Ph OH OH CO2Et + H 397a 6% H CO2Et Ph 398a 5% + Ph CO2Et N2 399a 6% To a 10 mL flame-dried single-necked round bottom flask equipped with a stir bar and filled with argon was added in the following order (S)-VAPOL (14 mg, 0.025 mmol), B(OPh)3 (22 mg, 0.075 mmol), 4Å Molecular Sieves (150 mg, freshly flame-dried), aldehyde 127a (52.0 µL, 0.525 mmoL, 1.05 equiv), ethyl diazoacetate (EDA) 85 (62 µL, 0.60 mmoL, 1.2 equiv). Dry CDCl3 (1 mL) was added under an argon atmosphere to dissolve the reagents. The flask was 665 fitted with a rubber septum and a nitrogen balloon. The resulting mixture was stirred for 24 h at room temperature. After 24 h, an internal standard Ph3CH (12.2 mg, 0.5000 mmol) was added. The resulting solution was then directly transferred to a NMR tube utilizing a filter syringe (Corning® syringe filters, Aldrich) to remove the 4Å Molecular Sieves. It was then subjected to 1 NMR analysis. The H NMR of the crude reaction mixture revealed the presence of several products as shown in the reaction scheme. The presence of each product was confirmed by 1 characteristic peaks (as discussed earlier) in the H NMR previously published for these compounds. There was also 26% of unreacted benzaldehyde 127a. There was also monoalkylated (S)-VAPOL derivative 230 in 11% yield (with respect to (S)-VAPOL). (B) MCAZ with 0.9 equivalents of benzaldehyde 127a and amine 126a (Table 7.8) 1. 4 Å MS (p) 2. O H H2N 10 mol% (S)-VAPOL 126a 127a 0.9 equiv O OEt N2 85 1.2 equiv N 25 °C, 24 h 30 mol% B(OPh)3 CHCl3, 25 °C, 1 h CO2Et 86a (2R,3R)-ethyl 1-benzhydryl-3-phenylaziridine-2-carboxylate 86a: Aldehyde 127a (46.0 µL, 0.450 mmol, 0.900 equiv) was reacted according to the general Procedure IIIA described above with (S)-VAPOL as ligand. Purification of the crude aziridine by silica gel chromatography (30 mm × 300 mm column, 19:1 hexanes/EtOAc as eluent, gravity column) afforded pure cisaziridine 86a as a white solid (mp. 127.5-128.5 °C) in 73% isolated yield (117 mg, 0.323 mmol); cis/trans: 25:1. Enamine side products: 8% yield of enamines. The optical purity of 86a was 666 determined to be 89% ee by HPLC analysis (CHIRALCEL OD-H column, 90:10 hexane/2propanol at 226 nm, flow-rate: 0.7 mL/min): retention times; Rt = 9.01 min (major enantiomer, 86a) and Rt = 4.67 min (minor enantiomer, ent-86a). There was 8% of unreacted imine 78a was also observed. Same procedure was followed to do MCAZ for 0.6-1.0 equivalents of benzaldehyde 127a and the results are presented in the chapter. 1 Spectral data for 86a: Rf = 0.3 (1:9 EtOAc/hexanes); H NMR (CDCl3, 500 MHz) δ 0.95 (t, 3H, J = 7.3 Hz), 2.64 (d, 1H, J = 6.8 Hz), 3.19 (d, 1H, J = 6.8 Hz), 3.91 (q, 2H, J = 7.1 Hz), 3.93 (s, 1H), 7.16-7.38 (m, 11H), 7.47 (d, 2H, J = 7.1 Hz), 7.58 (d, 2H, J = 7.6 Hz); 13C NMR (CDCl3, 125 MHz) δ 13.93, 46.36, 48.01, 60.57, 77.68, 127.18, 127.31, 127.39, 127.52, 127.76, 127.78, 2 128.48, 135.00, 142.37, 142.49, 167.75 (one sp carbon not located); [α ]20 +33.4 (c 1.0, D CH2Cl2) on 91% ee material (HPLC). These spectral data match those previously reported for this compound. (C) Aziridination with preformed imine 78a with added bases illustrated by utilizing amine 126a as the base (Table 7.9) N H2N 10 mol% (S)-VAPOL 126a (10 mol%) 78a 1.0 equiv O OEt N2 85 1.2 equiv N 25 °C, 24 h 30 mol% B(OPh)3 CHCl3, 25 °C, 1 h CO2Et 86a 667 (2R,3R)-ethyl 1-benzhydryl-3-phenylaziridine-2-carboxylate 86a: To a 10 mL flame-dried single-necked round bottom flask equipped with a stir bar and filled with argon was added (S)VAPOL (54 mg, 0.10 mmol), B(OPh)3 (87 mg, 0.30 mmol) and amine 126a (17.2 µL, 0.10 mmol). Dry toluene (2 mL) was added under an argon atmosphere to dissolve the reagents. The flask was fitted with a rubber septum and a nitrogen balloon. The reaction mixture was stirred at room temperature for 1 h. Thereafter, imine 78a (271 mg, 1.00 mmoL) was added to the catalyst solution and stirred for 5 min. To this solution was rapidly added ethyl diazoacetate (EDA) 85 (124 µL, 1.20 mmoL, 1.2 equiv). The resulting mixture was stirred for 24 h at room temperature. The reaction was dilluted by addition of hexane (6 mL). The resulting solution was then concentrated in vacuo followed by exposure to high vacuum (0.05 mm Hg) for 1 h to afford the crude aziridine as an off-white solid. Purification of the crude aziridine by silica gel chromatography (30 mm × 300 mm column, 19:1 hexanes/EtOAc as eluent, gravity column) afforded pure cis-aziridine 86a as a white solid (mp. 127.5-128.5 °C) in 80% isolated yield (286 mg, 0.800 mmol); cis/trans: 27:1. Enamine side products: 10% yield of enamines. The optical purity of 86a was determined to be 89% ee by HPLC analysis (CHIRALCEL OD-H column, 90:10 hexane/2-propanol at 226 nm, flow-rate: 0.7 mL/min): retention times; Rt = 9.01 min (major enantiomer, 86a) and Rt = 4.67 min (minor enantiomer, ent-86a). Same procedure was followed to do MCAZ for other bases. 7.15.10 MCAZ using BH3•Me2S as the boron source: Procedures (Iʹ′-III) (Table 7.10) 668 A) Procedure Iʹ′: 5 mol% (S)-VAPOL 1. PhOH (10 mol%) 2. amine 126a (100 mol%) 3. toluene (2 mL) 4. BH3•Me2S (15 mol%) 5. H2O (15 mol%) 6. 4 Å MS (p) 7. O H O OEt N2 85 120 mol% 25 °C 25 °C, 1 h 127a 105 mol% 25 °C, 24 h N CO2Et 86a (2R,3R)-ethyl 1-benzhydryl-3-phenylaziridine-2-carboxylate 86a: To a 10 mL flame-dried single-necked round bottom flask equipped with a stir bar and filled with argon was added (S)VAPOL (27 mg, 0.05 mmol), PhOH (9.4 mg, 0.10 mmol) and amine 126a (183.3 mg, 1.00 mmol). Dry toluene (2 mL) was added under an argon atmosphere to dissolve the reagents. The flask was fitted with a rubber septum and a nitrogen balloon. To this mixture was added BH3•Me2S (75 µL, 0.15 mmol, 2.0 M in toluene) and H2O (2.7 µL, 0.15 mmol). The reaction mixture was stirred at room temperature for 1 h. Thereafter, 4Å Molecular Sieves (300 mg, freshly flame-dried) was added followed by the addition of the aldehyde 127a (104 µL, 1.05 mmoL, 1.05 equiv). To this solution was rapidly added ethyl diazoacetate (EDA) 85 (124 µL, 1.20 mmoL, 1.2 equiv). The resulting mixture was stirred for 24 h at room temperature. The reaction was dilluted by addition of hexane (6 mL). The reaction mixture was then filtered through a Celite pad to a 100 mL round bottom flask. The reaction flask was rinsed with EtOAc (3 mL × 3) and the rinse was filtered through the same Celite pad. The resulting solution was then concentrated in vacuo followed by exposure to high vacuum (0.05 mm Hg) for 1 h to afford 1 the crude reaction mixture. The H NMR analysis of crude reaction mixture revealed no presence of aziridine and only imine 78a was observed. 669 B) Procedure I: 5 mol% (S)-VAPOL 1. PhOH (10 mol%) 2. amine 126a (100 mol%) 3. toluene (2 mL) 4. BH3•Me2S (15 mol%) 5. H2O (15 mol%) 100 °C, 1 h 6. 4 Å MS (p) 7. O O H 127a 105 mol% OEt N2 85 120 mol% 25 °C 25 °C, 24 h N CO2Et 86a (2R,3R)-ethyl 1-benzhydryl-3-phenylaziridine-2-carboxylate 86a: Same as procedure Iʹ′ except that the temperature of the catalyst preparation was 100 ºC. Purification of the crude aziridine by silica gel chromatography (30 mm × 300 mm column, 19:1 hexanes/EtOAc as eluent, gravity column) afforded pure cis-aziridine 86a as a white solid (mp. 127.5-128.5 °C) in 82% isolated yield (293 mg, 0.820 mmol); cis/trans: 50:1. Enamine side products: 7% yield of enamines. The optical purity of 86a was determined to be 95% ee by HPLC analysis (CHIRALCEL OD-H column, 90:10 hexane/2-propanol at 226 nm, flow-rate: 0.7 mL/min): retention times; Rt = 9.01 min (major enantiomer, 86a) and Rt = 4.67 min (minor enantiomer, ent-86a). C) Procedure II: 5. amine 126c (100 mol%) 25 °C, 1 h 6. 4 Å MS (p) 7. O 5 mol% (S)-VAPOL 1. PhOH (10 mol%) H 2. toluene (2 mL) 3. BH3•Me2S (15 mol%) 127a 105 mol% 4. H2O (15 mol%) 100 °C, 1 h 25 °C O OEt N2 85 120 mol% 25 °C, 24 h MeO OMe N CO2Et 114a 670 (2R,3R)-ethyl-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-phenylaziridine-2carboxylate 114a: To a 10 mL flame-dried home-made Schlenk flask, prepared from a singlenecked 25 mL pear-shaped flask that had its 14/20 glass joint replaced with a high vacuum threaded Teflon valve, equipped with a stir bar and filled with argon was added (S)-VAPOL (27 mg, 0.05 mmol), PhOH (9.4 mg, 0.10 mmol). Under an argon flow through the side-arm of the Schlenk flask, dry toluene (2 mL) was added through the top of the Teflon valve to dissolve the reagents and this was followed by the addition of BH3•Me2S (75 µL, 0.15 mmol, 2.0 M in toluene) and H2O (2.7 µL, 0.15 mmol). The flask was sealed by closing the Teflon valve, and then placed in an 100 ºC (oil bath) for 1 h. The flask was then allowed to cool to room temperature and opened to argon through the side-arm of the Schlenk flask. To the flask containing the pre-catalyst was added the amine 126c (299.4 mg, 1.000 mmol) under an argon flow through side-arm of the Schlenk flask. The flask was sealed by closing the Teflon valve, and then the resulting mixture was allowed to stir at room temperature for 1 h. The flask was then open to argon through side-arm of the Schlenk flask. To the flask containing the precatalyst was added the 4Å Molecular Sieves (300 mg, freshly flame-dried) and aldehyde 127a (104 µL, 1.05 mmoL, 1.05 equiv). To this solution was rapidly added ethyl diazoacetate (EDA) 85 (124 µL, 1.20 mmoL, 1.2 equiv). The resulting mixture was stirred for 24 h at room temperature. After 24 h, the reaction was dilluted by addition of hexane (6 mL). The reaction mixture was then filtered through a Celite pad to a 100 mL round bottom flask. The reaction flask was rinsed with EtOAc (3 mL × 3) and the rinse was filtered through the same Celite pad. The resulting solution was then concentrated in vacuo followed by exposure to high vacuum (0.05 mm Hg) for 1 h to afford the crude aziridine as an off-white solid. Purification of the crude 671 aziridine by silica gel chromatography (30 mm × 300 mm column, 9:1 hexanes/EtOAc as eluent, gravity column) afforded pure cis-aziridine 114a as a white solid (mp 107-108 ºC on 99.8% ee material) in 90% isolated yield (426 mg, 0.9 mmol); cis/trans: >50:1. Enamine side products: <1% yield of 118a and <1% yield of 119a. The optical purity of 114a was determined to be 97% ee by HPLC analysis (CHIRALCEL OD-H column, 99:1 hexane/2-propanol at 226nm, flow-rate: 0.7 mL/min): retention times; Rt = 9.26 min (major enantiomer, 114a) and Rt = 12.52 min (minor enantiomer, ent-114a). D) Procedure III: 5 mol% (S)-VAPOL 1. PhOH (10 mol%) 2. toluene (2 mL) 3. BH3•Me2S (15 mol%) 4. H2O (15 mol%) 100 °C, 1 h then 0.5 mm Hg 100 °C, 0.5 h 5. amine 126c (100 mol%) toluene (2 mL) 25 °C, 1 h 6. 4 Å MS (p) 7. O H O 127a 105 mol% OEt N2 85 120 mol% 25 °C MeO OMe 25 °C, 24 h N CO2Et 114a (2R,3R)-ethyl-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-phenylaziridine-2carboxylate 114a: Same as procedure II except that after 1 h of the stirring of the reaction mixture containing (S)-VAPOL (27 mg, 0.05 mmol), PhOH (9.4 mg, 0.10 mmol), BH3•Me2S (75 µL, 0.15 mmol, 2.0 M in toluene) and H2O (2.7 µL, 0.15 mmol), a vacuum (0.5 mm Hg) was carefully applied by slightly opening the Teflon valve to remove the volatiles. After the volatiles are removed completely, a full vacuum is applied and is maintained for a period of 30 min at a temperature of 100 ºC (oil bath). The flask was then allowed to cool to room temperature and 672 opened to argon through the side-arm of the Schlenk flask. To the flask containing the precatalyst was added the amine 126c (299.4 mg, 1.000 mmol) and toluene (1 mL) under an argon flow through side-arm of the Schlenk flask. The flask was sealed by closing the Teflon valve, and then the resulting mixture was allowed to stir at room temperature for 1 h. The procedure is similar to procedure to II from this point. Purification of the crude aziridine by silica gel chromatography (30 mm × 300 mm column, 9:1 hexanes/EtOAc as eluent, gravity column) afforded pure cis-aziridine 114a as a white solid (mp 107-108 ºC on 99.8% ee material) in 89% isolated yield (422 mg, 0.89 mmol); cis/trans: >50:1. Enamine side products: <1% yield of 118a and <1% yield of 119a. The optical purity of 114a was determined to be 97% ee by HPLC analysis (CHIRALCEL OD-H column, 99:1 hexane/2-propanol at 226nm, flow-rate: 0.7 mL/min): retention times; Rt = 9.26 min (major enantiomer, 114a) and Rt = 12.52 min (minor enantiomer, ent-114a). 7.15.11 MCAZ using BH3•THF as the boron source: Procedures (I-III) (Table 7.11) A) Procedure I: 5 mol% (S)-VAPOL 1. PhOH (10 mol%) 2. amine 126a (100 mol%) 3. toluene (2 mL) 4. BH3•THF (15 mol%) 5. H2O (15 mol%) 25 °C, 1 h 6. 4 Å MS (p) 7. O H O 127a 105 mol% OEt N2 85 120 mol% 25 °C 25 °C, 24 h N CO2Et 86a 673 (2R,3R)-ethyl 1-benzhydryl-3-phenylaziridine-2-carboxylate 86a: Same as procedure I of 7.14.11 except that the temperature of the catalyst preparation was 25 ºC and BH3•THF was used in place of BH3•Me2S. B) Procedure II: 5. amine 126a (100 mol%) 25 °C, 1 h 5 mol% (S)-VAPOL 1. PhOH (10 mol%) 2. toluene (2 mL) 3. BH3•THF (15 mol%) 4. H2O (15 mol%) 25 °C, 15 min 6. 4 Å MS (p) 7. O H O 127a 105 mol% OEt N2 85 120 mol% 25 °C 25 °C, 24 h N CO2Et 86a (2R,3R)-ethyl 1-benzhydryl-3-phenylaziridine-2-carboxylate 86a: Same as procedure II of 7.14.11 except that the temperature of the catalyst preparation was 25 ºC, time of stirring was 15 min, amine 126a was used and BH3•THF was used in place of BH3•Me2S. C) Procedure III: 5 mol% (S)-VAPOL 1. PhOH (10 mol%) 2. toluene (2 mL) 3. BH3•THF (15 mol%) 4. H2O (15 mol%) 25 °C, 15 min then 0.5 mm Hg 25 °C, 0.5 h 5. amine 126a (100 mol%) toluene (2 mL) 25 °C, 1 h 6. 4 Å MS (p) 7. O H O OEt 127a 105 mol% N2 85 120 mol% 25 °C 25 °C, 24 h N CO2Et 86a 674 (2R,3R)-ethyl 1-benzhydryl-3-phenylaziridine-2-carboxylate 86a: Same as procedure III of 7.14.11 except that the temperature of the catalyst preparation was 25 ºC, time of stirring was 15 min, amine 126a was used and BH3•THF was used in place of BH3•Me2S. 7.15.12 Initial attempts towards multi-component trans-aziridination (Table 7.12) A) Reaction with benzaldehyde 127a and diazoacetamide 123a: O (S)-VANOL (10 mol%) MEDAM NH2 B(OPh)3 (30 mol%) toluene 25 °C, 1 h 126c 1. Ph H 127a MEDAM 4 Å MS, –10 ºC, 1 h N 2. O CONHPh NHPh 125a N2 123a –10 °C, 24 h (2R,3S)-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-N,3-diphenylaziridine-2carboxamide: Aldehyde 127a was reacted with diazoacetamide 123a (85 mg, 0.6 mmol, 1.2 equiv) according to the general aziridination Procedure IIIA described above with (S)-VANOL (22 mg, 0.05 mmol, 10 mol%) as ligand at –20 ºC, to afford trans-aziridine 125a. The mixture containing the catalyst, aldehyde and 4Å MS was stirred for 1 h prior to the addition of 1 diazoacetamide. The H NMR analysis of crude reaction mixture revealed the presence of transaziridine 125a in 43% NMR yield using Ph3CH as the internal standard. No further attempt was made to isolate the aziridine. The trans:cis ratio was found to be 2.2:1. 675 B) Reaction with n-hexadecanal 127p and diazoacetamide 128a: (S)-VANOL (10 mol%) MEDAM NH2 126c O 1. 12 B(OPh)3 (30 mol%) toluene 80 °C, 0.5 h H 127p MEDAM 4 Å MS 2. N O CONHBu 12 NHBu 129p N2 128a –10 °C, 24 h (2R,3S)-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-N-butyl-3-pentadecylaziridine-2carboxamide 129p: Aldehyde 127p was reacted with N-butyl-2-diazoacetamide 128a (85 mg, 0.6 mmol, 1.2 equiv) according to the general aziridination Procedure IIA described above with (S)-VANOL (22 mg, 0.05 mmol, 10 mol%) as ligand at –10 ºC, to afford trans-aziridine 129p. The concentration of the reaction is 0.2 M in amine 126c. Purification of the crude aziridine by silica gel chromatography (30 mm × 300 mm column, 5:1 hexanes/Et2O as eluent, gravity column) afforded trans-aziridine 129p as a colorless viscous liquid in 70% isolated yield (222 mg, 0.350 mmol). The optical purity of 129p was determined to be 93% ee by HPLC analysis (CHIRALPAK AD column, 90:10 hexane/2-propanol at 222 nm, flow-rate: 0.7 mL/min): retention times; Rt = 5.11 min (major enantiomer, 129p) and Rt = 8.93 min (minor enantiomer, ent-129p). Spectral data for 129p: Rf = 0.34 (1:1 Et2O / hexanes). 1 H-NMR (CDCl3, 500 MHz): δ 0.88 (t, J = 5.7 Hz, 3H), 0.90 (t, J = 6.0 Hz, 3H), 1.20-1.29 (m, 30H), 1.42 (dd, J = 14.5, 7.4 Hz, 2H), 1.48-1.53 (m, 1H), 2.04 (d, J = 2.9 Hz, 1H), 2.21 (s, 6H), 2.27 (s, 6H), 2.99 (dtd, J = 13.3, 6.8, 676 5.2 Hz, 1H), 3.34 (dq, J = 13.6, 6.9 Hz, 1H), 3.66 (s, 3H), 3.68 (s, 3H), 4.10 (s, 1H), 6.63 (dd, J = 7.1, 5.0 Hz, 1H), 6.94 (s, 2H), 7.07 (s, 2H); 13 C-NMR (CDCl3, 126 MHz): δ 13.71, 14.04, 16.14, 16.22, 19.85, 22.62, 26.03, 28.06, 29.25, 29.29, 29.41, 29.44, 29.58, 29.59, 29.63, 31.81, 3 31.86, 38.23, 44.79, 47.29, 59.44, 59.52, 67.54, (3 sp carbon not located), 126.88, 127.60, 130.45, 130.63, 138.53, 138.55, 155.76, 156.04, 170.45; IR (thin film) 3312br, 2926vs, 2855vs, -1 + 1647s, 1484s, 1221s, 1143s cm ; HRMS (ESI-TOF) m/z 635.5151 [(M+H ); calcd. for C41H67N2O3: 635.5152]; [α ]20 –22.0 (c 1.0, CH2Cl2) on 93% ee material. D C) Reaction with 3-phenylpropiolaldehyde 102a and diazoacetamide 128a: € (S)-VANOL (10 mol%) MEDAM NH2 126c H Ph B(OPh)3 (30 mol%) toluene 80 °C, 0.5 h O 1. MEDAM 102a 4 Å MS 2. N O CONHBu NHBu Ph 130a N2 128a –20 °C, 24 h (2S,3S)-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-N-butyl-3-(phenylethynyl)aziridine2-carboxamide 130a: Aldehyde 102a was reacted with N-butyl-2-diazoacetamide 128a (85 mg, 0.6 mmol, 1.2 equiv) according to the general aziridination Procedure IIA described above with (S)-VANOL (22 mg, 0.05 mmol, 10 mol%) as ligand at –20 ºC, to afford cis-aziridine 130a. The concentration of the reaction is 0.2 M in amine 126c. Purification of the crude aziridine by silica gel chromatography (30 mm × 300 mm column, 2:1 to 1:1 hexanes/Et2O as eluent) afforded cis- 677 aziridine 130a (mp. 68-71 ºC on 88% ee material) as a yellow solid in 89% isolated yield (234 mg, 0.450 mmol). The optical purity of 130a was determined to be 88% ee by HPLC analysis (CHIRALPAK AD column, 90:10 hexane/2-propanol at 222nm, flow-rate: 0.7 mL/min): retention times; Rt = 10.76 min (major enantiomer, 130a) and Rt = 19.48 min (minor enantiomer, ent-130a). Spectral data for 130a: Rf = 0.07 (1:5 EtOAc / hexanes). 1 H-NMR (CDCl3, 500 MHz): δ 0.80 (t, J = 7.3 Hz, 3H), 1.20-1.32 (m, 2H), 1.35-1.52(m, 2H), 2.25 (s, 6H), 2.29 (s, 6H), 2.58 (d, J = 6.6 Hz, 1H), 2.66 (d, J = 6.6 Hz, 1H), 3.25-3.18 (m, 1H), 3.27-3.33 (m, 1H), 3.68 (s, 1H), 3.70 (s, 3H), 3.72 (s, 3H), 6.71 (t, J = 6.1 Hz, 1H), 6.95 (s, 2H), 7.11 (s, 2H), 7.29-7.32 (m, 3H), 7.39 (dd, J = 7.4, 2.1 Hz, 2H); 13 C-NMR (CDCl3, 125 MHz): δ 13.62, 16.15, 16.25, 19.90, 31.91, 35.38, 38.63, 46.08, 59.51, 59.57, 75.64, 82.62, 84.44, 122.44, 127.39, 127.78, 128.21, 128.43, 130.68, 130.87, 131.79, 136.74, 136.92, 156.06, 156.38, 167.11. These spectral data matched those previously reported for this compound. MeO OMe 18 (2S,3S)-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-Nbutyl-3-(hept-1-yn-1-yl)aziridine-2-carboxamide Aldehyde 102b was reacted with N-butyl-2-diazoacetamide N CONHBu C5H11 130b 130b: 128a (85 mg, 0.6 mmol, 1.2 equiv) according to the general aziridination Procedure IIA described above with (S)-VANOL (22 mg, 0.05 mmol, 10 mol%) as ligand at –20 ºC, to afford cis-aziridine 130b. The concentration of the reaction is 0.2 M in amine 126c. Purification of the crude aziridine by silica 678 gel chromatography (30 mm × 300 mm column, 2:1 to 1:1 hexanes/Et2O as eluent) afforded cisaziridine 130b (mp. 90-92 ºC on 88% ee material) as a yellow solid in 70% isolated yield (182 mg, 0.350 mmol). The optical purity of 130b was determined to be 88% ee by HPLC analysis (CHIRALPAK AD column, 90:10 hexane/2-propanol at 222nm, flow-rate: 0.7 mL/min): retention times; Rt = 12.45 min (major enantiomer, 130b) and Rt = 30.86 min (minor enantiomer, ent-130b). Spectral data for 130b: Rf = 0.17 (1:5 EtOAc / hexanes). 1 H-NMR (CDCl3, 500 MHz): δ 0.90 (td, J = 7.2, 2.9 Hz, 6H), 1.25-1.38 (m, 8H), 1.42-1.50 (m, 4H), 2.16-2.13 (m, 2H), 2.23 (s, 6H), 2.27 (s, 6H), 3.15 (dq, J = 13.1, 6.6 Hz, 1H), 3.31 (dq, J = 13.7, 6.9 Hz, 1H), 3.57 (s, 1H), 3.68 (s, 3H), 3.70 (s, 3H), 6.62 (t, J = 6.1 Hz, 1H), 6.90 (s, 2H), 7.05 (s, 2H); 13 C-NMR (CDCl3, 125 MHz): δ 13.76, 13.89, 16.15, 16.23, 18.69, 19.91, 22.14, 28.27, 30.91, 31.87, 35.41, 38.52, 45.61, 59.53, 59.58, 74.97, 75.65, 83.50, 127.37, 127.83, 130.58, 130.80, 136.93, 137.10, 155.98, - 156.32, 167.42; IR (thin film) 3401br, 2957vs, 2932vs, 2241w, 1680s, 1485s, 1223s, 1147s cm 1 + ; HRMS (ESI-TOF) m/z 519.3597 [(M+H ); calcd. for C33H47N2O3: 519.3587]; [α ]20 +23.0 D (c 0.78, CH2Cl2) on 88% ee material. € MeO OMe (2S,3S)-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-Nbutyl-3-(triisopropylsilyl)ethynyl)aziridine-2-carboxamide 130c: N Aldehyde CONHBu TIPS 130c 679 102c was reacted with N-butyl-2- diazoacetamide 128a (85 mg, 0.6 mmol, 1.2 equiv) according to the general aziridination Procedure IIA described above with (S)-VANOL (22 mg, 0.05 mmol, 10 mol%) as ligand at –20 ºC, to afford cis-aziridine 130a. The concentration of the reaction is 0.2 M in amine 126c. Purification of the crude aziridine by silica gel chromatography (30 mm × 300 mm column, 6:1 hexanes/EtOAc as eluent) afforded cis-aziridine 130c (mp. 62-64 ºC on 88% ee material) as a yellow solid in 93% isolated yield (281 mg, 0.465 mmol). The optical purity of 130c was determined to be 88% ee by HPLC analysis (CHIRALPAK AD column, 90:10 hexane/2propanol at 222nm, flow-rate: 0.7 mL/min): retention times; Rt = 9.59 min (major enantiomer, 130c) and Rt = 6.20 min (minor enantiomer, ent-130c). 1 Spectral data for 130c: Rf = 0.28 (1:5 EtOAc/ hexanes). H-NMR (CDCl3, 500 MHz): δ 0.89 (t, J = 7.3 Hz, 3H), 1.02-1.07 (m, 21H), 1.24-1.29 (m, 2H), 1.39-1.49 (m, 2H), 2.19-2.30 (m, 14H), 2.88-2.94 (m, 1H), 3.49 (dt, J = 13.7, 7.0 Hz, 1H), 3.59 (s, 1H), 3.68 (s, 3H), 3.70 (s, 3H), 6.62 (dd, J = 7.5, 4.1 Hz, 1H), 6.90 (s, 2H), 7.08 (s, 2H); 13 C-NMR (CDCl3, 125 MHz): δ 11.07, 13.70, 16.11, 16.18, 18.52, 18.54, 19.86, 31.51, 35.77, 38.64, 45.85, 59.50, 59.57, 75.59, 84.13, 102.19, 127.16, 127.81, 130.64, 130.88, 136.81, 137.07, 155.97, 156.41, 166.97; IR (thin film) -1 3401br, 2943vs, 2866vs, 1680s, 1484s, 1223s, 1147s cm ; HRMS (ESI-TOF) m/z 605.4129 + [(M+H ); calcd. for C37H57N2O3: 605.4138]; [α ]20 +52.1 (c 1.0, CH2Cl2) on 88% ee material. D € 680 REFERENCES 681 REFERENCES (1) (a) de Graaff, C.; Ruijter, E.; Orru, R. V. A. Chem. Soc. Rev. 2012, 41, 3969-4009. (b) Guillena, G.; Ramon, D. J.; Yus, M. Tetrahedron: Asymmetry 2007, 18, 693-700. (c) Ramon, D. J.; Yus, M. Angew. Chem., Int. Ed. 2005, 44, 1602-1634. (d) Multicomponent Reactions; Zhu, J.; Bienayme, H., Eds.; Wiley-VCH: Weinheim, 2005. (2) Osborn, H. M. I.; Sweeney, J. Tetrahedron: Asymmetry 1997, 8, 1693-1715. (3) (a) Pellissier, H. Tetrahedron 2010, 66, 1509-1555. (b) Müller, P.; Fruit, C. Chem. Rev. 2003, 103, 2905-2919. (4) (a) Evans, D. A.; Faul, M. M.; Bilodeau, M. T.; Anderson, B. A.; Barnes, D. M. J. Am. Chem. Soc. 1993, 115, 5328-5329. (b) Li, Z.; Conser, K. R.; Jacobsen, E. N. J. Am. Chem. Soc. 1993, 115, 5326-5327. (c) Noda, K.; Hosoya, N.; Irie, R.; Ito, Y.; Katsuki, T. Synlett 1993, 469-471. (d) Subbarayan, V.; Ruppel, J. V.; Zhu, S.; Perman, J. A.; Zhang, X. P. Chem. Commun. 2009, 4266-4268. (e) Kawabata, H.; Omura, K.; Uchida, T.; Katsuki, T. Chem.–Asian. J. 2007, 2, 248256. (5) Deiana, L.; Dziedzic, P.; Zhao, G. L.; Vesely, J.; Ibrahem, I.; Rios, R.; Sun, J. L.; Cordova, A. Chem.–Eur. J. 2011, 17, 7904-7917. (6) (a) Hansen, K. B.; Finney, N. S.; Jacobsen, E. N. Angew. Chem., Int. Ed. 1995, 34, 676-678. (b) Aggarwal, V. K.; Ferrara, M.; O'Brien, C. J.; Thompson, A.; Jones, R. V. H.; Fieldhouse, R. J. Chem. Soc., Perkin Trans. 1 2001, 1635-1643. (c) Aggarwal, V. K.; Alonso, E.; Fang, G. Y.; Ferrara, M.; Hynd, G.; Porcelloni, M. Angew. Chem., Int. Ed. 2001, 40, 1433-1436. (d) Aggarwal, V. K.; Winn, C. L. Acc. Chem. Res. 2004, 37, 611-620. (7) (a) Casarrubios, L.; Perez, J. A.; Brookhart, M.; Templeton, J. L. J. Org. Chem. 1996, 61, 8358-8359. (b) G. Rasmussen, K.; Anker Jorgensen, K. J. Chem. Soc., Perkin Trans. 1 1997, 1287-1292. (c) Juhl, K.; G. Hazell, R.; Anker Jorgensen, K. J. Chem. Soc., Perkin Trans. 1 1999, 2293-2297. (d) Mayer, M. F.; Hossain, M. M. J. Organomet. Chem. 2002, 654, 202-209. (e) Morales, D.; Pérez, J.; Riera, L.; Riera, V.; Corzo-Suárez, R.; García-Granda, S.; Miguel, D. Organometallics 2002, 21, 1540-1545. (f) Krumper, J. R.; Gerisch, M.; Suh, J. M.; Bergman, R. G.; Tilley, T. D. J. Org. Chem. 2003, 68, 9705-9710. (g) Redlich, M.; Hossain, M. M. Tetrahedron Lett. 2004, 45, 8987-8990. (8) (a) Williams, A. L.; Johnston, J. N. J. Am. Chem. Soc. 2004, 126, 1612-1613. (b) Wipf, P.; Lyon, M. A. ARKIVOC 2007, xii, 91-98. (c) Hashimoto, T.; Uchiyama, N.; Maruoka, K. J. Am. 682 Chem. Soc. 2008, 130, 14380-14381. (d) Akiyama, T.; Suzuki, T.; Mori, K. Org. Lett. 2009, 11, 2445-2447. (e) Zeng, X.; Zeng, X.; Xu, Z.; Lu, M.; Zhong, G. Org. Lett. 2009, 11, 3036–3039. (f) Johnston, J. N.; Muchalski, H.; Troyer, T. L. Angew. Chem., Int. Ed. 2010, 49, 2290-2298. (9) (a) Zhang, Y.; Desai, A.; Lu, A.; Hu, G.; Ding, Z.; Wulff, W. D. Chem. –Eur. J. 2008, 14, 3785-3803. (b) Zhang, Y.; Lu, Z.; Desai, A.; Wulff, W. D. Org. Lett. 2008, 10, 5429-5432. (c) Mukherjee, M.; Gupta, A. K.; Lu, Z.; Zhang, Y.; Wulff, W. D. J. Org. Chem. 2010, 75, 56435660. (d) Ren, H.; Wulff, W. D. Org. Lett. 2010, 12, 4908-4911. (e) Hu, G.; Huang, L.; Huang, R. H.; Wulff, W. D. J. Am. Chem. Soc. 2009, 131, 15615-15617. (f) Hu, G.; Gupta, A. K.; Huang, R. H.; Mukherjee, M.; Wulff, W. D. J. Am. Chem. Soc. 2010, 132, 14669–14675. (g) Desai, A. A.; Wulff, W. D. J. Am. Chem. Soc. 2010, 132, 13100-13103. (h) Vetticatt, M. J.; Desai, A. A.; Wulff, W. D. J. Am. Chem. Soc. 2010, 132, 13104-13107. (i) Desai, A. A.; MoránRamallal, R.; Wulff, W. D. Org. Synth. 2011, 88, 224-237. (10) (a) Nagayama, S.; Kobayashi, S. Chem. Lett. 1998, 685-686. (b) Kubo, T.; Sakaguchi, S.; Ishii, Y. Chem. Commun. 2000, 625-626. (c) Yadav, J. S.; Reddy, B. V. S.; Rao, M. S.; Reddy, P. N. Tetrahedron Lett. 2003, 44, 5275-5278. (d) Yadav, J. S.; Reddy, B. V. S.; Reddy, P. N.; Rao, M. S. Synthesis 2003, 1387-1390. (e) Ishii, Y.; Sakaguchi, S. Bull. Chem. Soc. Jpn. 2004, 77, 909-920. (11) (a) Minakata, S.; Ando, T.; Nishimura, M.; Ryu, I.; Komatsu, M. Angew. Chem., Int. Ed. 1998, 37, 3392-3394. (b) Nishimura, M.; Minakata, S.; Takahashi, T.; Oderaotoshi, Y.; Komatsu, M. J. Org. Chem. 2002, 67, 2101-2110. (12) Gupta, A. K.; Mukherjee, M.; Wulff, W. D. Org. Lett. 2011, 13, 5866-5869. (13) Gupta, A. K.; Mukherjee, M.; Hu, G.; Wulff, W. D. J. Org. Chem. 2012, ASAP. (14) Wulff, W. D.; Antilla, J. A.; Pulgam, V. R.; Zhang, Y.; Gilson-Osminksi, W., Unpublished results. (15) (a) Ismail, F. M. D.; Levitsky, D. O.; Dembitsky, V. M. Eur. J. Med. Chem. 2009, 44, 33733387. (b) Kabara, J.; Vrable, R.; Lie Ken Jie, M. Lipids 1977, 12, 753-759. (c) Metzger, J. O.; Fürmeier, S. Eur. J. Org. Chem. 1999, 661-664. (d) Falck, J. R.; Manna, S.; Viala, J.; Siddhanta, A. K.; Moustakis, C. A.; Capdevila, J. Tetrahedron Lett. 1985, 26, 2287-2290. (e) Howell, A. R.; So, R. C.; Richardson, S. K. Tetrahedron 2004, 60, 11327-11347. (16) Newman, C. A.; Antilla, J. C.; Chen, P.; Predeus, A. V.; Fielding, L.; Wulff, W. D. J. Am. Chem. Soc. 2007, 129, 7216-7217. 683 (17) (a) Li, W.; Wang, J.; Hu, X.; Shen, K.; Wang, W.; Chu, Y.; Lin, L.; Liu, X.; Feng, X. J. Am. Chem. Soc. 2010, 132, 8532-8533. (b) Hashimoto, T.; Miyamoto, H.; Naganawa, Y.; Maruoka, K. J. Am. Chem. Soc. 2009, 131, 11280-11281. (c) Liu, W. J.; Lv, B. D.; Gong, L. Z. Angew. Chem., Int. Ed. 2009, 48, 6503-6506. (d) Trost, B. M.; Malhotra, S.; Fried, B. A. J. Am. Chem. Soc. 2009, 131, 1674-+. (e) Hashimoto, T.; Naganawa, Y.; Maruoka, K. J. Am. Chem. Soc. 2008, 130, 2434-2435. (f) Hasegawa, K.; Arai, S.; Nishida, A. Tetrahedron 2006, 62, 1390-1401. (g) Dudley, M. E.; Morshed, M. M.; Brennan, C. L.; Islam, M. S.; Ahmad, M. S.; Atuu, M.-R.; Branstetter, B.; Hossain, M. M. J. Org. Chem. 2004, 69, 7599-7608. (h) Yao, W.; Wang, J. Org. Lett. 2003, 5, 1527-1530. (i) Jiang, N.; Wang, J. B. Tetrahedron Lett. 2002, 43, 1285-1287. (j) Mahmood, S. J.; Hossain, M. M. J. Org. Chem. 1998, 63, 3333-3336. (k) Holmquist, C. R.; Roskamp, E. J. J. Org. Chem. 1989, 54, 3258-3260. (l) Zhu, Z.; Espenson, J. H. J. Org. Chem. 1995, 60, 7090-7091. (m) Curini, M.; Epifano, F.; Marcotullio, Maria C.; Rosati, O. Eur. J. Org. Chem. 2002, 1562-1565. (n) Zhu, Z.; Espenson, J. H. J. Am. Chem. Soc. 1996, 118, 9901-9907. (18) Guan, Y.; Wulff, W. D., Unpublished results. (19) Mukherjee, M.; Gupta, A. K.; Wulff, W. D. Org. Lett. 2012, manuscript in preparation. (20) Zhou, Y.; Wulff, W. D., Unpublished results. (21) Favrot, J.; Vocelle, D.; Sandorfy, C. Photochem. Photobiol. 1979, 30, 417-421. (22) Ren, H.; Wulff, W. D. J. Am. Chem. Soc. 2011, 133, 5656-5659. (23) Gilson-Osminksi, W.; Wulff, W. D., Unpublished results. (24) Li, X.; Burrell, C. E.; Staples, R. J.; Borhan, B. J. Am. Chem. Soc. 2012, 134, 9026-9029. (25) Friedman, L.; Shechter, H. J. Org. Chem. 1961, 26, 2522-2524. (26) Mukherjee, M.; Wulff, W. D., Unpublished results. (27) Zhao, W.; Wulff, W. D., Unpublished results. (28) Katritzky, A. R.; Fan, W. Q.; Li, Q. L. Tetrahedron Lett. 1987, 28, 1195-1198. 684 (29) (a) Chem. Eng. News. 2011, 89, 25. (b) McLaughlin, M.; Widegren, M.; Ramirez, A.; Richardson, P.; Zlota, A.; Laird, T. Org. Process Res. Dev. 2012, 16, 3-10. (30) Lu, Z.; Zhang, Y.; Wulff, W. D. J. Am. Chem. Soc. 2007, 129, 7185-7194. (31) Deng, L.; Jacobsen, E. N. J. Org. Chem. 1992, 57, 4320-4323. (32) Bolvig, S.; Hansen, P. E. Magn. Reson. Chem. 1996, 34, 467-478. 685 CHAPTER 8   SULFOX-BOROX CATALYSIS CATALYTIC ASYMMETRIC EPOXIDATION OF ALDEHYDES I think you can just a write a small chapter on this and someone else would take it further. -William D. Wulff 8.1 Introduction The field of asymmetric catalysis and organic synthesis has been enriched with many breakthrough developments in the last fifty years. One of those moments was the development of the Sharpless asymmetric epoxidation of allylic alcohols for the synthesis of the chiral epoxides. 1 When any modern day synthetic organic chemist ponders the construction of a typical organic molecule, that chemist’s thought process will reflexively consider how a disconnection can be sought to a Sharpless asymmetric epoxidation. In addition, this thought process will also include a similar analysis for many of the more recent asymmetric epoxidations 2 3 4 5 including the Jacobsen and Katsuki epoxidations, the Shi epoxidation and many others. It is now also instinctive for the synthetic organic chemist to analyze a retro-synthesis in terms any possible asymmetric catalytic kinetic resolution of epoxides due to the great applicability and reliability of the Jacobsen hydrolytic kinetic resolution process. 6 Clearly asymmetric catalysis has had a great impact on the way chemist think about using epoxides in making organic molecules. In all, chiral epoxides are highly versatile synthetic intermediates and for this reason a great deal of effort has been expended over the last three or four decades by both academic and 686 commercial laboratories to develop more catalytic asymmetric methods for the preparation of epoxides. 5 The following chapter describes a novel method for the catalytic asymmetric synthesis of epoxides from aldehydes using our new SULFOX-BOROX catalyst. 8.2 Previous approaches towards catalytic asymmetric synthesis of epoxides With the advent of vast applications of epoxides, a new method for the catalytic asymmetric synthesis of epoxides surfaces at regular intervals. Likewise the case of aziridines, there are primarily two approaches: a) oxidation of olefins using i) metal catalysts organocatalysis organocatalysis 4,8 1-3,5a,5c,7 ii) 9 ; oxidation of α,β-unsaturated carbonyl compounds using i) metal catalysts ii) 10 (Darzens reaction) b) addition of carbon to the aldehydes via i) α-halo enolate epoxidation 11 ii) metal-carbene transfer (carbene generated from sulfur ylides) 12 13 reaction of a diazo compound with an aldehyde activated by Lewis acid (Scheme 8.1). iii) a The former approach of oxidation of olefins has been benefitted from pioneering contributions from Sharpless, 1 Jacobsen 2,7e 3,7e and Katsuki epoxidation using metal catalysis and from Shi 4 epoxidation using organocatalysis. Yamamoto and coworkers have also reported epoxidation of allylic alcohols using various chiral Lewis acids. 7c,7d 687 Scheme 8.1 Different approaches towards catalytic asymmetric epoxidation R1 R2 R4 R3 R1 R4 Dioxirane RCOOH NaOCl RCO3H PhIO R1 O R2 chiral catalyst R4 * * R3 NaOCl RCOOH RCO3H chiral catalyst O O R1 R2 H X chiral catalyst R3 O R1 H O R1 chiral catalyst H chiral catalyst O H R5 SR2 O H N2 Y N H Z In terms of the addition of carbon to an aldehyde, one of the early approaches is the Darzens reaction, which involves an α-halo enolate. Very recently, Deng and co-workers reported the first example of a highly successful catalytic asymmetric Darzens reaction between α-chloro ketones and aldehydes using a phase transfer catalyst 421 (Scheme 8.2). 11a It must be noted that they obtained trans- and tri-substituted epoxides. Prior to Deng’s work, Arai and Shiroi have shown the use of cinchona alkaloid derived phase transfer catalyst to obtain only 11c-11g moderate enantioselectivity. Also, in 2007, Jeong and coworkers obtained enantiomeric excess of over 90% for reactions between a highly limited range of aromatic aldehydes and a 11b single nucleophile, α-chloromethyl phenyl sulfone using a phase transfer catalyst. 688 Scheme 8.2 Catalytic asymmetric Darzens reaction 421 (5 mol %) LiOH•H2O (4-6 equiv) O O Cl + R' R 419 11a H O R R' CH2Cl2 0 °C, 24-72 h 127 R' = H, 4-F, 4-Cl, 4-OMe O 420 20 examples Yield = 76–96% ee = 80–99% R = aryl alkyl OH O + N F Br – N F F 421 Aggarwal and coworkers reported asymmetric epoxidation using chiral sulfur ylides as the chiral auxiliaries. However, they did report one example of catalytic asymmetric epoxidation where they utilized chiral sulfide 424 to afford trans-epoxides 423 and 425 (Scheme 8.3). Scheme 8.3 Catalytic asymmetric epoxidation using sulfur ylides Ph N – N 422a + Na Ts + R1 12 Rh2(OAc)4 (1 mol%) Sulfide 424 (5-20 mol%) O H 127 R1 = aryl, alkyl olefin BnEt3N+Cl– (5-10 mol%) CH3CN 40 °C, 24-48 h 689 12 O R1 Ph 423 16 examples Yield = 21–100% ee = 87–94% t/c = 3:1 to ≥98:2 Scheme 8.3 cont’d R2 N – N + Na Ts Rh2(OAc)4 (1 mol%) Sulfide 424 (5-100 mol%) O + Ph 422 BnEt3N+Cl– (0-20 mol%) various solvents 20-40 °C H 127a R2 = aryl, olefin O R2 Ph 425 19 examples Yield = 10–95% ee = 20–94% t/c = 1:1 to ≥98:2 S O 424 R1CHO + – * R2S–CHR2 Rh2(OAc)4 O R1 * R2S R2 [Rh]=CHR2 + – R2CHN2 + Na Ts + – BnEt3N Cl 40 °C + – Na N N2 R2 N Ts More recently, Gong and coworkers reported the first example of asymmetric epoxidation of aldehydes involving diazoacetamides as the nucleophile to afford cis-epoxides 426 in high yields and ees (Scheme 8.3). 13 They used chiral Lewis acids derived from either a combination i n of (R)-BINOL 55 and Ti(O Pr)4 or (R)-3,3ʹ′-I2-BINOL 56e and Zr(O Bu)4. Interestingly, they observed opposite enantiomers of 426 when they moved from one catalytic system to another using the same enantiomer of the ligands 55 and 56e. 690 Scheme 8.4 Catalytic asymmetric epoxidation using diazoacetamides R (R)-BINOL/Ti(OiPr)4 (10 mol%) O O + H NHPh N2 127 CH2Cl2, 4 Å MS 0 °C,1 h O R 123a 28 examples Yield = 52–95% ee = 87–99% (R)-3,3'-I2-BINOL Zr(OnBu)4 (10 mol%) O O + H 127 CONHPh 426 R = aryl, alkyl R 13 NHPh N2 CH3CN, 3 Å MS 25 °C,1 h O R CONHPh ent-426 123a 26 examples Yield = 73–96% ee = 91–99% R = aryl, alkyl The reaction between aldehyde and diazoacetamide 123a reported by Gong and coworkers is mediated by chiral Lewis acids. There are no examples of this reaction with a chiral Brønsted acid. This is probably due to the high acidity (pKa ~ –7) of protonated aldehydes. With the advent of a variety of BOROX catalysts developed during this doctoral research, we decided to examine novel BOROX catalysts in the case of the catalytic asymmetric epoxidation of the aldehydes. Prior to the screening of our catalyst, we decided to perform a background reaction in the presence of B(OPh)3. It was interesting to observe that the epoxidation reaction is favored with diazoacetamide 123a as compared to diazoester 85 when reacted with benzaldehyde 127a (Scheme 8.5). The reaction of benzaldehyde and 1.14 equiv of ethyl diazoacetate 85 mediated by 14 mol% B(OPh)3 gave the five products shown in Scheme 8.5A with the major 691 component as the β-keto ester 396a and its tautomer 397a in a total of 55% yield. A literature search revealed that several different products including the epoxide 395a (trans-epoxide is major) are known from the reaction of benzaldehyde and EDA mediated by Lewis or Brønsted acids. 14 The same reaction afforded cis-epoxide 426a and β-keto amide 427a in 62% and 9% yield respectively when diazoacetamide 123a was used in the place of diazo ester 85. The cistrans ratio was found to be 10:1. It must be noted that there is no report for the racemic reaction between an aldehyde and the diazoacetamides. Moreover, it was found there was no reaction in the presence of VAPOL or VANOL ligand and in the absence of any catalyst. Hence, the challenges in this case were the high background reaction and the formation of the byproduct in the form of the β-keto amide 427a. These issues have been addressed and are discussed in the subsequent sections. Meanwhile, other diazoacetamides 128a and 128c were also tried for the racemic reaction (Scheme 8.5C). Scheme 8.5 B(OPh)3 catalyzed reaction between benzaldehyde and (A) diazoester 85 (B) diazoacetamide 123a (C) diazoacetamides 128a and 128c A O Ph B(OPh)3 (14 mol%) O + H 127a OEt N2 85 (1.14 equiv) CDCl3, 25 °C, 24 h 0.5M O O OEt Ph Ph OEt O 395a 3% 396a 47% OH O + Ph OH O OEt + H H OEt Ph 398a 1% 397a 8% OH O + Ph OEt N2 399a 2% 692 O + Scheme 8.5 cont’d B O Ph B(OPh)3 (14 mol%) O + NHPh H N2 127a 123a (1.14 equiv) O O NHPh Ph CDCl3, 25 °C, 24 h 0.5 M NHPh Ph O 426a 62% c:t = 10:1 427a 9% OH O + Ph O + OH O NHPh + NHPh H H Ph 428a <1% 429a <1% OH O + Ph NHPh N2 430a <1% C O Ph B(OPh)3 (z mol%) O + NHX H N2 127a (2 equiv) NHX Ph CDCl3, 25 °C, 24 h %z (cat) Conc (M) %y (epoxide) Ph NHX 136a (X=nBu) 445a (X=CHPh2) c:t %y (keto-amide) nBu 20 0.2 50 3.3:1 6 CHPh2 8.3 O + O 135a (X=nBu) 443a (X=CHPh2) 128a (X=nBu) 128c (X=CHPh2) X O O 10 0.4 70 25:1 24 Initial optimization of catalytic asymmetric epoxidation of aldehydes Given the result we got from the background reaction mediated by B(OPh)3, we performed the reaction of diazocetamide 123a with benzaldehyde in the presence of various BOROX catalysts (10 mol%) derived from the VAPOL ligand (Table 8.1, entries 1-4). Low yields and 693 ees were obtained employing the catalysts 215k, 220 and 222a derived from aniline 126k, dimethylacetamide 219 and DMSO 221a, respectively (Table 8.1, entries 2-4). In fact, racemic epoxide was obtained in the case of the catalyst 215k derived from aniline. Interestingly, a slight increase in the asymmetric induction was observed when the SULFOX-BOROX catalyst 432 derived from VANOL was used (Table 8.1, entry 5 vs. 4). A huge jump in the enantioinduction was observed at –40 °C using the catalyst 432 derived from DMSO and the VANOL ligand (Table 8.1, entries 6). As a control, the reaction was also, performed without any base using both the ligands (Table 8.1, entries 1 and 9). An ee of 45% in the case of catalyst 434 derived from the VANOL ligand suggests that there is a possibility of the reaction catalyzed by a BOROX catalyst derived from diazoacetamide 123a. Another viable possibility of its being a chiral Lewis acid catalyzed reaction cannot be excluded. Nonetheless, based on the results obtained from Table 8.1, it seems that the realization of an epoxidation reaction using a novel SULFOXBOROX catalyst was quite possible. Table 8.1 Initial screening of various BOROX catalysts for asymmetric epoxidation reaction O O Ph + H NHPh N2 123a 127a * OH (S)-BOROX catalyst (10 mol%) O Ph CDCl3 Temp, 24 h B(OPh)3 (3 equiv) H2O (3 equiv) OH THF, 80 °C, 1 h (10 mol%) then 0.5 mm Hg 80 °C, 0.5 h + CONHPh Ph O + [H-Base] OPh O –O B B O * O O B OPh (S)-BOROX catalyst O NHPh 427a 426a pre-catalyst 694 Base 1h (S)-BOROX catalyst a * OH OH = (S)-Ligand Table 8.1 cont’d # Ligand Base Cat. Temp (°C) 1 2 (S)-VAPOL (S)-VAPOL none PhNH2 431 215k 25 25 1.2:1 1.2:1 Yield 426a b (%) 20 (25) 35 (36) 3 4 5 6 7 8 (S)-VAPOL (S)-VAPOL (S)-VANOL (S)-VANOL (S)-VANOL (S)-VANOL Me2NCOMe DMSO DMSO DMSO 220 222a 432 432 433 434 25 25 25 –40 –40 –40 1.2:1 1.2:1 1.2:1 1:1.25 1:1.25 1:1.25 29 (31) 20 (27) 35 (41) 50 (56) 57 (71) 40 (48) Me2NCOMe none 127a :123a ee 426a c (%) 13 <1 13 1 20 63 35 45 9:1 8:1 Yield 427a e (%) 5.1 4.2 7:1 10:1 13:1 50:1 50:1 21:1 2.3 3.4 6.2 15.3 5.3 8.6 c/t d a Unless otherwise specified, all reactions were performed with 10 mol% BOROX catalyst. Entries 1-5 were performed with 0.50 mmol diazoacetamide 123a (1.0 equiv, 0.5 M), 0.6 mmol benzaldehyde 127a (1.2 equiv) and entries 6-9 were performed with 0.50 mmol diazo 123a (1.25 equiv), 0.4 mmol benzaldehyde 127a (1.0 equiv, 0.4 M). The pre-catalyst was prepared by heating 1 equiv of (S)-ligand (10 mol%), 3 equiv of commercial B(OPh)3 and and 3 equiv of H2O in THF at 80 °C for 1 h, followed by removing all volatiles under high vacuum (0.1 mm Hg) for 0.5 h at 80 °C. Thereafter, the BOROX catalyst was prepared by b stirring the pre-catalyst with 10 mol % base in CDCl3 for 1 h at 25 °C. Isolated Yield. 1 c Yield in parenthesis determined by H NMR spectra with Ph3CH as internal standard. Determined by HPLC. 1 d Ratio determined by integration of the methine protons of cis- and trans-epoxide in the H NMR spectrum of the crude reaction mixture. e 1 Determined by H NMR spectra with Ph3CH as internal standard. After initial success, we then thought to do an initial screening of various diazoacetamides and the results are presented in Table 8.2. Almost similar ees were obtained irrespective of the diazoacetamide used with 10 mol% catalyst loading. We decided to choose diazoacetamide 123a and 128a for further screening. This was done for two reasons: a) one is aromatic and the other one is aliphatic b) diazoactamide 128a is more soluble than other diazoacetamides. 695 Table 8.2 Initial screening of various diazoacetamides for asymmetric epoxidation. a (S)-SULFOX-BOROX + catalyst 432 [DMSO-H] OPh O O O O (10 mol%) + + O –O B NHX Ph CONHX Ph NHX B CHCl3 O Ph H * N2 O O B –40 °C, 24 h 127a 123a (Ph) OPh 426a (Ph) 427a (Ph) 123b (4-Cl-C6H4) 435a (4-Cl-C6H4) 437a (4-Cl-C6H4) SULFOX-BOROX catalyst 432 128a (nBu) 135a (nBu) 136a (nBu) 128b (Bn) 436a (Bn) 438a (Bn) O * B(OPh)3 (3 equiv) H2O (3 equiv) OH OH THF, 80 °C, 1 h 59 then 0.5 mm Hg (10 mol%) 80 °C, 0.5 h pre-catalyst DMSO 1h Ph Ph (S)-SULFOX-BOROX catalyst 432 OH OH 59 40:1 Yield β-keto amide e (%) 13.6 52 29:1 8.5 50 (55) 62 16:1 13.7 55 (59) 62 >50:1 15.5 # Diazo (X) 1 C6H5 Yield epoxide b (%) 68 (71) 2 4-Cl-C6H4 60 (66) 3 n-C4H9 4 C6H5CH2 ee epoxide c (%) 62 cis/trans d a Unless otherwise specified, all reactions were performed with 10 mol % (S)-SULFOXBOROX catalyst 432 and 0.50 mmol diazoacetamide (1.25 equiv), 0.4 mmol benzaldehyde 127a (1.0 equiv, 0.4 M) at –40 °C in CHCl3. The pre-catalyst was prepared by heating 1 equiv of (S)-VANOL (10 mol %), 3 equiv of commercial B(OPh)3 and 3 equiv of H2O in THF at 80 °C for 1 h, followed by removing all volatiles under high vacuum (0.1 mm Hg) for 0.5 h at 80 °C. Thereafter, the (S)-SULFOX-BOROX catalyst 432 was prepared by stirring b the pre-catalyst with 10 mol % DMSO in CHCl3 for 1 h at 25 °C. Isolated Yield. Yield in 1 c parenthesis determined by H NMR spectra with Ph3CH as internal standard. Determined d by HPLC. Ratio determined by integration of the methine protons of cis- and trans-epoxide 1 in the H NMR spectrum of the crude reaction mixture. with Ph3CH as internal standard. 696 e 1 Determined by H NMR spectra We then examined variations in the temperature and concentration of the epoxidation reaction using the two diazoacetamides 123a and 128a and 10 mol% catalyst loading. The results are presented in Table 8.3. On decreasing the concentration from 0.4 M to 0.2 M, a marginal increase in asymmetric induction was observed in the cases of both diazoacetamides (Table 8.3, entries 1-2 verses 3-4). At this point, we decided to change the solvent from CHCl3 to toluene and a huge increase in the ee up to 91% was observed in the case of diazoacetamide 128a (Table 8.3, entries 4 verses 5). This, probably, can be explained by the assumption that the charged ion-pairs i.e. protonated DMSO (interacting with either of the reactants) and boroxinate anion are more stabilized and separated in a polar solvent (CHCl3) than a non-polar solvent (toluene) due to solvation. However, similar increase in ee (90%) was observed in the case of CHCl3 when the concentration of the reaction was further decreased to 0.1 M (Table 8.3, entry 6). It must be noted that the cis:trans ratio is also higher when toluene is used as the solvent as compared to CHCl3. Nonetheless, we were able to obtain ee up to 97% when the reaction was performed in toluene at –60 °C and 0.1 M with diazoacetamide 128a (Table 8.3, entry 7). It must be noted that the amount of β-keto amide 136a was also minimized during this optimization. However, the major concern was the low yield of the epoxide in almost all the cases. Thereafter, further optimization was carried out using diazoacetamide 128a keeping the temperature at –60 °C and concentration at 0.1 M. 697 a Table 8.3 Screening of diazoacetamides at different concentrations, solvents and temperatures. (S)-SULFOX-BOROX + [DMSO-H] OPh catalyst 432 O O O O (10 mol%) + + O –O B NHX Ph CONHX Ph B O * NHX Solvent Ph H N2 O O B Temp, 24 h OPh 127a 123a (Ph) 426a (Ph) 427a (Ph) nBu) nBu) nBu) 128a ( 135a ( 136a ( SULFOX-BOROX catalyst 432 B(OPh)3 (3 equiv) DMSO OH H2O (3 equiv) OH (S)-SULFOX-BOROX pre-catalyst * * OH OH catalyst 432 1h THF, 80 °C, 1 h 59 then 0.5 mm Hg = (S)-VANOL (10 mol%) 80 °C, 0.5 h O 5 n 6 7 f n n 44 (45) 70 24:1 20.0 0.2 55 (59) 73 31:1 9.8 –40 0.2 46 (50) 91 90:1 7.0 CHCl3 –40 0.1 60 (64) 90 54:1 5.5 PhCH3 –60 0.1 58 (62) 97 >100:1 7.0 50 (55) CHCl3 –40 0.2 Bu CHCl3 –40 Bu PhCH3 Bu Bu Bu Ph 4 13.7 0.4 n n 16:1 –40 Ph Solvent Temp (°C) Conc. (M) CHCl3 1 3 62 0.4 ee epoxide c (%) 62 # 2 40:1 Yield β-keto amide e (%) 13.6 Yield epoxide b (%) 68 (71) Diazo (X) –40 CHCl3 c/t d a Unless otherwise specified, all reactions were performed with 10 mol % (S)-SULFOXBOROX catalyst 432 and 0.50 mmol diazoacetamide (1.25 equiv), 0.4 mmol benzaldehyde 127a (1.0 equiv, C M) at temp °C in the solvent. The pre-catalyst was prepared by heating 1 equiv of (S)-VANOL (10 mol %), 3 equiv of commercial B(OPh)3 and 3 equiv of H2O in THF at 80 °C for 1 h, followed by removing all volatiles under high vacuum (0.1 mm Hg) for 0.5 h at 80 °C. Thereafter, the (S)-SULFOX-BOROX catalyst 432 was prepared by stirring b the pre-catalyst with 10 mol % DMSO in solvent for 1 h at 25 °C. Isolated Yield. Yield in 1 parenthesis determined by H NMR spectra with Ph3CH as internal standard. by HPLC. 1 d c Determined Ratio determined by integration of the methine protons of cis- and trans-epoxide in the H NMR spectrum of the crude reaction mixture. f e with Ph3CH as internal standard. The ratio of 127a:128a is 2:1. 698 1 Determined by H NMR spectra In order to increase the yield of the epoxide 135a, we then thought to vary the equivalents of both components i.e. diazoacetamide 128a and benzaldehyde 127a (Table 8.4, entries 1-7). A drop of 5% in ee along with increase of 10% in yield was observed when 3 equivalents of diazoacetamide 128a was employed (Table 8.4, entry 2). To our delight, substantial increase in yield was observed when 3 or 5 equivalents of benzaldehyde 127a were employed in asymmetric epoxidation reaction (Table 8.4, entries 4 and 6). Although, high yields were obtained, it is impractical to utilize such a high excess of one reagent. So we decided to utilize 2 equivalents of benzaldehyde, which resulted the epoxide 135a in 65% yield and 98% ee. At this point, it worth mentioning that when the entry 4 of table 8.4 was repeated with the catalyst generated from 3 equivalents of DMSO, only 15% of epoxide was obtained (Table 8.4, entry 5). One of the variation was to utilize the purified B(OPh)3 to prepare the catalyst. However, a substantial decrease in yield and ee were observed when freshly distilled B(OPh)3 was employed (Table 8.4, entries 8-9). The reason for this dip is not known yet. At this point of time we decided to utilize BH3•Me2S as the boron source in place of B(OPh)3. Not only this was expected to give better results, but also this would provide us a handle to screen different alcohols facilitating the screening of various boroxinate catalysts. Unfortunately, it resulted epoxide 135a in 60% yield and 94% ee only (Table 8.4, entry 10). One of the important observations was that the diazoacetamide 128a was added as solid which resulted in low solubility of the diazo compound at –60 °C. Hence, we decided to add the diazo as a solution in toluene. An appreciable increase in the yield up to 82% was observed (Table 8.4, entry 11). Thereafter, utilizing 1.1 equiv of benzaldehyde with 10 mol% catalyst 432, we were able to obtain epoxide 135a in 82% yield and 98% ee (Table 8.4, entry 12). To our delight, the reaction resulted in 98% ee with a slight drop 699 in yield (73%) when 5 mol% catalyst was employed (Table 8.4, entry 13). Last but not least, we tried another variation where diazoacetamide 128a was added prior to the addition of the benzaldehyde 127a (Table 8.4, entry 14). This was done to bring the large volume (diazo 128a was added as a solution) of the toluene to –60 °C before the reaction starts. An improved result of 88% yield and 99.3% ee was obtained and thus this became the procedure of choice (Table 8.4, entry 14). In fact, high yield and ee was obtained with 5 mol% catalyst loading (Table 8.4, entry 15). It must be remembered that in order to screen various diazoaceatmides, which are insoluble in toluene, procedure used in entry 4 of Table 8.4 with either B(OPh)3 or BH3•Me2S would be the procedure of choice. a Table 8.4 Varying the equivalents of aldehydes and boron sources and sequence of events. (S)-SULFOX-BOROX + catalyst 432 [DMSO-H] OPh O O O O O (10 mol%) + + O –O B NHBu Ph CONHBu Ph B O NHBu * Toluene Ph H N2 O O B –60 ºC, 24 h OPh 127a 128a 135a 136a SULFOX-BOROX catalyst 432 Boron source DMSO OH OH (S)-SULFOX-BOROX pre-catalyst * * catalyst 432 OH 1h Method B or D OH 59 = (S)-VANOL (10 mol%) 1.25 Yield 135a b (%) 58 (62) ee 135a c (%) 97 Yield 136a d (%) 7 1 3 68 (72) 92 9 0.1 1 1 60 (63) 98 6 B 0.1 3 1 75 (80) 97 9 B 0.1 3 1 – (15) – 6 # Boron source Precatalyst (method) Conc. (M) 127a (equiv) 128a (equiv) 1 B(OPh)3 B 0.1 1 2 B(OPh)3 B 0.1 3 B(OPh)3 B 4 B(OPh)3 e 5 B(OPh)3 6 B(OPh)3 B 0.1 5 1 80 (89) 99 8 7 B(OPh)3 B 0.1 2 1 65 (72) 98 9 700 Table 8.4 cont’d 8 B(OPh)3 f B 0.1 2 1 50 (55) 73 10 f, g B 0.1 2 1 50 (59) 80 8 9 B(OPh)3 10 BH3•Me2S 11 12 13 14 15 BH3•Me2S E 0.1 2 1 60 (64) 94 17 g,h E 0.05 2 1 82 (85) 95 6 g,h E 0.05 1.1 1 82 (84) 98 1 g,i E 0.05 1.1 1 73 (75) 98 2 g,j E 0.05 1.1 1 88 (90) 99.3 <1 g,i,j E 0.05 1.1 1 79 (80) 99 2 BH3•Me2S BH3•Me2S BH3•Me2S BH3•Me2S a Unless otherwise specified, all reactions were performed with 10 mol % SULFOX-BOROX catalyst 432 and 0.2 mmol diazo 128a (1.0 equiv, C M), benzaldehyde 127a (x equiv) at –60 °C in toluene. The pre-catalyst was prepared either by Method B or Method E. Method B: By heating 1 equiv of (S)-VANOL (10 mol %), 3 equiv of commercial B(OPh)3 and 3 equiv of H2O in THF at 80 °C for 1 h, followed by removing all volatiles under high vacuum (0.1 mm Hg) for 0.5 h at 80 °C. Method E: By heating 1 equiv of (S)-VANOL (10 mol %), 3 equiv of BH3•Me2S, 2 equiv of PhOH and 3 equiv of H2O in toluene at 100 °C for 1 h, followed by removing all volatiles under high vacuum (0.1 mm Hg) for 0.5 h at 100 °C. Thereafter, the SULFOX-BOROX catalyst 432 was prepared by stirring the pre-catalyst (prepared by either method B or D) with 10 mol% DMSO in toluene for 1 h at 25 °C. All but entry 8 have shown the cis:trans ratio to be >100:1. The cis:trans ratio is 45:1 for entry 8. The cis:trans ratio is determined by integration of the methine protons of cis- and trans1 b epoxide in the H NMR spectrum of the crude reaction mixture. Isolated Yield. Yield in 1 c parenthesis determined by H NMR spectra with Ph3CH as internal standard. Determined d 1 e by HPLC. Determined by H NMR spectra with Ph3CH as internal standard. 3 equivalents of DMSO were added to make the catalyst. f Diazoacetamide 128a was added as a solution in toluene. catalyst loading. 127a. j Freshly distilled B(OPh)3 used. h Reaction time = 1.5 h. i g 5 mol% Diazoacetamide 128a was added prior to the addition of benzaldehyde One of the last experiments undertaken was utilizing the BOROX catalyst generated by the simple mixing of the (S)-VANOL, 3 equiv B(OPh)3 and 1 equiv DMSO. This would ideally simplify the procedure to a great deal and would lead to a one-pot procedure. Unfortunately, an 701 appreciable decrease in ee (~17%) and cis:trans ratio was observed in these cases (Table 8.5, entry 5 vs. 6). However, this method can be used for the large scale synthesis of epoxides as the purification can be done by crystallization, which in turn, increases the diastereoselectivity and enantioselectivity (discussed in later sections of this chapter). Table 8.5 Screening of the one-pot procedure for asymmetric epoxidation. 1. * OH B(OPh)3 (3 equiv) DMSO (1 equiv) solvent, 25 ºC, 1 h OH then cooled to temp 59 (10 mol%) O Ph 2. a H 127a O + Ph O O O CONHBu Ph 135a NHBu 136a NHBu N2 128a temp, 24 h 0.2 Yield 135a b (%) 55 (59) ee 135a c (%) 73 31:1 Yield 136a e (%) 9.8 –40 0.2 66 (70) 69 11:1 2.0 CHCl3 –60 0.1 65 (70) 60 11:1 3.0 CHCl3 –60 0.1 60 (64) 70 11:1 4.0 PhCH3 –60 0.1 75 (80) 97 >100:1 9.0 PhCH3 –60 0.1 75 (79) 80 13:1 4.0 7 PhCH3 –60 0.2 68 (75) 74 15:1 3.5 8 PhCH3 –40 0.1 66 (71) 82 13:1 4.0 Solvent # 1 2 3 4 5 6 f,g f h h,i g Temp (°C) Conc. (M) CHCl3 –40 CHCl3 c:t d a Unless otherwise specified, all reactions were performed with 10 mol % (S)-SULFOXBOROX catalyst 432 and 0.2 mmol diazoacetamide (1.0 equiv, C M), 0.6 mmol benzaldehyde 127a (3.0 equiv) at temp °C in the solvent. The (S)-SULFOX-BOROX catalyst 432 was prepared directly by stirring a mixture of 1 equiv of (S)-VANOL (10 mol %), 3 equiv of b commercial B(OPh)3 and 10 mol % DMSO in solvent for 1 h at 25 °C. Isolated Yield. 1 Yield in parenthesis determined by H NMR spectra with Ph3CH as internal standard. 702 Table 8.5 cont’d c Determined by HPLC. d 1 Ratio determined by integration of the methine protons of cis- and trans-epoxide in the H NMR spectrum of the crude reaction mixture. f e 1 Determined by H g NMR spectra with Ph3CH as internal standard. The ratio of 127a:128a is 1:1.25. The precatalyst was prepared by heating 1 equiv of (S)-VANOL (10 mol %), 3 equiv of commercial B(OPh)3 and 3 equiv of H2O in THF at 80 °C for 1 h, followed by removing all volatiles under high vacuum (0.1 mm Hg) for 0.5 h at 80 °C. Thereafter, the (S)-SULFOX-BOROX catalyst 432 was prepared by stirring the pre-catalyst with 10 mol % DMSO in solvent for 1 h h i at 25 °C. The diazoacetamide 128a was added as a solution in CHCl3. Tetramethylene sulfoxide (TMSO) is used as the base. 8.4 Substrate Scope After we obtained the final optimized procedure, we then carried out a general screen for the catalytic asymmetric epoxidation reaction. The results of an examination of the scope of epoxidation reaction are presented in Table 8.5. Excellent yields and asymmetric inductions were observed for a number of substituted benzaldehydes (Table 8.5, entries 1, 4-12) and polyaromatic compounds (Table 8.5, entries 2-3). While the p-tolualdehyde gave high induction (entry 5), the o-tolualdehyde is slower and resulted the epoxide 135c in 60% yield and 80% ee only (entry 4). Excellent result was obtained with m-anisaldehyde (entry 5). The reactions with electron-withdrawing groups at para-position gave high inductions (entries 7-8 and 11-12). These electron-withdrawing groups include nitro, bromide, cyanide and acetate. In fact, even mbromobenzaldehyde gave excellent yield and asymmetric induction (entry 9). However, the reaction with 2-F,4-Br-C6H4CHO 127x afforded the epoxide 135x in 70% yield and 80% ee only (entry 10). Unfortunately, the reaction with 2-picolinaldehyde resulted the epoxide in 20% yield only (not shown here). 703 Table 8.6 Catalytic asymmetric epoxidation of aryl and alkyl aldehydes a (S)-SULFOX-BOROX + catalyst 432 [DMSO-H] OPh O O O O O (10 mol%) + + O –O B NHBu R CONHBu R B O NHBu * Toluene R H N2 O O B –60 ºC, 24 h OPh 127 128a 135 136 SULFOX-BOROX BH3•Me2S (3 equiv) catalyst 432 PhOH (2 equiv) OH H2O (3 equiv) DMSO OH * (S)-SULFOX-BOROX pre-catalyst * OH OH Toluene, 100 °C, 1 h catalyst 432 1h = (S)-VANOL 59 then 0.5 mm Hg (10 mol%) 100 °C, 0.5 h series Yield 135 b (%) ee 135 c (%) cis/trans 1 a 88 99 >100:1 2 b 97 92 35:1 <1 3 bʹ′ 92 98 >100:1 <1 c 60 80 >100:1 <1 d 80 99 >100:1 <1 eʹ′ 80 90 31:1 6 f 70 92 13:1 8 # R d 136 e (%) g <1 Me 4 5 Me OMe 6 7 NO2 704 Table 8.6 cont’d 8 g 88 99 >100:1 <1 gʹ′ Br 88 96 >100:1 4 Br 9 F 10 Br x 70 80 39:1 9 11 CN y 84 96 >100:1 <1 12 OAc z 82 97 >100:1 4 o 65 78 nd 9 pʹ′ 84 90 nd 6 13 14 5 a Unless otherwise specified, all reactions were performed with 10 mol % (S)-SULFOXBOROX catalyst 432 and 0.2 mmol diazo 128a (1.0 equiv, 0.05 M), aldehyde 127 (1.1 equiv) at –60 °C in toluene. The pre-catalyst was prepared either by heating 1 equiv of (S)-VANOL (10 mol %), 3 equiv of BH3•Me2S, 2 equiv of PhOH and 3 equiv of H2O in toluene at 100 °C for 1 h, followed by removing all volatiles under high vacuum (0.1 mm Hg) for 0.5 h at 100 °C. Thereafter, the (S)-SULFOX-BOROX catalyst 432 was prepared by stirring the precatalyst with 10 mol % DMSO in toluene for 1 h at 25 °C. In all cases, diazoacetamide 128a was added a solution in toluene and prior to the addition of aldehyde. All liquid aldehydes are added in neat form whereas all solid aldehydes are added as a solution in toluene maintaining b c the concentration of the reaction to be 0.05 M in diazoaceatamide 128a. Isolated Yield. Determined by HPLC. d The cis:trans ratio is determined by integration of the methine 1 protons of cis- and trans-epoxide in the H NMR spectrum of the crude reaction mixture. e 1 Determined by H NMR spectra with Ph3CH as internal standard. In terms of aliphatic substrates, while the n-nonanal gave high induction (entry 14), the nbutanal is slower and resulted the epoxide 135o in 65% yield and 78% ee only (entry 13). Recently, our group reported the first example of catalytic asymmetric aziridination for the 705 synthesis of tri-substituted aziridines. 15 So we thought of employing the same protocol for tri- substituted epoxidation. Intial experiments suggested the formation of the tri-substituted epoxide 1 using diazoacetamide 439a as shown as in Scheme 8.6. The H NMR analysis of the crude reaction mixture indicates that the ratio of the epoxide 440a and β-keto amide 441a is approximately 1:2. (Scheme 8.6A). In another experiment, same ratio (1:2) of epoxide 440b and β-keto amide 441b was obtained when diazoacetamide 439b was utilized (Scheme 8.6B). The peak for Ha in CDCl3 has been assumed to appear at δ = 4.25 ppm for 440a and δ = 4.08 ppm for 440b respectively. Scheme 8.6 Tri-substitute epoxidation between PhCHO and (A) 439a and (B) 439b A O O Ph + H 127a O N N2 439a * OH O O pre-catalyst (10 mol%) CH2Cl2 –78 °C, 24 h 0.1 M Ha N Ph O O 440a BH3•Me2S (3 equiv) PhOH (2 equiv) H2O (3 equiv) O + N R O OH Toluene, 100 °C, 1 h 59 then 0.5 mm Hg (10 mol%) 100 °C, 0.5 h B O O O 441a 440a:441a = 1:2 (70% combined yield) pre-catalyst (S)-SULFOX-BOROX catalyst 432 O O O O (10 mol%) Ha + + NHBn Ph CONHBn R toluene NHBn Ph H N2 –60 °C, 24 h 0.05 M 127a 439b 440b 441b 440b:441b = 1:2 BH3•Me2S (3 equiv) (40% combined yield) PhOH (2 equiv) DMSO OH H2O (3 equiv) pre-catalyst (S)-SULFOX-BOROX * OH catalyst 432 1h Toluene, 100 °C, 1 h 59 then 0.5 mm Hg (10 mol%) 100 °C, 0.5 h O 706 8.5 Determination of absolute stereochemistry of epoxides The absolute configurations of the major diastereomer i.e. cis-epoxide 426a and 135a has been determined by three different ways. 8.5.1 Via optical rotation 13 The epoxide 426a is a reported in literature; hence we compared the optical rotation of the epoxide 426a with 62% ee to the reported value for the known epoxide 426a with 99% ee (Scheme 8.7). It was quite surprising to know that the cis-epoxide 426a results from a Re face attack of the diazoacetamide 123a on the aldehyde using the (S)-SULFOX-BOROX catalyst 432 derived from (S)-VANOL. Interestingly, this indicates that the facial selectivity of the cisepoxidation with diazoacetamide is opposite for cis-aziridination with ethyldiazoacetate using the same enantiomer of the ligand because the cis-aziridine results from a Si face attack of the diazoacetate on the (S)-catalyst-imine complex. Similar kind of observation was made in the case of trans-aziridination when compared to cis-aziridination. 16 Scheme 8.7 Comparison of the optical rotation values of epoxide (S,S)-426a obtained from the current work and from the literature O O Ph + H 127a NHPh N2 (S)-SULFOX-BOROX catalyst 432 (10 mol%) Ph CHCl3 –40 °C, 24 h 123a O O CONHPh Ph (S,S)-426a 68% yield, 62% ee [α] 20 = +14.7 (c=1.0, CH2Cl2, 62%ee) D [α] 20 = +19.1 (c=0.9, CH2Cl2, 99%ee) D 707 O + This work Literature value (Reference 13) NHPh 427a 14% yield 8.5.2 Via X-ray structure The absolute configuration of the epoxides obtained in our catalytic asymmetric epoxidation protocol was further confirmed by X-ray crystallography. To our delight, we were able to obtain X-ray diffraction analysis of epoxides 135g and 435a, which further confirms cisepoxidation and the absolute configuration. It must be noted that epoxides 135g and 435a were obtained from (S)-SULFOX-BOROX catalyst 432 derived from (S)-VANOL ligand (Table 8.6, entry 8 and Table 8.2, entry 2). The ORTEP drawing of cis-epoxides (S,S)-135g and (S,S)-435a are shown in Figure 8.1. Figure 8.1 ORTEP drawing of cis-epoxides (A) (S,S)-135g and (B) (S,S)-435a A Br H O HN H O (S,S)-135g B Cl N H O O H H (S,S)-435a 8.5.3 Via circular dichroism Last but not the least, the absolute configuration of epoxides 135 was confirmed by the excellent method developed by Borhan and coworkers using circular dichroism. 708 17 This work was done in collaboration with Carmin Burrell, a current graduate student in Borhan group. The method was applied to a number of epoxides as listed in Figure 8.2B. The absolute stereochemistry of the cis-epoxides was confirmed through evaluation by exciton coupled circular dichroism (ECCD). The sign of the observed ECCD curve is a reflection of the stereochemistry of the epoxides in that a pair of enantiomeric molecules will exhibit ECCD signals with opposite sign. To develop a mnemonic for this class of substrates, initially an enantiomeric pair of epoxides was submitted to ECCD conditions. Each epoxide (40 equivalents, 0.04 µmol) was added to a 1µM solution of the porphyrin tweezer, Zn-C5-TPFP-Tz, in hexanes at 0 °C. To our delight, under these conditions, the enantiomers did provide ECCD signal of opposite sign (Figure 8.2A). Figure 8.2 Determination of absolute stereochemistry of cis-epoxides 135, 426a and 436a. (A) CD spectra for the two enantiomers of cis-epoxide 135g (B) Observed ECCD amplitudes for chiral cis-epoxides. All measurements were performed with 40 equivalents of the substrates (except 150 equiv used for (S,S)-426a) and 1µM tweezer in hexanes at 0 ºC. (C) Proposed mnemonic explaining the signs of the observed ECCD signals. A O 160   CONHBu 60   -­‐40  380 Br 401 422 443 (S,S)-135g (90% ee) A = +295 O CONHBu -­‐140   Br -­‐240   709 (R,R)-135g (99% ee) A = –371 Figure 8.2 cont’d B O Me O CONHBu CONHBu (S,S)-135a (99% ee) A = +225 CONHBu (R,R)-135c (80% ee) A = –80 (S,S)-135b (92% ee) A = +189 O O CONHBu O MeO O CONHBu Me CONHBu O2N (R,R)-135d (99% ee) A = –440 (S,S)-135e' (90% ee) A = +432 O (S,S)-135f (92% ee) A = +134 O CONHBu Br O CONHBu Br CONHBu Br (R,R)-135g (99% ee) A = –371 (S,S)-135g (90% ee) A = +295 F O O O CONHBu CONHBu NC Br (S,S)-135x (80% ee) A = +96 O 5 (S,S)-135g' (96% ee) A = +233 AcO (S,S)-135y (96% ee) A = +85 O CONHBu (S,S)-135p' (90% ee) A = +1109 CONHBu O CONHPh (S,S)-426a (55% ee) A = +53 710 (R,R)-135z (97% ee) A = –231 CONHBn (S,S)-436a (62% ee) A = +86 Figure 8.2 cont’d C P2 Y N Y H O HH N R' R RR O N Zn N Y N Zn H O R P2 P1 P1 P2 HH N R' O Zn Y O N Zn Y O O N R N Y N H N O HH O H N S S R R' O Zn-C5-TPFP-Tz (Y = C6F5 ) O P1 R' O P2 Zn H H O H N R' R O Zn P1 The host-guest, epoxide-tweezer, complex is formed by coordination of the epoxidic oxygen and the oxygen of the amide carbonyl to the zinc centers of the porphyrin tweezer. The sterics of the epoxide governs the overall rotation of the porphyrins relative to one another and the sign of the ECCD signal. As shown in Figure 8.2C, the rear porphyrin, P2, coordinates to rear face of the epoxide via the oxygen lone pair electrons. This rear face of the epoxide has two hydrogen substituents and so this porphyrin remains essentially static. The amide substituent is positioned to the front face of the epoxide; therefore, P1 approaches the molecule to the front face. Once bound, there is a steric interaction between the R group and the porphyrin forcing the porphyrin to rotate away from the R group. In the case of the (2R,3R) epoxides, P1 rotates clockwise and results in an overall counterclockwise orientation of P1 relative to P2 . Hence, for these epoxides, a negative ECCD signal is expected. For the enantiomeric (2S,3S) epoxides, an overall clockwise arrangement and a positive ECCD signal are expected. It was delightful to 711 observe the correct prediction of the absolute stereochemistry of cis-epoxide when compared to the already established absolute stereochemistry of (S,S)-135g via X-ray crystal structure. In fact, all the substrates do follow the proposed mnemonic. In the case of trans-epoxide (minor product) obtained from the catalyst derived from the (S)-VANOL, the shown absolute configuration (Figure 8.3A) is based on a hypothetical mnemonic that will require conformation by other means. It is hypothesized that the rear porphyrin P2 binds to the epoxide to the rear face and rotates away from the R group. The front porphyrin binds to the carbonyl of the amide from the front face and rotates toward the hydrogen. This gives an overall clockwise helicity of the porphyrins and a positive sign is expected for S,R configured substrates and a negative signal for R,S substrates. Based on this hypothesis, the absolute configuration of the trans-epoxide is believed to be R,S. Figure 8.3 Determination of absolute stereochemistry of trans-epoxide (R,S)-135g. (A) Observed ECCD amplitude for chiral trans-epoxide (R,S)-135g. All measurements were performed with 20 equivalents of the substrate and 1µM tweezer in hexanes at 0 ºC. (C) Proposed mnemonic explaining the signs of the observed ECCD signal. A O CONHBu Br (R,S)-135g (20% ee) A = –25 712 Figure 8.3 cont’d B P2 Y N Y R R O HH N R' H SR O N Zn N Y N Y Zn Y O O N N R Y H N R S HH O R N S R H R' O O P2 P2 P1 O R' P2 O N Zn-C5-TPFP-Tz (Y = C6F5 ) H Zn P1 P1 O N Zn HH N R' O O Zn H O HN R' O R H Zn P1 Finally, the absolute configuration of both the major (cis-epoxide) and minor (transepoxide) diastereomers have been determined using various techniques. Although, the absolute configuration of trans-epoxide needs to be confirmed by other means, it is quite surprising to observe opposite facial selectivity for cis- and trans-epoxide diastereomers using the catalyst derived from the same enantiomer of the ligand ((S)-VANOL in this case). To summarize, the cis-epoxide is obtained from a Re face attack of the diazoacetaamide on the aldehyde and the trans-epoxide is resulted from a Si face attack, when the catalyst derived from (S)-ligand is employed. 8.6 Mechanistic study towards the identification of the actual catalyst in the epoxidation reaction A small amount of time of this doctoral research has been spent in the understanding of the 713 mechanism of the current catalytic asymmetric epoxidation reaction. A few of the experiments are described below. 8.6.1 Investigating non-covalent interactions In the process of screening different diazo compunds, we found that the diazoacetamide 128c derived from benzhydryl amine 126a resulted the epoxide 443a in 68% yield and 74%ee (Table 8.6, entry 1). This reflects an increase of 9% yield and 12% ee when compared to the epoxide 436a (59% yield and 62%ee; Table 8.6, entry 2) obtained from the diazoacetamide 128b derived from benzyl amine. This result indicates the possibility of certain non-covalent interactions (CH-π or π-π type) operating in the epoxidation reaction. Up till now, we have used secondary diazoacetamide for the epoxidation reaction. In the case of aziridination reaction, it is observed that while diazoacetamides of the type 123/128 containing a secondary amide give trans-aziridines, 16 tertiary diazoacetamides lacking the N-H bond will react with a switch in the diastereoselectivity to give cis-aziridines. 16,18 The pertinent question thus becomes, will a tertiary diazoacetamide of type 442a (Table 8.7) also reverse the diastereoselectivity to give the trans-epoxides? The answer is no. Surprisingly, β-keto amide 19 446a and its enol form were observed when the benzaldehyde 127a was reacted with diazoacetamide 442a (Table 8.6, entry 3). In fact, same was observed when a) the reaction was carried out with EDA 85; b) the reaction was performed in the presence of commercial B(OPh)3 only for all three cases. It suggests the importance of the secondary diazoacetamide for the successful realization of the catalytic asymmetric epoxidation reaction. Also, likewise the case of trans-aziridines, 20 it indicates the possibility of a potential hydrogen bonding interaction 714 between the catalyst and the N-H of the secondary diazoacetamide in the transition state of the reaction. Table 8.7 N-H verses N-Me and O in the catalytic asymmetric epoxidation reaction (S)-SULFOX-BOROX catalyst 432 O O (10 mol%) + + X Ph COX CHCl3 Ph H N2 –40 °C, 24 h 127a 128b (NHBn) 436a (NHBn) 128c (NHBh) 443a (NHBh) 442a (N(Me)Bn) 444a (N(Me)Bn) 85 (OEt) 395a (OEt) O * OH B(OPh)3 (3 equiv) H2O (3 equiv) OH THF, 80 °C, 1 h 59 then 0.5 mm Hg (10 mol%) 80 °C, 0.5 h pre-catalyst DMSO 1h + [DMSO-H] OPh O O O –O B Ph X B O * O O B OPh 437a (NHBn) 445a (NHBh) SULFOX-BOROX catalyst 432 446a (N(Me)Bn) 396a (OEt) Ph Ph (S)-SULFOX-BOROX catalyst 432 OH OH 59 >50:1 Yield β-keto amide e (%) 9.5 62 >50:1 15.5 <1 – – <1 – – 25 40 # Diazo (X) 1 NHCHPh2 Yield epoxide b (%) 65 (68) 2 NHCH2Ph 59 (55) 3 4 N(Me)CH2Ph OCH2CH3 ee epoxide c (%) 74 cis/trans d f a Unless otherwise specified, all reactions were performed with 10 mol % SULFOX-BOROX catalyst 432 and 0.50 mmol diazoacetamide (1.25 equiv), 0.4 mmol benzaldehyde 127a (1.0 equiv, 0.4 M) at –40 °C in CHCl3. The pre-catalyst was prepared by heating 1 equiv of (S)- VANOL (10 mol %), 3 equiv of commercial B(OPh)3 and 3 equiv of H2O in THF at 80 °C for 1 h, followed by removing all volatiles under high vacuum (0.1 mm Hg) for 0.5 h at 80 °C. Thereafter, the SULFOX-BOROX catalyst 432 was prepared by stirring the pre-catalyst b 1 with 10 mol % DMSO in CHCl3 for 1 h at 25 °C. Determined by H NMR spectra of the crude reaction mixture with Ph3CH as internal standard. Yield in parenthesis is isolated yield. c Determined by HPLC. 1 d Ratio determined by integration of the methine protons of cis- and trans-epoxide in the H NMR spectrum of the crude reaction mixture. e NMR spectra of the crude reaction mixture with Ph3CH as internal standard. the enol form of 446a was also observed. 715 1 Determined by H f 50% yield of 8.6.2 Screening of a different catalytic system We then decided to change the catalytic system in order to have a better understanding of the possible interactions of the substrate and the catalyst. One of the changes was the removal of the phenol component from the SULFOX-BOROX catalyst 432. This would ideally result in a catalyst of type 447 (Scheme 8.8). Although the structure of the proposed catalyst is not confirmed, the epoxidation reaction resulted in epoxide 135g in 85% yield and 90% ee with cis:trans = 55:1 using the catalyst 447. Upon comparison to the reaction performed with catalyst 432, a slight drop of 9% ee was observed in this case. Scheme 8.8 Epoxidation reaction with catalyst 432 and 447 R catalyst (10 mol%) O O + H 127g R = 4-Br-C6H4 NHBu N2 O O toluene –60 °C, 24 h 128a R CONHBu BH3•Me2S (3 equiv) PhOH (2 equiv) H2O (3 equiv) (S)-VANOL Toluene, 100 °C, 1 h 59 then 0.5 mm Hg (10 mol%) 100 °C, 0.5 h BH3•Me2S (1 equiv) PhOH (1 equiv) (S)-VANOL Toluene, 100 °C, 1 h 59 then 0.5 mm Hg (10 mol%) 100 °C, 0.5 h 136g c:t %y %ee 432 447 88 85 NHBu R 135g catalyst O + 99 90 >100:1 55:1 %y <1 1.4 + [DMSO-H] pre-catalyst DMSO 1h OPh O –O B B O * O O B OPh catalyst 432 PhB(OH)2 (2 equiv) DMSO Toluene, 100 °C, 1 h then 0.5 mm Hg 100 °C, 0.5 h 1h 716 + [DMSO-H] Ph O –O B B O * O O B Ph catalyst 447 8.6.3 Catalytic asymmetric epoxidation reaction with and without DMSO We have seen before that reaction also works in the absence of any base (Table 8.1, entry 1 and 8). The asymmetric induction observed in those cases was low as compared to the results obtained from SULFOX-BOROX catalyst 432 (Table 8.1, entry 6 vs. 9) respectively. At this point we became interested to employ newly optimized procedure and diazoacetamide 128a for the epoxidation reaction where no base is used as an additive. Surprisingly, a drop of only 7% yield and 16% ee was noticed when the aldehyde was added prior to the addition of the diazoacetamide 128a in the absence of DMSO (Table 8.8, entry 4 vs. 3). However, the difference was reduced to 8% when the order of the addition of the aldehyde and diazoacetamide was switched (Table 8.8, entry 6 vs. 5). Similar observation was made for p-bromobenzaldehyde 127g (Table 8.8, entry 8 vs. 7). These intriguing results suggested the possibility of a different catalytic system where boroxinate of type 448a is generated by the diazoacetamide 128a itself, when there is no DMSO added. If this is true, then the epoxidation reaction would be similar to our aziridination reaction where the boroxinate catalyst is actual a substrate induced catalyst. However, a different mechanism along the idea of chiral Lewis acid type cannot be discarded. Table 8.8 Catalytic asymmetric epoxidation with and without SULFOX-BOROX catalyst. R + H 127 catalyst (10 mol%) O O NHBu N2 R toluene –60 °C, 24 h 128a BH3•Me2S (3 equiv) PhOH (2 equiv) H2O (3 equiv) (S)-VANOL Toluene, 100 °C, 1 h 59 then 0.5 mm Hg (10 mol%) 100 °C, 0.5 h O O CONHBu 135 O + R NHBu 136 + [DMSO-H] pre-catalyst DMSO 1h 717 a OPh O B O – B O * O O B OPh catalyst 432 Table 8.8 cont’d BH3•Me2S (3 equiv) PhOH (2 equiv) H2O (3 equiv) (S)-VANOL Toluene, 100 °C, 1 h 59 then 0.5 mm Hg (10 mol%) 100 °C, 0.5 h + [Diazo-H] OPh O B O – pre-catalyst B O * O O B –60 °C OPh catalyst 448a ? Diazo 128a # R Base Cat. (x mol%) 1 C6H5 DMSO 432 (5) Yield 135 b (%) 73 (75) 2 C6H5 – 448a (5) 61 (60) 86 49:1 6 3 C6H5 DMSO 432 (10) 82 (84) 98 >100:1 1 C6H5 – 448a (10) 75 (77) 82 49:1 9 C6H5 DMSO 432 (10) 88 (90) 99.3 >100:1 <1 C6H5 – 448a (10) 78 (79) 90 55:1 5 4-Br-C6H4 DMSO 432 (10) 88 (92) 99 >100:1 <1 4-Br-C6H4 – 448a (10) 86 (87) 91 56:1 2 4 5 6 7 8 f f f f ee 135 c (%) 98 c/t Yield 136 e (%) 2 d >100:1 a Unless otherwise specified, all reactions were performed with 10 mol % catalyst 432 or 448a and 0.2 mmol diazo 128a (1.0 equiv, 0.05 M), aldehyde 127 (1.1 equiv) at –60 °C in toluene. The pre-catalyst was prepared by by heating 1 equiv of (S)-VANOL (10 mol %), 3 equiv of BH3•Me2S, 2 equiv of PhOH and 3 equiv of H2O in toluene at 100 °C for 1 h, followed by removing all volatiles under high vacuum (0.1 mm Hg) for 0.5 h at 100 °C. Thereafter, the catalyst 432 was prepared by stirring the pre-catalyst with 10 mol % DMSO in toluene for 1 h at 25 °C. And, the catalyst 448a was prepared by stirring the pre-catalyst with b 100 mol % diazoacetamide in toluene for 10 min at –60 °C. Isolated Yield. Yield in 1 c parenthesis determined by H NMR spectra with Ph3CH as internal standard. Determined d by HPLC. The cis:trans ratio is determined by integration of the methine protons of cis- and 1 trans-epoxide in the H NMR spectrum of the crude reaction mixture. NMR spectra with Ph3CH as internal standard. of aldehyde. 718 f e 1 Determined by H Diazoacetamide added prior to the addition 8.6.4 Temperature study The role of the temperature in the asymmetric epoxidation was also examined and is presented in Table 8.9. This study was performed with 5 mol% catalyst loading. It is quite clear from the entries in Table 8.9 that the reaction slows down to a great extent at higher temperature. Only 31% yield of epoxide 135a was obtained when the reaction was performed at room temperature (Table 8.9, entry 4). This corresponds to a difference of 44% yield compared to the reaction performed at – 60 ºC (Table 8.9, entry 1 vs. 4). Also, a decrease in cis:trans ratio was observed as the temperature of the reaction was increased. Table 8.9 Screening of various temperatures for asymmetric epoxidation. a (S)-SULFOX-BOROX + catalyst 432 [DMSO-H] OPh O O O O O (5 mol%) + + O –O B NHBu Ph CONHBu Ph B O NHBu * Toluene Ph H N2 O O B temp, 24 h OPh 127a 128a 135 136 0.05 M SULFOX-BOROX BH3•Me2S (3 equiv) catalyst 432 PhOH (2 equiv) OH H2O (3 equiv) DMSO OH * (S)-SULFOX-BOROX pre-catalyst * OH OH Toluene, 100 °C, 1 h catalyst 432 1h = (S)-VANOL 59 then 0.5 mm Hg (10 mol%) 100 °C, 0.5 h # Temp (°C) 1 2 3 4 –60 –40 –20 +25 Yield 135a b (%) 75 (73) 51 38 31 ee 135a c (%) 98 – – – c:t d >100:1 81:1 24:1 16:1 a Yield 136a e (%) 2.0 7.0 8.0 6.0 Yield 128a e,f (%) 7 24 12 19 Unless otherwise specified, all reactions were performed with 5 mol % (S)-SULFOXBOROX catalyst 432 and 0.2 mmol diazoacetamide (1.0 equiv, 0.05 M), 0.22 mmol benzaldehyde 127a (1.1 equiv) at temp °C in the toluene. The (S)-SULFOX-BOROX catalyst 432 was prepared directly by stirring a mixture of 1 equiv of (S)-VANOL (10 mol %), 3 equiv of commercial B(OPh)3 and 5 mol % DMSO in solvent for 1 h at 25 °C. The diazoacetamide 719 Table 8.9 cont’d 128a is added as a solution in toluene and added after the addition of benzaldehyde. 1 b Yield is determined by H NMR spectra with Ph3CH as internal standard. Yield in parenthesis is c isolated yield. Determined by HPLC. d 1 Ratio determined by integration of the methine protons of cis- and trans-epoxide in the H NMR spectrum of the crude reaction mixture. 1 e f Determined by H NMR spectra with Ph3CH as internal standard. unreacted diazoacetamide 128a. 8.6.5 NMR Study In order to have an understanding towards the identification of the catalytic system operational in the case where no base is employed, a detailed NMR study was performed. The aim of this study was to analyze the formation of the boroxinate using DMSO 221a and diazoacetamide by locating the characteristic peaks for the boroxinate catalyst i.e. δ = ~ 5-6 ppm and ~ 8.5 ppm in 11 1 B NMR and H NMR respectively (for VANOL derived catalyst). Using the procedure listed in Table 8.6, pre-catalyst was prepared and it was found to contain B1 107, B2 1 109 and unreacted VANOL 59 in the ratio 1:1.5:0.2. A new doublet at δ = 8.66 ppm in the H NMR spectrum was observed upon the addition of one equivalent of DMSO 221a to the precatalyst at room temperature (Figure 8.4B, entry 3). Also, a peak at δ = 6.44 ppm in the 11 B NMR spectrum was observed (Figure 8.4C, entry 3). These observations suggest the formation of the SULFOX-BOROX catalyst 432. There is also an up field shift (1.81 vs. 1.64) in the chemical shift of the methyl groups of DMSO 221a possibly due to CH-π interaction (Figure 1 8.4D). No change in the H NMR or 11 B NMR spectra was observed when one equiv of p- bromobenzaldehyde 127g was added to the pre-catalyst (Figure 8.4B and 8.4C, entry 4). This result is supportive of the idea that aldehyde is not activated in the absence of DMSO 221a or 720 diazoacetamide 128a. When one equiv of diazoacetamide 128a (solid or a solution in toluene) was treated with the pre-catalyst at room temperature, a tiny peak was observed at δ = 6.24 ppm in the 11 B NMR spectrum (Figure 8.4C, entries 6-7). However, a characteristic peak at δ = 5.91 ppm was observed when the same experiment was performed at –60 °C (Figure 8.4C, entry 8). Another interesting feature of the 11 B NMR was the shift in the tri-coordinate boron atoms (δ = 10.11 ppm) at –60 ºC in d8-toluene (Figure 8.4C, entry 9). The same peak is observed at δ = 1 17.19 at room temperature (Figure 8.4C, entry 7). The corresponding H NMR did show a broadening at ~ δ = 8.5 ppm, however, it was not conclusive. Nonetheless, initial experiments do suggest the possibility of the BOROX catalyst, perhaps, induced by the diazoacetamide itself. Figure 8.4 (A) DMSO 221a and diazoacetamide 128a induced boroxinate formation. (B) NMR spectra of the reaction mixture in d8-toluene. (C) 1 11 a 1 H B NMR spectra corresponding to 1 entries in the H NMR spectra in Figure 8.4B. (D) H NMR spectra (methyl region); Entry 1. 1 Pure DMSO 221a in d8-toluene. Entry 2: same as entry 3 in the H NMR spectrum in Figure 8.4B. A BH3•Me2S (3 equiv) + [B-H] OPh PhOH (2 equiv) O B B H2O (3 equiv) (S)-VANOL O – preB O * 59 Toluene, 100 °C, 1 h catalyst temp O O B (0.1 mmol) d8-toluene then 0.5 mm Hg OPh 100 °C, 0.5 h 432 (B = 221a) 448a (B = 128a) 721 B E-2 @ –60 ºC Figure 8.4 cont’d B3 448a ? E-2 + Diazoacetamide 128a @ –60 ºC E-2 + Diazoacetamide 128a (solution) E-2 + Diazoacetamide 128a (solid) B3 432 E-2 + Aldehyde 127g + DMSO B2 E-2 + Aldehyde 127g B3 432 E-2 + DMSO B2 Pre-catalyst (B1+B2) 59 (S)-VANOL 59 C B3 448a ? B3 432 B3 432 722 Figure 8.4 cont’d D Me Pre-catalyst + DMSO (1:1) Me DMSO a Note for Figure 8.4B: Entry 1: pure (S)-59. Entry 2: (S)-59 (0.1 mmol) plus 3 equiv BH3•Me2S 192a, 2 equiv PhOH and 3 equiv H2O were heated at 100 °C in toluene for 1 h followed by removal of volatiles under vacuum for 0.5 h. Entry 3: 1.0 equiv of DMSO 221a and d8-toluene (1 mL) was added to the entry 2 (pre-catalyst) for 10 min at 25 °C. Entry 4: 1.0 equiv of p-bromobenzaldehyde 127g and d8-toluene (1 mL) was added to the entry 2 (precatalyst) for 10 min at 25 °C. Entry 5: 1.0 equiv of DMSO 221a was added to the entry 4 for 10 min at 25 °C. Entry 6: 1.0 equiv of diazoacetamide 128a and d8-toluene (1 mL) was added to the entry 2 (pre-catalyst) for 10 min at 25 °C. Entry 7: 1 mL of d8-toluene was added to the pre- 723 catalyst followed by the addition of 1.0 equiv of diazoacetamide 128a as a solution in d8-toluene (1 mL) for 10 min at 25 °C. Entry 8: 1 mL of d8-toluene was added to the pre-catalyst and the resulting solution was cooled to –60 ºC. Thereafter, a pre-cooled (–60 ºC) solution of 1.0 equiv of diazoacetamide 128a in d8-toluene (1 mL) was added and the NMR was taken at –60 ºC. Entry 9: 1 mL of d8-toluene was added to the pre-catalyst and the resulting solution was cooled to –60 ºC. Thereafter, the NMR was taken at –60 ºC. 8.6.6 Calculated structures of boroxinate catalysts from DMSO and diazoacetamides While looking for the possibility of the boroxinate generated by diazoacetamide 128a and DMSO using the VANOL ligand, we decided to compute the probable structures of 432, 448a (Diazo = 128a) and 448ʹ′a (Diazo = 123a). Calculations were preformed using Gaussian 03 at B3LYP/6-31g* level of theory. 21 The resulted structures are presented in Figure 8.5. Likewise the case of the calculated structure of the BOROX catalyst 222a derived from DMSO and the VAPOL ligand, we observed two probable CH-π interactions between the methyl groups of DMSO and the naphthalene ring of the VANOL ligand (Figure 8.5A, d2 = 3.89 Å and d3 = 3.63 Å). The boroxinate 448a and 448ʹ′a from diazoacetamides 128a and 123a were also computed and presented in Figure 8.5C-F. a Figure 8.5 Calculated structure of SULFOX-BOROX catalyst 432, DIAZO-BOROX catalyst 448a and 448ʹ′a using Gaussian ʹ′03. They are visualized by the Mercury Program (C, gray; O, red; S, orange; B, yellow; H, white). Hydrogen atoms omitted for clarity (except protonated DMSO and diazoacetamides). 724 Figure 8.5 cont’d A B d1 d3 d2 432 C D d4 d2 d1 d3 448a E F d2 d1 d3 448ʹ′a 725 a Note for Figure 8.5: (A) Calculated B3LYP/6-31g* structure of 432. Some secondary interactions are highlighted: d1 = 1.44 Å (H-bonding), d2 = 3.89 Å (CH-π), d3 = 3.63 Å (CH-π). (B) Space-filling rendition of 432 with the same orientation and showing hydrogens. The boroxinate anion is given in green and the protonated DMSO is in traditional colors. (C) Calculated B3LYP/6-31g* structure of 448a. Some secondary interactions are highlighted: d1 = 1.50 Å (H-bonding), d2 = 1.92 Å (H-bonding), d3 = 3.95 Å (CH-π), d4 = 4.51 Å (CH-π). (D) Space-filling rendition of 448a with the same orientation and showing hydrogens. The boroxinate anion is given in green and the protonated 128a is in traditional colors. (E) Calculated B3LYP/6-31g* structure of 448ʹ′a. Some secondary interactions are highlighted: d1 = 1.47 Å (Hbonding), d2 = 1.85 Å (H-bonding), d3 = 4.02 Å (CH-π). (F) Space-filling rendition of 448ʹ′a with the same orientation and showing hydrogens. The boroxinate anion is given in green and the protonated 123a is in traditional colors. In the case of the possible boroxinate 448a generated from diazoacetamide 128a, two potential hydrogen bonding interactions were located (Figure 8.5C, d1 = 1.50 Å and d2 = 1.92 Å). Additionally, we observed two probable CH-π interactions between the methylene units of the diazo compound and the boroxinate ring (Figure 8.5C, d3 = 3.95 Å and d4 = 4.51 Å). Similarly, boroxinate 448ʹ′a generated from diazoacetamide 123a also revealed two potential hydrogen bonding interactions (Figure 8.5E, d1 = 1.47 Å and d2 = 1.85 Å) and one probable CHπ interaction (Figure 8.5E, d3 = 4.02 Å). 726 8.6.7 Possible rationale for the observed stereochemical outcome of asymmetric epoxidation reaction Although, we do not have any concrete evidence for the mechanism for the epoxidation reaction yet, there are some proposals based on the initial mechanistic findings during this doctoral research. These proposals are explained below. 8.6.7.1 With DMSO When the reaction is performed with (S)-SULFOX-BOROX catalyst, two mechanisms can be proposed via; a) Brønsted acid catalysis (model I) b) Brønsted acid-assisted Lewis acid catalysis (model II). In both the models, hydrogen bonding interactions between the substrates and the catalyst have been assumed and point of interactions (oxygens (O1-O3) on the boroxinate anion) can be different from that shown in the Figure 8.6. The shift in the hydrogen bonding between DMSO and boroxinate anion from O2 to O1 has been proposed based on the similar studies reported on the aziridination reaction by our group. 20 In model I, both reactants are held by the hydrogen bonding and an extra hydrogen bonding stabilization comes from the secondary diazoacetamide. The third H-bond involving the diazoacetamide is crucial given the observation that there is no reaction when tertiary diazoacetamide is utilized. Also, the diazoacetamide is proposed to attack from the Re face of the aldehyde based on the absolute stereochemistry of the cis-epoxide. For trans-epoxide, the facial selectivity has been switched i.e. the Si face attack has been proposed to be favorable (Figure 8.6B). The proposed model suggests that the approach of diazoacetamide leading to the cis-epoxide in more favorable + compared to trans-epoxide due to the dipolar interaction between the N2 on the diazoacetamide and the carbonyl oxygen on the aldehyde. In the case of model II, the interactions were assumed 727 to be similar to model I except the interaction between the aldehyde and catalyst. The aldehyde is proposed to be coordinated to the sulfur of the DMSO as the Lewis acid-Lewis base complex. Figure 8.6 Proposed models (I and II) for the mechanisms involving (S)-SULFOX-BOROX catalyst (derived from (S)-VANOL) leading to (A) cis-epoxide (B) trans-epoxide A O R OPh B O O CONHBu 3 B 2 B– O PhO O O * + 1 N2 H R O O+ O H S Me H N Me Bu H Cis (Model I) R H OPh B O O 3 B 2 B– O PhO O O * + N2 H 1 O O+ O S Me H N Me Bu H Cis (Model II) B O R OPh B O O CONHBu 3 B 2 B– O PhO O O * 1 H H R O O+ + O – S Me N2 H N Me Bu H Trans (Model I) 8.6.7.2 OPh B O O 3 B 2 B– O PhO O O * H 1 H R + N2 O – O H N Bu H O+ S Me Me Trans (Model II) Without DMSO As shown earlier, that the reaction works well even in the absence of SULFOX-BOROX catalyst. In those cases, preliminary NMR studies suggest the possibility of the DIAZO-BOROX 728 catalyst of type 448a (Figure 8.5B). After initial assumption of the formation of 448a, the working model III has been proposed and shown in Figure 8.7. In addition to 448a, it has been proposed that the aldehyde is either hydrogen bonded to O1 (red in color) or O2 (green in color). As discussed earlier, an extra hydrogen bonding stabilization is proposed to be present due to the hydrogen bonding between the boroxinate core and the secondary diazoacetamide. Figure 8.7 Proposed model III for the mechanism involving (S)-DIAZO-BOROX catalyst (derived from (S)-VANOL) leading to both cis-epoxide and trans-epoxide. R H OPh B O O 3 B 2 B– O PhO O O * + 1 N2 H O + O H R + N2 H N Bu H – H N Bu H O R OPh B O O 3 B 2 B– O PhO O O * 1 H O + O O R CONHBu Cis (Model III) CONHBu Trans (Model III) 8.6.7.3 Lewis acid catalysis Last but not the least, a completely different mechanism along the idea of chiral Lewis acid type cannot be discarded. In fact, as shown in Figure 8.8, a fourth model is proposed where a chiral Lewis acid in involved in the active site. As of now, the structure of the chiral Lewis cannot be predicted. It may or may not involve DMSO in the active site. However, it seems like 729 that there is a possibility of a hydrogen bonding site for the hydrogen bond with the secondary diazoacetamide. Figure 8.8 Proposed model IV for the mechanism involving chiral Lewis catalyst (derived from (S)-VANOL) leading to both cis-epoxide and trans-epoxide. H:B R * + N2 * H:B LA O R + N2 O H H N Bu H O – O H N Bu H O R LA H O R CONHBu Cis (Model IV) CONHBu Trans (Model IV) In all models proposed above, transoid transition structures have been assumed to be operating, however, there is no evidence to exclude cisoid transition structures. The mechanistic investigations regarding asymmetric epoxidation reaction discussed in this chapter is still in its infant state. Hopefully, future studies will reveal the actual catalyst involved in this case. 8.6.8 Kinetic Isotopic effect studies of asymmetric epoxidation reaction In order to probe further the mechanism of the catalytic asymmetric epoxidation reaction, we decided to probe the transition state geometry of the rate-limiting step using 730 13 C kinetic 22 isotope effects (KIE) measured at natural abundance using the Singleton protocol. As shown in Scheme 8.9A, the epoxidation reaction is generally assumed to go through a two step mechanism with addition of the diazoacetamide 128a to the p-bromobenzaldehyde 127g to form the diazonium ion intermediate (step I) followed by SN2-like elimination (step II) of N2 by the intramolecular nucleophile (the alkoxide). In the given mechanism, transoid transition structures have been assumed to be operating, however, there is no evidence to exclude cisoid transition structures (Scheme 8.9A). If the first step were rate-limiting, a significant KIE would be observed at the aldehyde carbon atom of p-bromobenzaldehyde 127g while rate-limiting SN2like attack would result in a much smaller KIE on the aldehyde carbon. An additional benefit of such a high resolution picture of the transition state geometry is that differences in the transition state geometry with and without the DMSO additive can be probed effectively. With these goals in mind, we performed two experiments - one with and one without DMSO - where we took the starting p-bromobenzaldehyde to 80+/–2% conversion (Scheme 8.10). The unreacted p- bromobenzaldehyde 127g was recovered and its isotopic composition was compared to that of pbromobenzaldehyde 127g from the same bottle, which was not subjected to the reaction conditions. From the relative fractional conversion, the 13 13 C content at each carbon atom for the two samples and the C KIEs for each carbon of p-bromobenzaldehyde 127g was computed using the equation given in Scheme 8.9B. 731 Scheme 8.9 (A) General mechanism of the epoxidation reaction of aldehydes and diazoacetamides catalyzed by our catalyst. (B) Equation used for the calculation of the 13 C KIE values. A R chiral catalyst O O + H 127 O NHBu O R N2 128a CONHBu + R CONHBu trans-135 cis-135 carbon-carbon bond formation (step 1) ‡ ‡ + N2 H H Cat* O CONHBu R H R CONHBu H O N2 + Cat* ring-closure (step 2) O R O R CONHBu CONHBu trans-135 cis-135 B KIE = ln(1-F) ln[(1-F)(R/Ro)] F = fractional conversion R/Ro = ratio of the 13 C in aldehyde prior to and after reaction as determined by quantitative 732 13 C NMR. For the reaction with added DMSO, the aldehyde carbon exhibited a KIE of 1.025 (8) while for the reaction without DMSO, a KIE of 1.030 (6) was measured. The number in parenthesis is the uncertainty in the last digit of the measurement obtained with 95% confidence from 6 independent measurements. All other carbon atoms exhibited KIEs within error of unity. The qualitative interpretation of the KIEs is that the aldehyde carbon atom is involved in the ratelimiting transition state and assuming the above mentioned two-step mechanism, the carboncarbon bond forming (step I) is the rate-limiting step. The quality of the NMR results was not sufficient to ascertain the slight difference between the experiments performed with and without DMSO but the different values suggest that the addition of DMSO slightly alters the transition state geometry (especially since the KIEs for the other carbon atoms are nearly identical). Further validation of these results can be obtained by calculation of the transition state and theoretical prediction of the 8.7 13 C KIEs. Gram scale catalysis and large scale synthesis The real application of any methodology lies in its easy adaption towards the large-scale synthesis. The catalytic asymmetric epoxidation was easily applicable to gram scale (Scheme 8.10). The large scale synthesis (4.8 mmol in diazoacetamide 128a) was performed using the catalysts 432 (with DMSO) and 448a (without DMSO). The same reaction was utilized in obtaining the sample of the unreacted p-bromobenzaldehyde 127g for the KIE studies (section 8.6.8). The only downfall of the large scale reaction was the drop in the ee by ~9–11% in both the cases. However, the enantiomeric excess can easily be increased up to 99% ee by a single crystallization. It is advisable to reproduce this result so as to check whether the drop in ee is genuine or is actually an experimental error. 733 Scheme 8.10 Gram scale asymmetric catalysis R catalyst (10 mol%) O O + H 127g (6.0 mmol) NHBu R toluene –60 °C, 24 h N2 O O 128a (4.8 mmol) CONHBu R 135g R = 4-Br-C6H4 %ee %ee %yield before 1st 1st recryst Crop Crop 135g 135g 135g 135g 432 (with DMSO) 448a (without DMSO) 78 70 90 79 NHBu 136g %y catalyst O + 99 97 65 60 c:t %y 136g 30:1 15:1 5 13 In order to perform the large scale epoxidation reaction, we needed a large quantity of the diazoacetamide 128a. Since, the same diazo compound has been the used in all the epoxidations we performed, we thought of devising an easy and economic route to prepare diazoacetamide 128a. In doing so, we came across the large scale synthesis of the parent diazo compound i.e. succinimidyl diazoacetate 454. This compound has been widely used in the synthesis of various diazo compounds. 23 The synthesis of this compound was reported via DCC coupling of the acid 23 451 and N-hydroxy succinimide 453. The reported procedure was often low yielding and irreproducible. In fact, the purification involved several column chromatographies and was too cumbersome. So, we decided to follow another reported procedure that involved the synthesis 24 starting from acid chloride 452. We prepared the acid chloride 452 in large quantities (210 mmol scale) using a reported procedure. 25 Delightfully, the synthesis of 454 (50 mmol scale) 734 was found to be much cleaner using the second procedure where the reaction was started with acid chloride 452. The crude succinimidyl diazoacetate 454 was purified by crystallization only. Thereafter, the diazoacetamide 128a was prepared on a large scale (40 mmol) in 90–93% yield. The entire process of preparation of diazo compounds 454 and 128a was carried out efficiently without the use of any column chromatography purification. Scheme 8.11 Large scale synthesis of diazo compounds 454 and 128a OH OH HO O p-Ts N H O 450 NH2 p-Ts 2.5 M HCl, H2O 79% (96.4 g) 500 mmol scale 449 N N H OH 451 O HO O N O O p-Ts N Na2CO3, CH2Cl2 O N2 (35.6 g) 210 mmol scale reflux, 1h 453 O 65% benzene O SOCl2 0 °C to 25 °C, 6 h 454 452 60% (5.51 g) 50 mmol scale H2N (2 equiv) O 126n THF, rt, 1 h 40 mmol 90-93% (5.1-5.25 g) scale 735 N N H N2 N H 128a Cl 8.8 Conclusions We have been able to successfully realize the catalytic asymmetric epoxidation of the aldehydes, probably, using either SULFOX-BOROX catalyst or DIAZO-BOROX catalyst. Although the mode of catalysis has not been completely determined, it seems that the reaction is potentially is a Brønsted acid catalyzed reaction based on the initial studies towards the mechanism of the reaction. Also, it is quite general for a wide range of aldehydes in terms of substrate group. 736 APPENDIX 737 8.9 Experimental 8.9.1   General Information ........................................................................................................ 739   8.9.2   Synthesis of diazoacetate 450, diazoacetamides 123a-b and 128a-f ............................. 739   8.9.3   Initial screening of various diazoacetamides (Table 8.2) ............................................... 751   8.9.4   Synthesis of epoxides 135a-g (Table 8.6)....................................................................... 759   8.9.5   One pot procedure for epoxidation reaction (Table 8.5)................................................. 776   8.9.6   Epoxidation using catalyst 447 (Scheme 8.8) ................................................................. 777   8.9.7   Epoxidation using the DIAZO-BOROX catalyst 448a (Table 8.8) ................................ 779   8.9.8   NMR analysis of boroxinate catalysts 432 and 448a (Figure 8.4) ................................. 780   8.9.9   Gram scale asymmetric catalysis and KIE studies (Scheme 8.9-8.11) ........................... 782 738 8.9.1 General Information Same as Chapter 2. 8.9.2 Synthesis of diazoacetate 450, diazoacetamides 123a-b and 128a-f OH OH HO O p-Ts N H NH2 O 450 p-Ts 2.5 M HCl, H2O 79% (96.4 g) 500 mmol scale 449 N N H OH 451 O HO O N O O 454 O p-Ts N N2 (35.6 g) 210 mmol scale reflux, 1h 453 O 65% benzene O SOCl2 Na2CO3, CH2Cl2 0 °C to 25 °C, 6h 60% (5.51 g) N H N Cl 452 50 mmol scale 2-(2-tosylhydrazono)acetic acid 451: To a 1 L single-necked round bottom flask was added glyoxylic acid monohydrate 450 (46.3 g, 500 mmol) and water (500 mL). The mixture was stirred at 65 ºC (oil bath) until 450 dissolved completely. To this solution was then added a warm suspension (at approximately 65ºC) of p-toluenesulfonylhydrazide 449 (93.1 g, 500 mmol) in 2.5 M aqueous hydrochloric acid (300 mL). The reaction mixture was stirred at 65 ºC for 15 min, then allowed to cool to room temperature gradually until all of the oil solidified and then the flask was kept in a refrigerator overnight. The crude product was collected on filter paper using a Büchner funnel (8 cm diameter), washed with cold water (70 mL), and dried for 2 days in open 739 air followed by exposure to high vacuum overnight. To a 1 L single-necked round bottom flask containing acid 451 and equipped with a stir bar and with a condenser was added boiling EtOAc until the entire solid dissolved. Hexanes were added until the solution became cloudy. Thereafter, hot EtOAc was added until it just became clear again. The solution was then allowed to cool to room temperature and then allowed to set in a refrigerator overnight (–20 ºC). The solid was filtered and washed with ice-cold 1:2 EtOAc/hexanes to afford 451 as a white solid (mp 150-152 ºC) in 79% isolated yield (96.4 g, 400 mmol). 1 Spectral data for 451: Rf = 0.45 (1:1, EtOAc/hexane); H NMR (CDCl3, 300 MHz) δ 2.39(s, 3H), 7.29 (s, 1H), 7.40 (d, 2H, J = 8.5Hz), 7.78 (d, 2H, J = 8.3Hz), 10.05 (brs, 1H), 11.00 (brs, 1H); 13 C NMR (CD3COCD3, 75 MHz) δ 21.37, 128.42, 130.57, 136.81, 137.28, 145.28, 163.72. 18 These spectral data match those previously reported for this compound. 2-(2-tosylhydrazono)acetyl chloride 452: To a suspension of acid 451 (50.2 g, 210 mmol) in benzene (250 mL) was added SOCl2 (30 mL, 420 mmol, freshly distilled). The reaction mixture was heated to reflux (90 ºC oil bath) until vigorous gas evolution has ceased and most of the suspended solid has dissolved (~2 h). The heating period is critical to the success of this reaction. After a heating period of 45-90 minutes the initially white suspension begins to turn yellow and the color gradually deepens as heating is continued. The correct heating period is normally reached about 10 minutes after vigorous gas evolution ceases; at this time the color of the reaction mixture is yellow-orange to orange. At this point the mixture is not clear, but relatively little suspended material separates when the stirrer is stopped for a short period. If heating is stopped too soon, a large amount of acid is lost during the filtration and the product is 740 difficult to crystallize. If heating is continued too long, the product is contaminated with a brown colored impurity and is difficult to crystallize. The reaction mixture then was cooled under nitrogen and filtrated through a Celite pad on a sintered-glass funnel. After the filtrate has been concentrated to dryness under reduced pressure, the residual solid is mixed with anhydrous benzene (50 mL, warmed to ~40 to 50 ºC), and the solid mass was broken up to give a fine suspension. The suspension was cooled and filtered quickly using a Büchner funnel (8 cm diameter) and then the solid was washed quickly with cold benzene (30 mL × 2) to remove most of the residual colored impurities. The combined filtrates were stripped of solvent on the rotovapor and the residue was washed quickly with cold benzene (30 mL × 2) to give a second crop of the crude product. Purification by crystallization was achieved by dissolving the crude product in boiling benzene (~100 mL), followed by the addition of hexanes (~100 mL, bp. 60-90 ℃). The mixture was allowed to cool down to room temperature, and stand overnight. The acid chloride 452 was collected as a white solid (mp. 100-103℃) in 65% isolated yield (35.6g, 137 mmol). 1 Spectral data for 452: H NMR (CDCl3, 500 MHz) δ 2.46 (s, 3H), 7.25 (d, 1H, J = 0.9 Hz), 7.38 (d, 2H, J = 8.0 Hz), 7.86 (d, 2H, J = 8.4 Hz), 9.38 (s, 1H); 13 C NMR (CDCl3, 125 MHz) δ 21.70, 128.10, 130.14, 133.78, 136.05, 145.81, 165.01. These spectral data match those previously reported for this compound. 18 2,5-dioxopyrrolidin-1-yl 2-diazoacetate 454: To a flame dried 500 mL single-necked roundbottom flask was added N-hydroxysuccinimide 453 (6.33 g, 55.0 mmol) and Na2CO3 (7.95 g, 741 75.0 mmol) and dry CH2Cl2 (75 mL). The flask was then brought to 0 °C using a chiller over a period of 30 min. Meanwhile, to another flame-dried 250 mL single-necked round-bottom flask was added acid chloride 452 (13.04 g, 50.00 mmol) and dry CH2Cl2 (100 mL). This solution was added to the suspension of succinimide at 0 °C over a period of 2 h utilizing a syringe pump. Two syringe pumps were used and two 60 mL plastic syringes, containing 50 mL of the CH2Cl2 solution of 452, were employed. The resulting mixture was stirred for an additional hour at 0 ºC. After 1 h, the solution was warmed to room temperature and then stirred for 3 h at room temperature. The reaction mixture was then filtered using a Büchner funnel (8 cm diameter) with filter paper and the filtrate was collected in a 500 mL round-bottom flask. It must be noted that a direct passage of the reaction mixture through a short plug of silica plug results in the clogged plug, thereby a substantial loss of the material. The residue was then washed with EtOAc (200 mL × 2). A small amount of solid is observed in the filtrate. The solid impurities remaining in the filtrate were removed by passing through a short plug (35 mm × 60 mm) of silica gel. The filtrate was collected in a 500 mL round-bottom flask. The silica plug was then washed with EtOAc (150 mL × 2). The washing was monitored by TLC. The resulting solution was then concentrated under reduced pressure to provide crude succinimidyl diazoacetate as a light yellow solid (~6.36 g). The crude diazo compound was kept under vacuum for a period of 1 h. Recrystallization from CH2Cl2/ hexanes (55 mL, 4:1) gave diazo 454 (mp 113.5-115.0 °C) as light yellow solid crystals in 29% yield (2.68 g, 14.5 mmol, first crop). Successive crystallization yielded the diazo 454 a combined yield of 60% (29%, 2.68 g, mp 113.5-115.0 °C, first crop; 15%, 1.40 g, mp 115.0-118.0 °C, second crop; 16%, 1.43 g, mp 115.0-118.0 °C, third 742 crop). The amounts of solvent (CH2Cl2/ hexanes, 4:1) used for second and third crystallizations are 29 mL and 19 mL respectively. The amounts of the solid residue from the mother liquor after the first and second crystallizations are 3.57g and 2.15 g respectively. The second run of the reaction resulted in 56% yield of the diazoacetate 454. 1 Spectral data for 454: Rf = 0.13 (3:1 ether/hexanes); H NMR (CDCl3, 500 MHz) δ 2.81 (s, 4H), 5.10 (brs, 1H); 13 C NMR (CDCl3, 125 MHz) δ 25.44, 45.11, 162.24, 169.36; IR (thin film) -1 3105w, 2135s, 1736vs, 1375s, 1206s, 1105s cm ; mass spectrum, m/z (% rel intensity) 183 M + (1), 155 (3), 69 (100), 56 (16), 42 (11). These spectral data match those previously reported for this compound. O 18 O O O + N O N2 454 H2N THF, rt, 1 h (2 equiv) 126n 90-93% (5.1-5.25 g) 40 mmol scale N2 N H 128a N-butyl-2-diazoacetamide 128a: To a flame dried 100 mL single-necked round-bottom flask was added succinimidyl diazoacetate 454 (7.33 g, 40 mmol) and THF (400 mL). To the solution was added n-butylamine 126n (8 mL, 80 mmol, freshly distilled) in one portion. Appearance of a yellow solid was observed after 1-2 min. The reaction mixture was stirred for 1 h at room temperature. The reaction was complete and the solvent was removed under reduced pressure. Purification of the crude diazo by silica gel chromatography (30 mm × 300 mm column, 1:3 hexanes/EtOAc) afforded pure diazo 128a as a yellow solid (mp 75-76 ºC) in 90-93% isolated yield (5.10-5.25 g, 35-37.2 mmol). Alternatively, the crude product, after the evaporation of the 743 solvent, was directly passed through a short plug (35 mm × 60 mm) of silica gel. The silica plug was then washed with 1:3 hexanes/EtOAc (100 mL). The washing is continued until the yellow color has stopped coming down the plug. All yellow fractions can be collected in a flask and the solvent is evaporated to afford pure diazo 128a as a yellow solid. No difference in the yield was observed when the purification was performed in this way compared to column chromatography. 1 Spectral data for 128a: Rf = 0.33 (1:1 EtOAc:hexanes); H NMR (CDCl3, 500 MHz) δ 0.90 (t, 3H, J = 7.3 Hz), 1.29-1.36 (m, 2H), 1.44-1.50 (m, 2H), 3.26 (brs, 2H), 4.68 (brs, 1H), 5.10 (brs, 1H); 13 C NMR (CDCl3,125 MHz) δ 13.42, 19.82, 31.90, 39.76, 46.82, 165.34. These spectral data match those previously reported for this compound. N-benyl-2-diazoacetamide 128b: O N2 N H 128b 16 Diazoacetamide 128b was prepared Ph according to the procedure described above for diazoacetamide 128a except that the scale of the reaction was 4 mmol. Purification of the crude diazo by silica gel chromatography (30 mm × 300 mm column, 1:3 hexanes/EtOAc) afforded pure diazo 128b as a yellow solid (mp 97-98 ºC) in 91% isolated yield (638 mg, 3.64 mmol). 1 Spectral data for 128b: Rf = 0.33 (1:1 EtOAc:hexanes); H NMR (CDCl3, 500 MHz) δ 4.37 (d, 2H, J = 5.5 Hz), 4.82 (s, 1H), 6.22 (bs, 1H), 7.23-7.32 (m, 5H); 13 C NMR (CDCl3,125 MHz) δ 43.74, 46.99, 127.34, 127.43, 128.56, 138.36, 165.51. These spectral data match those previously reported for this compound. 16 744 O O O Ph + N H2N O N2 Ph (1.5 equiv) 450 Et3N CH2Cl2 0 ºC to 25 ºC, 24 h 80% 126a Ph O N2 N H Ph 128c N-benzhydryl-2-diazoacetamide 128c: To a flame-dried 50 mL round bottom flask filled with argon was added benzhydrylamine 126a (1.03 mL, 6.00 mmol) and CH2Cl2 (4 mL), followed by dry Et3N (0.84 mL, 6.00 mmol) at 0 ºC. After stirring for 5 min, the solution of succinimidyl diazoacetate 454 (733 mg, 4.00 mmol) in CH2Cl2 (6 mL) was added slowly over a period of 10 min. The reaction mixture was stirred for 0.5 h at 0 ºC, then allowed to warm up to room temperature and stirred for another 24 h. The reaction was complete and the solvent was removed under reduced pressure, and the crude product was purified by silica gel chromatography (20 mm × 200 mm, 1:3 EtOAc/ hexanes as eluent) to afford diazoacetamide 128c (mp 175-176 ºC) as a yellow solid in 80% yield (1.21 g, 3.20 mmol). 1 Spectral data for 128c: Rf = 0.73 (1:1, EtOAc/hexanes). H NMR (CDCl3, 600 MHz) δ 4.76 (s, 1H), 5.56 (d, J = 6.6 Hz, 1H), 6.26 (brs, 1H), 7.23 (d, J = 7.3 Hz, 4H), 7.28 (d, J = 7.2 Hz, 2H), 1 7.33 (t, J = 7.3 Hz, 4H); H NMR (DMSO-d6, 500 MHz) δ 5.42 (s, 1H), 6.14 (d, J = 8.4 Hz, 1H), 7.25-7.35 (m, 10H), 8.52 (d, J = 8.3 Hz, 1H); 13 C (DMSO-d6, 125 MHz) 46.37, 56.31, 126.94, 127.11, 128.37, 142.54, 164.28; IR (thin film) 3250br, 3090m, 2103vs, 1605s, 1543s, 745 -1 + 1495w, 1371s cm ; HRMS (ESI-TOF) m/z 252.1140 [(M+H ); calcd. for C15H14N3O : 252.1137]. 2-diazo-N-nonylacetamide 128d: O N2 N H 6 128d Diazoacetamide 128d was prepared according to the procedure described above for diazoacetamide 128a except that the scale of the reaction was 1 mmol and the reaction time was 3 h. Purification of the crude diazo by silica gel chromatography (30 mm × 300 mm column, 1:3 hexanes/EtOAc) afforded pure diazo 128d as a yellow solid (mp 68-69 ºC) in 87% isolated yield (184 mg, 0.87 mmol). 1 Spectral data for 128d: Rf = 0.62 (1:1 EtOAc:hexanes); H NMR (CDCl3, 500 MHz) δ 0.87 (t, J = 6.9 Hz, 3H), 1.25-1.29 (m, 12H), 1.47-1.51 (m, 2H), 3.25-3.28 (m, 2H), 4.69 (s, 1H), 5.07 (s, 1H); 13 C NMR (CDCl3,125 MHz) δ 14.02, 22.59, 26.83, 29.19, 29.26, 29.45, 29.90, 31.80, 40.04, 46.88, 165.52. IR (thin film) 3297s, 3098w, 2922s, 2851m, 2108vs, 1603s, 1549s, 1474w, -1 + 1397m cm ; HRMS (ESI-TOF) m/z 212.1756 [(M+H ); calcd. for C11H22N3O: 212.1763]. N-cyclohexyl-2-diazoacetamide 128e: Diazoacetamide 128e was prepared O N2 N H 128e according to the procedure described above for diazoacetamide 128a except that the scale of the reaction was 1 mmol and the reaction time was 3 h. 746 Purification of the crude diazo by silica gel chromatography (30 mm × 300 mm column, 1:3 hexanes/EtOAc) afforded pure diazo 128e as a yellow solid (mp 152-153 ºC) in 91% isolated yield (152 mg, 0.91 mmol). 1 Spectral data for 128e: Rf = 0.50 (1:1 EtOAc:hexanes); H NMR (CDCl3, 500 MHz) δ 1.08-1.19 (m, 3H), 1.32-1.40 (m, 2H), 1.61 (dt, J = 13.0, 3.8 Hz, 1H), 1.67-1.72 (m, 2H), 1.91-1.94 (m, 2H), 3.79 (s, 1H), 4.68 (s, 1H), 5.01 (s, 1H); 13 C NMR (CDCl3,125 MHz) δ 24.85, 25.47, 33.53, 47.00, 48.87, 164.48. IR (thin film) 3279s, 3100m, 2924s, 2853m, 2101vs, 1614s, 1562s, 1447w, -1 + 1387m cm ; HRMS (ESI-TOF) m/z 168.1138 [(M+H ); calcd. for C8H14N3O: 168.1137]. N-(tert-butyl)-2-diazoacetamide 128f: O Diazoacetamide 128f was prepared according to the procedure described above for diazoacetamide 128a except that 128f N2 N H the scale of the reaction was 1 mmol, the reaction time was 36 h and 4 equivalents of tert-butyl amine was used. Purification of the crude diazo by silica gel chromatography (30 mm × 300 mm column, 1:3 hexanes/EtOAc) afforded pure diazo 128f as a yellow solid (mp 141142 ºC) in 81% isolated yield (114 mg, 0.81 mmol). 1 Spectral data for 128f: Rf = 0.62 (1:1 EtOAc:hexanes); H NMR (CDCl3, 600 MHz) δ 1.37 (s, 9H), 4.61 (s, 1H), 4.86 (s, 1H); 13 C NMR (CDCl3,125 MHz) δ 29.17, 47.45, 51.88, 164.75. IR -1 (thin film) 3279s, 3098m, 2968m, 2091vs, 1616s, 1559s, 1456w, 1375s cm ; HRMS (ESI-TOF) + m/z 142.0984 [(M+H ); calcd. for C6H12N3O: 142.0980]. 747 O O O + N O N2 O Et3N N H N Ph CH2Cl2 (1.17 equiv) 126s N2 0 ºC to 25 ºC, 1.5 h 92% 454 Ph 442a N-benzyl-2-diazo-N-methylacetamide 442a: To a flame-dried 50 mL round bottom flask filled with argon was added amine 126s (0.85 mL, 6.55 mmol) and CH2Cl2 (5 mL), followed by dry Et3N (1.15 mL, 8.19 mmol) at 0 ºC. After stirring for 5 min, the solution of succinimidyl diazoacetate 454 (1.0 g, 5.6 mmol) in CH2Cl2 (10 mL) was added slowly over a period of 10 min. The reaction mixture was stirred for 0.5 h at 0 ºC, then allowed to warm up to room temperature and stirred for another 1 h. The reaction was complete and the solvent was removed under reduced pressure, and the crude product was purified by silica gel chromatography (25 mm × 450 mm, 1:1 EtOAc/ hexanes as eluent) to afford diazoacetamide 442a as a yellow liquid in 92% yield (0.97 g, 5.10 mmol). 1 Spectral data for 442a: Rf = 0.38 (1:1, EtOAc/hexanes). H NMR (CDCl3, 300 MHz) δ 2.84 (br s, 3H), 4.47 (br s, 2H), 4.96 (s, 1H), 7.19-7.34 (m, 5H); 13 C (CDCl3, 75 MHz) δ 46.34, 51.72, 2 127.39, 128.62, 136.84, 166.00 (two sp carbon not located); IR (thin film) 3065s, 2100vs, -1 + 1611vs, 1477s, 1408s cm ; mass spectrum, m/z (% rel intensity) 161 M –N2 (2), 117 (45), 103 (97), 91 (100), 64 (24), 50 (17). These spectral data match those previously reported for this compound. 18 748 O p-Ts N H N 452 + Cl DBU (2 equiv) H2N CH2Cl2 (1.10 equiv) 0 ºC , 2 h 126k 45% O N2 N H 123a 2-diazo-N-phenylacetamide 123a: To a flame-dried 100 mL round bottom flask equipped with a magnetic stir bar and flushed with argon was added acid chloride 452 (3.60 g, 13.82 mmol, 1 equiv) and dry CH2Cl2 (30 mL). The flask was then fitted with a rubber septum and an Argon balloon and cooled to 0 °C in an ice-bath. The reaction mixture was stirred at 0 °C for 15 min. Aniline 126k (1.40 mL, 15.2 mmol, 1.10 equiv) and DBU (4.20 mL, 27.6 mmol, 2.00 equiv) were then added sequentially to the reaction flask at 0 °C via plastic syringes. The reaction mixture was stirred at 0 °C for 2 h, and then warmed up to room temperature. It was then added to sat. NH4Cl (~30 mL), and the layers separated. The aqueous layer was extracted with CH2Cl2 once, the organic layers combined, washed with brine once, dried over Na2SO4, and filtered. The product solution thereafter was transferred to a 250 mL round bottom flask and enough silica gel was added for subsequent column chromatography (“dry load”). This was then subjected to rotary evaporation till dryness, and directly loaded on a silica gel column (30 mm × 270 mm). An eluent mixture of 1:50 MeOH:CH2Cl2 was used for the flash chromatography, all yellow colored fractions were collected, and subjected to rotary evaporation till dryness and finally high vacuum to afford the impure product 123a as a yellow solid. This was then washed with ether 1-4 times until a single spot was observed on TLC (1:29 MeOH:CH2Cl2), this 749 afforded pure diazoacetamide 123a (mp. 147-149 ºC) as a bright yellow solid in 45% yield (1.0 g, 6.2 mmol). 1 Spectral data for 123a: Rf = 0.18 (1:50 MeOH:CH2Cl2); H NMR (d6-DMSO, 500 MHz) δ 5.48 (s, 1H), 6.99 (t, J = 7.3 Hz, 1H), 7.26 (t, J = 8.5 Hz, 2H), 7.51 (d, J = 7.6 Hz, 2H), 9.69 (s, 1H); 13 C NMR (d6-DMSO, 125 MHz) δ 48.01, 118.58, 122.66, 128.75, 139.52, 163.53. These spectral data match those previously reported for this compound. Cl N-(4-chlorophenyl)-2-diazoacetamide 123b: Diazoacetamide 123b was O N2 16 N H 123b prepared according to the procedure described above for diazo 123a. Purification of the crude diazo afforded pure diazo 123b as a yellow solid (mp 145-146 ºC, decomposition) in 30% isolated yield (811 mg, 4.20 mmol). 1 Spectral data for 123b: Rf = 0.32 (1:50 MeOH:CH2Cl2); H NMR (d6-DMSO, 500 MHz) δ 5.48 (s, 1H), 7.32 (d, 2H, J = 8.7 Hz), 7.54 (d, 2H, J = 8.7 Hz), 9.84 (s, 1H); 13 C NMR (d6-DMSO, 125 MHz) δ 48.23, 120.08, 126.15, 128.64, 138.47, 163.68. These spectral data match those previously reported for this compound. 16 750 8.9.3 Initial screening of various diazoacetamides (Table 8.2) (S)-SULFOX-BOROX + [DMSO-H] OPh catalyst 432 O O O O O (10 mol%) + + O –O B NHPh Ph CONHPh Ph B O NHPh * CHCl3 Ph H N2 O O B –40 °C, 24 h OPh 127a 123a 426a 427a 0.4 M SULFOX-BOROX catalyst 432 B(OPh)3 (3 equiv) DMSO OH (10 mol%) OH H2O (3 equiv) * (S)-SULFOX-BOROX pre* OH OH catalyst 432 1h catalyst THF, 80 °C, 1 h 59 = (S)-VANOL then 0.5 mm Hg (10 mol%) 80 °C, 0.5 h (2S,3S)-N,3-diphenyloxirane-2-carboxamide 426a: Preparation of the pre-catalyst stock solution : To a 25 mL flame-dried home-made Schlenk flask , prepared from a single-necked 25 mL pear-shaped flask that had its 14/20 glass joint replaced with a high vacuum threaded Teflon valve, equipped with a stir bar and flushed with argon was added (S)-VANOL (52.6 mg, 0.120 mmol) and commercial B(OPh)3 (104.5 mg, 0.3600 mmol) and water (6.5 µL, 0.36 mmol). Under an argon flow through the side-arm of the Schlenk flask, dry THF (2 mL) was added through the top of the Teflon valve to effect dissolution. The flask was sealed by closing the Teflon valve, and then placed in a 80 ºC oil bath for 1 h. After 1 h, a vacuum (0.5 mm Hg) was carefully applied by slightly opening the Teflon valve to remove the volatiles. After the volatiles were removed completely, a full vacuum was applied and maintained for a period of 30 min at a temperature of 80 ºC (oil bath). The flask was then allowed to cool to room temperature and opened to argon through the side-arm of the Schlenk flask. This was then completely dissolved in dry CHCl3 (3 mL) under an argon flow through side-arm of the Schlenk flask to afford the 751 stock solution of the pre-catalyst. An aliquot of 1mL of the pre-catalyst was then transferred to a 10 mL flame-dried home-made Schlenk flask equipped with a stir bar and flushed with argon. Asymmetric epoxidation protocol: To the flask containing the pre-catalyst (1 mL aliquot from 0.04 M stock solution) was added the dimethyl sulfoxide 221a (2.84 µL, 0.040 mmol) under an argon flow through side-arm of the Schlenk flask. The resulting mixture was stirred for 1 h at room temperature to give SULFOX-BOROX catalyst 432. After 1 h, the flask containing the catalyst was cooled to –40 °C for 10 min. To this solution was added benzaldehyde 127a (40.4 µL, 0.400 mmol, freshly distilled). This was then followed by closing the Teflon valve and stirring the resulting mixture for 10 min at –40 °C. To this mixture was then added diazoacetamide 123a (80.6 mg, 0.500 mmol, 1.25 equiv) and the resulting mixture was stirred for 24 h at –40 °C. The reaction was quenched by the addition of Et3N (0.5 mL) and was then warmed to room temperature. The reaction mixture was then transferred to a 50 mL round bottom flask. The reaction flask was rinsed with EtOAc (3 mL × 2) and the rinse was added to the 50 mL round bottom flask. The resulting solution was then concentrated in vacuo followed by exposure to high vacuum (0.05 mm Hg) for 1 h to afford the crude epoxide as an off-white semi-solid. 1 The cis/trans ratio was determined by comparing the H NMR integration of the ring methine protons for each epoxide in the crude reaction mixture. The yield of the acyclic β1 ketoamide side product 427a was determined by H NMR analysis of the crude reaction mixture by integration of the methylene protons relative to the internal standard (Ph3CH). Purification of the crude epoxide by neutral alumina chromatography (17 mm × 300 mm column, 10:1 to 1:1 752 hexanes/ CH2Cl2 as eluent) afforded pure cis-epoxide 426a as a white solid (mp 101-103 ºC on 99% ee material) in 68% isolated yield (65.1 mg, 0.272 mmol); cis/trans: 40:1. β-ketoamide side product 427a: 13.6% yield. The optical purity of 426a was determined to be 62% ee by HPLC analysis (CHIRALCEL OD-H column, 90:10 hexane/2-propanol at 222 nm, flow-rate: 1 mL/min): retention times; Rt = 8.17 min (major enantiomer, 426a) and Rt = 10.33 min (minor enantiomer, ent-426a). The melting point was taken after a single crystallization. 1 Spectral data for 426a: Rf = 0.32 (1:3 EtOAc/hexanes); H NMR (CDCl3, 500 MHz) δ 3.94 (d, 1H, J = 4.6 Hz), 4.44 (d, 1H, J = 4.7 Hz), 7.07 (t, 1H, J = 7.1 Hz), 7.17-7.25 (m, 4H), 7.28-7.35 (m, 3H), 7.43 (d, 2H, J = 7.3 Hz), 7.55 (bs, 1H); 13 C (CDCl3, 125 MHz) δ 56.51, 58.65, 120.21, 124.86, 126.39, 128.55, 128.69, 128.85, 132.78, 135.96, 164.40; IR (thin film) 3321w, 3061w, -1 + 2922w, 1672s, 1599m, 1529s, 1444s cm ; HRMS (ESI-TOF) m/z 240.1027 [(M+H ); calcd. for C15H14NO2 : 240.1025]; [α ]20 +14.7 (c 1.0, CH2Cl2) on 62% ee material (HPLC). D O O 435a (2S,3S)-N-(4-chlorophenyl)-3-phenyloxirane-2- H N carboxamide 435a: Aldehyde 127a was reacted with Cl diazoacetamide 123b according to the method described above for epoxide 426a with (S)-VANOL as ligand. Purification of the crude epoxide by neutral alumina chromatography (17 mm × 300 mm column, 10:1 to 1:1 hexanes/ CH2Cl2 as eluent) afforded pure cis-epoxide 435a as a white solid (mp 113-114 ºC on 52% ee material) in 60% isolated yield (65.7 mg, 0.240 mmol); cis/trans: 29:1. β-ketoamide side product 437a: 8.5% 753 yield. The optical purity of 435a was determined to be 52% ee by HPLC analysis (PIRKLE COVALENT (R,R) WHELK-O 1 column, 93:7 hexane/2-propanol at 228 nm, flow-rate: 1 mL/min): retention times; Rt = 25.69 min (major enantiomer, 435a) and Rt = 39.42 min (minor enantiomer, ent-435a). 1 Spectral data for 435a: Rf = 0.48 (1:2 EtOAc/hexane); H NMR (CDCl3, 500 MHz): δ 3.91 (d, J = 4.8 Hz, 1H), 4.43 (d, J = 4.8 Hz, 1H), 7.10 (d, J = 8.9 Hz, 2H), 7.16 (d, J = 8.8 Hz, 2H), 7.28 (d, J = 7.1 Hz, 1H), 7.32 (t, J = 7.2 Hz, 2H), 7.39 (d, J = 7.2 Hz, 2H), 7.50 (s, 1H). 13 C (CDCl3, 125 MHz) δ 56.35, 58.64, 121.34, 126.35, 128.58, 128.77, 128.92, 129.95, 132.69, 134.51, -1 164.49; IR (thin film) 3312 br, 3080 s, 1676 vs, 1589s, 1516vs, 1402 s cm ; HRMS (ESI-TOF) + m/z 274.0641 [(M+H ); calcd. for C15H13ClNO2 : 274.0635]; [α ]20 +47.9 (c 1.0, EtOAc) on D 52% ee material (HPLC). O H N O 135a (2S,3S)-N-butyl-3-phenyloxirane-2-carboxamide 135a: Aldehyde 127a was reacted with diazoacetamide 128a according to the method described above for epoxide 426a with (S)-VANOL as ligand. Purification of the crude epoxide by neutral alumina chromatography (17 mm × 300 mm column, 3:1 hexanes/ EtOAc as eluent) afforded pure cis-epoxide 135a as a white solid (52-53 ºC on 99.3 % ee material) in 50% isolated yield (43.9 mg, 0.200 mmol); cis/trans: 16:1. β-ketoamide side product 136a: 13.7% yield. The optical purity of 135a was determined to be 62% ee by HPLC analysis (PIRKLE COVALENT (R,R) WHELK-O 1 column, 93:7 754 hexane/2-propanol at 228 nm, flow-rate: 1 mL/min): retention times; Rt = 13.8 min (major enantiomer, 135a) and Rt = 24.6 min (minor enantiomer, ent-135a). 1 Spectral data for 135a: Rf = 0.61 (1:1 EtOAc/hexane); H NMR (CDCl3, 500 MHz) δ 0.72 (t, J = 7.2 Hz, 3H), 0.89-1.04 (m, 4H), 2.82-2.88 (m, 1H), 3.08 (dq, J = 13.6, 6.9 Hz, 1H), 3.77 (d, J = 4.8 Hz, 1H), 4.31 (d, J = 4.8 Hz, 1H), 5.84 (s, 1H), 7.35-7.28 (m, 5H); 13 C (CDCl3, 125 MHz) δ 13.53, 19.62, 31.17, 38.21, 56.27, 58.08, 126.49, 128.31, 128.38, 133.19, 165.95; IR (thin film) -1 3316 br, 2959 vs, 2932 vs, 1651 vs, 1545 s, 1454 s cm ; HRMS (ESI-TOF) m/z 220.1334 + [(M+H ); calcd. for C13H18NO2 : 220.1338]; [α ]20 +18.6 (c 1.0, EtOAc) on 99.3% ee material D (HPLC). O N-butyl-3-oxo-3-phenylpropanamide 136a: oil, isolated in 13% O N H Ph 136a yield. 1 Spectral data for 136a: Rf = 0.40 (1:3 EtOAc/hexane); H NMR (CDCl3, 500 MHz): δ 0.92 (t, J = 7.4 Hz, 3H), 1.33-1.39 (m, 2H), 1.49-1.55 (m, 2H), 3.30 (td, J = 7.1, 5.7 Hz, 2H), 3.94 (s, 2H), 7.07-7.15 (m, 1H), 7.47-7.51 (m, 2H), 7.61 (ddt, J = 8.4, 6.5, 1.6 Hz, 1H), 8.00 (dt, J = 8.4, 1.6 Hz, 2H); 13 C (CDCl3, 125 MHz): δ 13.69, 20.04, 31.43, 39.40, 45.26, 128.56, 128.85, 134.04, 136.23, 165.55, 196.37. previously reported for this compound. 26 755 These spectral data match those O H N (2S,3S)-N-benzyl-3-phenyloxirane-2-carboxamide 436a: Ph Aldehyde 127a was reacted with diazoacetamide 128b according to O the method described above for epoxide 426a with (S)-VANOL as 436a ligand. Purification of the crude epoxide by neutral alumina chromatography (17 mm × 300 mm column, 3:1 hexanes/ EtOAc as eluent) afforded pure cis-epoxide 436a as a white solid (mp 108110 ºC on 62% ee material) in 55% isolated yield (55.7 mg, 0.220 mmol); cis/trans: >50:1. βketoamide side product 438a: 15.5% yield. The optical purity of 436a was determined to be 62% ee by HPLC analysis (PIRKLE COVALENT (R,R) WHELK-O 1 column, 93:7 hexane/2propanol at 228 nm, flow-rate: 1 mL/min): retention times; Rt = 32.55 min (major enantiomer, 436a) and Rt = 18.91 min (minor enantiomer, ent-436a). 1 Spectral data for 436a: Rf = 0.63 (1:1 EtOAc/hexane); H NMR (CDCl3, 500 MHz): δ 3.84 (d, J = 4.8 Hz, 1H), 4.06 (dd, J = 14.9, 5.0 Hz, 1H), 4.29 (dd, J = 14.9, 6.9 Hz, 1H), 4.34 (d, J = 4.8 Hz, 1H), 6.17 (s, 1H), 6.72 (d, J = 6.8 Hz, 2H), 7.14-7.20 (m, 3H), 7.28-7.35 (m, 5H); 13 C (CDCl3, 125 MHz): δ 42.65, 56.31, 58.21, 126.51, 127.24, 127.37, 128.44, 128.47, 133.02, 2 137.00, 166.05 (one sp carbon not located); IR (thin film) 3312 br, 3063 s, 3012 s, 1669 vs, -1 + 1535s, 1454s cm ; HRMS (ESI-TOF) m/z 254.1171 [(M+H ); calcd. for C16H16NO2: 254.1181]; [α ]20 +23.2 (c 1.0, EtOAc) on 62% ee material (HPLC). D O N-benzyl-3-oxo-3-phenylpropanamide 438a: Isolated in 15% yield O Ph N H Ph (mp. 87-88 ºC). 438a 756 1 Spectral data for 438a: Rf = 0.34 (1:3 EtOAc/hexane); H NMR (CDCl3, 500 MHz): δ 4.01 (s, 2H), 4.51 (d, J = 5.7 Hz, 2H), 7.36-7.27 (m, 6H), 7.50 (t, J = 7.8 Hz, 2H), 7.62 (t, J = 7.4 Hz, 1H), 8.00 (d, J = 7.5 Hz, 2H); 13 C (CDCl3, 125 MHz): δ 43.67, 45.26, 127.48, 127.68, 128.57, 128.70, 128.89, 134.11, 136.17, 137.88, 165.60, 196.05. previously reported for this compound. O H N O 443a These spectral data match those 27 (2S,3S)-N-benzhydryl-3-phenyloxirane-2-carboxamide 443a: Ph Ph Aldehyde 127a was reacted with diazoacetamide 128c according to the method described above for epoxide 426a with (S)-VANOL as ligand. Purification of the crude epoxide by neutral alumina chromatography (17 mm × 300 mm column, 10:1 to 1:1 hexanes/ CH2Cl2 as eluent) afforded pure cis-epoxide 443a as a white solid (mp 82-84 ºC on 74% ee material) in 65% isolated yield (85.6 mg, 0.260 mmol); cis/trans: >50:1. β-ketoamide side product 445a: 9.5% yield. The optical purity of 443a was determined to be 74% ee by HPLC analysis (CHIRALPAK AS column, 93:7 hexane/2-propanol at 228 nm, flow-rate: 1 mL/min): retention times; Rt = 22.36 min (major enantiomer, 443a) and Rt = 12.94 min (minor enantiomer, ent-443a). 1 Spectral data for 443a: Rf = 0.26 (0.1:1:1 EtOAc/CH2Cl2/hexane); H NMR (CDCl3, 500 MHz) δ 3.85 (s, 1H), 4.37 (d, J = 4.8 Hz, 1H), 5.95 (d, J = 8.0 Hz, 1H), 6.40 (d, J = 7.4 Hz, 2H), 6.43 (d, J = 7.7 Hz, 1H), 7.05 (t, J = 7.5 Hz, 2H), 7.13 (d, J = 7.2 Hz, 3H), 7.27 (d, J = 7.1 Hz, 1H), 7.31 (t, J = 7.2 Hz, 4H), 7.36 (d, J = 7.3 Hz, 3H); 757 13 C (CDCl3, 125 MHz) δ 56.34, 56.53, 58.42, 126.66, 126.87, 126.97, 127.38, 127.60, 128.29, 128.55, 128.65, 128.68, 133.07, 140.34, 140.89, -1 165.35; IR (thin film) 3302 br, 3063 s, 3030 s, 1676 vs, 1518 vs, 1408 s cm ; HRMS (ESI-TOF) + m/z 330.1499 [(M+H ); calcd. for C22H20NO2 : 330.1494]; [α ]20 +22.0 (c 1.0, EtOAc) on 74% D ee material (HPLC). (2S,3S)-N-benzyl-N-methyl-3-phenyloxirane-2-carboxamide O N O Ph 444a: Aldehyde 127a was reacted with diazoacetamide 442a according to the method described above for epoxide 426a with (S)- 444a 1 VANOL as ligand. There was no epoxide observed based on the H NMR analysis of the crude reaction mixture. O N-benzyl-N-methyl-3-oxo-3-phenylpropanamide 446a: The presence O N Ph Ph of 446a was confirmed by the characteristic peak at δ = 4.13 19 ppm in 446a 1 the H NMR previously published for this compound and the amount (25%) of the compound was quantified by integration against an internal standard (Ph3CH). Additionally, 50% yield of the enol form of 446a was also observed based on the characteristic peak at δ = 5.83 1 the H NMR spectrum of crude reaction mixture. 758 19 ppm in (2S,3S)-ethyl-3-phenyloxirane-2-carboxylate 395a: Aldehyde 127a O O O was reacted with diazoacetate 85 according to the method described above for epoxide 426a with (S)-VANOL as ligand. There was no 395a 1 epoxide observed based on the H NMR analysis of the crude reaction mixture. O ethyl-3-oxo-3-phenylpropanoate 396a: The presence of 396a was O Ph O 396a 14i confirmed by the characteristic peak at δ = 3.98 1 ppm in the H NMR previously published for this compound and the amount (40%) of the compound was quantified by integration against an internal standard (Ph3CH). 8.9.4 Synthesis of epoxides 135a-g (Table 8.6) Method A (for Liquid aldehydes) (S)-SULFOX-BOROX + catalyst 432 [DMSO-H] OPh O O O O (10 mol%) + + O –O B NHBu Ph CONHBu Ph B O NHBu * Toluene Ph H N2 O O B –60 ºC, 24 h OPh 127a 128a 135a 136a 0.05 M SULFOX-BOROX catalyst 432 BH3•Me2S (3 equiv) PhOH (2 equiv) DMSO OH H2O (3 equiv) (10 mol%) OH * (S)-SULFOX-BOROX pre* OH 1h catalyst 432 OH Toluene, 100 °C, 1 h catalyst = (S)-VANOL 59 then 0.5 mm Hg (10 mol%) 100 °C, 0.5 h O (2S,3S)-N-butyl-3-phenyloxirane-2-carboxamide 135a: Preparation of the pre-catalyst stock solution : To a 25 mL flame-dried home-made Schlenk flask , prepared from a single-necked 25 mL pear-shaped flask that had its 14/20 glass joint replaced with a high vacuum threaded Teflon valve, equipped with a stir bar and flushed with argon was added (S)-VANOL (26.3 mg, 0.06 759 mmol) and PhOH (11.3 mg, 0.120 mmol, freshly sublimed). Under an argon flow through the side-arm of the Schlenk flask, dry toluene (2 mL) was added through the top of the Teflon valve to effect dissolution. After the addition of the toluene, BH3•Me2S (90 µL, 0.18 mmol, 2 M in toluene) and water (3.24 µL, 0.180 mmol) was added. The flask was sealed by closing the Teflon valve, and then placed in a 100 ºC oil bath for 1 h. After 1 h, a vacuum (0.5 mm Hg) was carefully applied by slightly opening the Teflon valve to remove the volatiles. After the volatiles were removed completely, a full vacuum was applied and maintained for a period of 30 min at a temperature of 100 ºC (oil bath). The flask was then allowed to cool to room temperature and opened to argon through the side-arm of the Schlenk flask. This was then completely dissolved in dry toluene (3 mL) under an argon flow through side-arm of the Schlenk flask to afford the stock solution of the pre-catalyst. An aliquot of 1mL of the pre-catalyst was then transferred to a 10 mL flame-dried home-made Schlenk flask equipped with a stir bar and flushed with argon. Asymmetric epoxidation protocol (method A): To the flask containing the pre-catalyst (1 mL aliquot from 0.02 M stock solution) was added the dimethyl sulfoxide 221a (1.42 µL, 0.020 mmol) under an argon flow through side-arm of the Schlenk flask. The resulting mixture was stirred for 1 h at room temperature to give SULFOX-BOROX catalyst 432. Meanwhile, to a separate 10 mL flame-dried round bottom flask was added diazoacetamide 128a (28.23 mg, 0.2000 mmol) and dry toluene (2.5 mL). After 1 h, the flask containing the catalyst was cooled to –60 °C for 10 min. To this solution was added pre-made solution of diazoacetamide 128a. The flask containing the diazoacetamide 128a was then rinsed with toluene (0.5 mL) and the rinse was then transferred to the flask containing the catalyst at –60 °C. This was then followed by closing the Teflon valve and stirring the resulting mixture for 10 min at –60 °C. To this 760 mixture was then added benzaldehyde 127a (22.2 µL, 0.220 mmol, freshly distilled) and the resulting mixture was stirred for 24 h at –60 °C. The reaction was quenched by the addition of Et3N (0.5 mL) and was then warmed to room temperature. The reaction mixture was then transferred to a 50 mL round bottom flask. The reaction flask was rinsed with EtOAc (3 mL × 2) and the rinse was added to the 50 mL round bottom flask. The resulting solution was then concentrated in vacuo followed by exposure to high vacuum (0.05 mm Hg) for 1 h to afford the crude epoxide as an off-white semi-solid. 1 The cis/trans ratio was determined by comparing the H NMR integration of the ring methine protons for each epoxide in the crude reaction mixture. The yield of the acyclic β1 ketoamide side product 136a was determined by H NMR analysis of the crude reaction mixture by integration of the methylene protons relative to the internal standard (Ph3CH). Purification of the crude epoxide by neutral alumina chromatography (17 mm × 300 mm column, 10:1 to 1:1 hexanes/ CH2Cl2 as eluent) afforded pure cis-epoxide 135a as a white solid (52-53 ºC on 99.3 % ee material) in 88% isolated yield (38.6 mg, 0.176 mmol); cis/trans: >100:1. β-ketoamide side product 136a: <1% yield. The optical purity of 135a was determined to be 99.3% ee by HPLC analysis (PIRKLE COVALENT (R,R) WHELK-O 1 column, 93:7 hexane/2-propanol at 228 nm, flow-rate: 1 mL/min): retention times; Rt = 13.8 min (major enantiomer, 135a) and Rt = 24.6 min (minor enantiomer, ent-135a). 1 Spectral data for 135a: Rf = 0.61 (1:1 EtOAc/hexane); H NMR (CDCl3, 500 MHz) δ 0.72 (t, J = 7.2 Hz, 3H), 0.89-1.04 (m, 4H), 2.82-2.88 (m, 1H), 3.08 (dq, J = 13.6, 6.9 Hz, 1H), 3.77 (d, J = 761 4.8 Hz, 1H), 4.31 (d, J = 4.8 Hz, 1H), 5.84 (s, 1H), 7.35-7.28 (m, 5H); 13 C (CDCl3, 125 MHz) δ 13.53, 19.62, 31.17, 38.21, 56.27, 58.08, 126.49, 128.31, 128.38, 133.19, 165.95; IR (thin film) -1 3316 br, 2959 vs, 2932 vs, 1651 vs, 1545 s, 1454 s cm ; HRMS (ESI-TOF) m/z 220.1334 + [(M+H ); calcd. for C13H18NO2 : 220.1338]; [α ]20 +18.6 (c 1.0, EtOAc) on 99.3% ee material D (HPLC). Method B (for solid aldehydes) (S)-SULFOX-BOROX catalyst 432 O O O O (10 mol%) + + NHBu R CONHBu R NHBu Toluene R H N2 –60 ºC, 24 h 127b' 128a 135b' 136b' 0.05 M O OH BH3•Me2S (3 equiv) PhOH (2 equiv) H2O (3 equiv) preOH Toluene, 100 °C, 1 h catalyst 59 then 0.5 mm Hg (10 mol%) 100 °C, 0.5 h * + [DMSO-H] OPh O –O B B O * O O B OPh SULFOX-BOROX catalyst 432 DMSO (10 mol%) 1h (S)-SULFOX-BOROX catalyst 432 * OH OH = (S)-VANOL R = 2-naphthaldehyde (2S,3S)-N-butyl-3-(naphthalen-2-yl)oxirane-2-carboxamide 135b': Preparation of the precatalyst stock solution : same as above. Asymmetric epoxidation protocol (method B): To the flask containing the pre-catalyst (1 mL aliquot from 0.02 M stock solution) was added the dimethyl sulfoxide 221a (1.42 µL, 0.020 mmol) under an argon flow through side-arm of the Schlenk flask. The resulting mixture was stirred for 1 h at room temperature to give SULFOX-BOROX catalyst 432. Meanwhile, to a 762 separate 10 mL flame-dried round bottom flask was added diazoacetamide 128a (28.23 mg, 0.2000 mmol) and dry toluene (1.5 mL). After 1 h, the flask containing the catalyst was cooled to –60 °C for 10 min. To this solution was added pre-made solution of diazoacetamide 128a. The flask containing the diazoacetamide 128a was then rinsed with toluene (0.5 mL) and the rinse was then transferred to the flask containing the catalyst at –60 °C. This was then followed by closing the Teflon valve and stirring the resulting mixture for 10 min at –60 °C. Meanwhile, to a separate 10 mL flame-dried round bottom flask was added aldehyde 127b' (34.4 mg, 0.220 mmol, freshly purified) and dry toluene (1.0 mL). To the mixture containing diazoacetamide 128a and catalyst was then added a pre-made solution of aldehyde 127b' and the resulting mixture was stirred for 24 h at –60 °C. The reaction was quenched by the addition of Et3N (0.5 mL) and was then warmed to room temperature. The reaction mixture was then transferred to a 50 mL round bottom flask. The reaction flask was rinsed with EtOAc (3 mL × 2) and the rinse was added to the 50 mL round bottom flask. The resulting solution was then concentrated in vacuo followed by exposure to high vacuum (0.05 mm Hg) for 1 h to afford the crude epoxide as an off-white semi-solid. Purification of the crude epoxide by neutral alumina chromatography (17 mm × 300 mm column, 10:1 to 1:1 hexanes/ CH2Cl2 as eluent) afforded pure cis-epoxide 135b' as a white solid (105-106 ºC on 98% ee material) in 92% isolated yield (49.6 mg, 0.184 mmol); cis/trans: >100:1. β-ketoamide side product 136b': <1 % yield. The optical purity of 135b' was determined to be 98% ee by HPLC analysis (PIRKLE COVALENT (R,R) WHELK-O 1 column, 93:7 hexane/2-propanol at 228 nm, flow-rate: 1 mL/min): retention times; Rt = 16.26 min (major enantiomer, 135b') and Rt = 19.95 min (minor enantiomer, ent-135b'). 763 1 Spectral data for 135b': Rf = 0.55 (1:1 EtOAc/hexane); H NMR (CDCl3, 500 MHz) δ 0.40 (t, J = 7.3 Hz, 3H), 0.65-0.72 (m, 2H), 0.80-0.86 (m, 2H), 2.75-2.81 (m, 1H), 3.05 (dq, J = 13.7, 6.9 Hz, 1H), 3.86 (d, J = 4.8 Hz, 1H), 4.47 (d, J = 4.8 Hz, 1H), 5.88 (s, 1H), 7.45-7.51 (m, 3H), 7.807.83 (m, 4H); 13 C (CDCl3, 125 MHz) δ 13.19, 19.50, 31.22, 38.25, 56.49, 58.30, 124.02, 125.70, 126.41, 126.53, 127.77, 127.82, 128.32, 130.66, 132.85, 133.18, 165.96; IR (thin film) 3308 br, -1 + 2959 s, 2932 s, 1651 vs, 1545 s, 1437 s cm ; HRMS (ESI-TOF) m/z 270.1494 [(M+H ); calcd. for C17H20NO2 : 270.1494]; [α ]20 –50.6 (c 1.0, EtOAc) on 98% ee material (HPLC). D O H N O 135b (2S,3S)-N-butyl-3-(naphthalen-1-yl)oxirane-2carboxamide 135b: Aldehyde 127b was reacted according to the general method A described above with (S)-VANOL as ligand. Purification of the crude epoxide by neutral alumina chromatography (17 mm × 300 mm column, 10:1 to 1:1 hexanes/ CH2Cl2 as eluent) afforded pure cis-epoxide 135b as a colorless viscous oil in 97% isolated yield (52.3 mg, 0.194 mmol); cis/trans: 35:1. β-ketoamide side product 136b: <1 % yield. The optical purity of 135b was determined to be 92% ee by HPLC analysis (PIRKLE COVALENT (R,R) WHELK-O 1 column, 93:7 hexane/2-propanol at 228 nm, flow-rate: 1 mL/min): retention times; Rt = 16.69 min (major enantiomer, 135b) and Rt = 54.29 min (minor enantiomer, ent-135b). 1 Spectral data for 135b: Rf = 0.56 (1:1 EtOAc/hexane); H NMR (CDCl3, 500 MHz) δ 0.57 (t, J = 7.1 Hz, 3H), 0.69 (dq, J = 14.7, 7.3 Hz, 2H), 0.74-0.81 (m, 2H), 2.73 (dq, J = 12.8, 6.4 Hz, 1H), 764 2.98 (dq, J = 13.7, 6.9 Hz, 1H), 4.02 (d, J = 4.7 Hz, 1H), 4.68 (d, J = 4.6 Hz, 1H), 5.73 (s, 1H), 7.42 (t, J = 7.6 Hz, 1H), 7.52 (d, J = 7.3 Hz, 2H), 7.57 (t, J = 7.6 Hz, 1H), 7.82 (d, J = 8.2 Hz, 1H), 7.85 (d, J = 8.1 Hz, 1H), 8.12 (d, J = 8.4 Hz, 1H); 13 C (CDCl3, 125 MHz) δ 13.41, 19.41, 31.08, 38.12, 56.17, 57.41, 123.64, 124.47, 124.75, 126.33, 126.82, 128.47, 128.94, 129.48, -1 131.14, 133.28, 166.17; IR (thin film) 3323 br, 2959 vs, 2932 s, 1668 vs, 1539 s, 1464 s cm ; + HRMS (ESI-TOF) m/z 270.1504 [(M+H ); calcd. for C17H20NO2 : 270.1494]; [α ]20 +110.3 (c D 1.0, EtOAc) on 92% ee material (HPLC). O H N (2S,3S)-N-butyl-3-(o-tolyl)oxirane-2-carboxamide 135c: Aldehyde 127c was reacted according to the general method A O 135c described above with (S)-VANOL as ligand. Purification of the crude epoxide by neutral alumina chromatography (17 mm × 300 mm column, 10:1 to 1:1 hexanes/ CH2Cl2 as eluent) afforded pure cis-epoxide 135c as a white solid (mp 41-43 ºC on 80% ee material) in 60% isolated yield (28 mg, 0.12 mmol); cis/trans: >100:1. β-ketoamide side product 136c: <1% yield. The optical purity of 135c was determined to be 80% ee by HPLC analysis (PIRKLE COVALENT (R,R) WHELK-O 1 column, 93:7 hexane/2-propanol at 228 nm, flow-rate: 1 mL/min): retention times; Rt = 17.11 min (major enantiomer, 135c) and Rt = 20.61 min (minor enantiomer, ent-135c). 1 Spectral data for 135c: Rf = 0.58 (1:1 EtOAc/hexane); H NMR (CDCl3, 500 MHz) δ 0.70 (t, J = 7.1 Hz, 3H), 0.87-0.96 (m, 4H), 2.36 (s, 3H), 2.78-2.83 (m, 1H), 3.07 (dq, J = 13.7, 6.9 Hz, 1H), 765 3.84 (d, J = 4.7 Hz, 1H), 4.25 (d, J = 4.7 Hz, 1H), 5.72 (s, 1H), 7.15 (dd, J = 11.6, 7.5 Hz, 2H), 7.21 (t, J = 7.2 Hz, 1H), 7.30 (d, J = 7.4 Hz, 1H); 13 C (CDCl3, 125 MHz) δ 13.56, 18.69, 19.59, 31.20, 38.20, 56.13, 57.69, 125.46, 126.15, 128.31, 130.02, 131.77, 136.73, 166.11; IR (thin -1 film) 3330 br, 2959 s, 2930 s, 1666 vs, 1539 vs, 1458 m cm ; HRMS (ESI-TOF) m/z 234.1503 + [(M+H ); calcd. for C14H20NO2 : 234.1494]; [α ]20 +39.8 (c 1.0, EtOAc) on 80% ee material D (HPLC). O H N O 135d (2S,3S)-N-butyl-3-(p-tolyl)oxirane-2-carboxamide 135d: Aldehyde 127d was reacted according to the general method A described above with (S)-VANOL as ligand. Purification of the crude epoxide by neutral alumina chromatography (17 mm × 300 mm column, 10:1 to 1:1 hexanes/ CH2Cl2 as eluent) afforded pure cis-epoxide 135d as a white solid (mp 58-59 ºC on 98% ee material) in 80% isolated yield (37.3 mg, 0.160 mmol); cis/trans: >100:1. β-ketoamide side product 136d: <1% yield. The optical purity of 135d was determined to be 98% ee by HPLC analysis (PIRKLE COVALENT (R,R) WHELK-O 1 column, 93:7 hexane/2-propanol at 228 nm, flow-rate: 1 mL/min): retention times; Rt = 23.76 min (major enantiomer, 135d) and Rt = 35.09 min (minor enantiomer, ent-135d). 1 Spectral data for 135d: Rf = 0.56 (1:1 EtOAc/hexane); H NMR (CDCl3, 500 MHz) δ 0.72 (t, J = 7.2 Hz, 3H), 0.88-0.96 (m, 2H), 1.00-1.06 (m, 2H), 2.32 (s, 3H), 2.83-2.89 (m, 1H), 3.11 (dq, J = 13.6, 6.9 Hz, 1H), 3.74 (d, J = 4.8 Hz, 1H), 4.27 (d, J = 4.7 Hz, 1H), 5.83 (s, 1H), 7.13 (d, J = 7.9 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H); 13 C (CDCl3, 125 MHz) δ 13.58, 19.66, 21.15, 31.28, 766 38.26, 56.32, 58.09, 126.45, 128.99, 130.21, 138.21, 166.12; IR (thin film) 3310 br, 2961 s, 2932 -1 + s, 1653 vs, 1547 vs, 1433 s cm ; HRMS (ESI-TOF) m/z 234.1504 [(M+H ); calcd. for C14H20NO2 : 234.1494]; [α ]20 +22.0 (c 1.0, EtOAc) on 98% ee material (HPLC). D O (2S,3S)-N-butyl-3-(3-methoxyphenyl)oxirane-2- H N MeO carboxamide 135e': Aldehyde 127e' was reacted O according to the general method A described above with 135e' (S)-VANOL as ligand. Purification of the crude epoxide by neutral alumina chromatography (17 mm × 300 mm column, 10:1 to 1:1 hexanes/ CH2Cl2 as eluent) afforded pure cis-epoxide 135e' as a white solid (mp 58-59 ºC on 90% ee material) in 80% isolated yield (40.0 mg, 0.160 mmol); cis/trans: 31:1. β-ketoamide side product 136e': 6% yield. The optical purity of 135e' was determined to be 90% ee by HPLC analysis (PIRKLE COVALENT (R,R) WHELK-O 1 column, 93:7 hexane/2-propanol at 228 nm, flow-rate: 1 mL/min): retention times; Rt = 17.09 min (major enantiomer, 135e') and Rt = 38.66 min (minor enantiomer, ent-135e'). 1 Spectral data for 135e': Rf = 0.55 (1:1 EtOAc/hexane); H NMR (CDCl3, 500 MHz) δ 0.73 (t, J = 7.2 Hz, 3H), 0.95 (dq, J = 14.8, 7.3 Hz, 2H), 1.05 (dt, J = 14.6, 7.1 Hz, 2H), 2.87 (dq, J = 12.8, 6.4 Hz, 1H), 3.12 (dq, J = 13.6, 6.9 Hz, 1H), 3.76 (d, J = 4.8 Hz, 1H), 3.78 (s, 3H), 4.29 (d, J = 4.7 Hz, 1H), 5.84 (s, 1H), 6.83 (dd, J = 8.2, 2.0 Hz, 1H), 6.88 (s, 1H), 6.93 (d, J = 7.6 Hz, 1H), 7.24 (t, J = 7.9 Hz, 1H); 13 C (CDCl3, 125 MHz) δ 13.57, 19.66, 31.29, 38.28, 55.23, 56.30, 58.05, 112.04, 114.07, 118.75, 129.54, 134.70, 159.61, 165.95; IR (thin film) 3312 br, 2959 s, -1 + 2934 s, 1663 vs, 1530 s, 1458 s cm ; HRMS (ESI-TOF) m/z 250.1443 [(M+H ); calcd. for 767 C14H20NO3 : 250.1443]; [α ]20 +5.4 (c 0.5, EtOAc) on 90% ee material (HPLC). D O O2N (2S,3S)-N-butyl-3-(4-nitrophenyl)oxirane-2- H N carboxamide O 135f: Aldehyde 127f was reacted according to the general method B described above with 135f (S)-VANOL as ligand. Purification of the crude epoxide by neutral alumina chromatography (17 mm × 300 mm column, 10:1 to 1:1 hexanes/ CH2Cl2 as eluent) afforded pure cis-epoxide 135f as a white solid (mp 95-96 ºC on 92% ee material) in 70% isolated yield (37.0 mg, 0.140 mmol); cis/trans: 13:1. β-ketoamide side product 136f: 8% yield. The optical purity of 135f was determined to be 92% ee by HPLC analysis (PIRKLE COVALENT (R,R) WHELK-O 1 column, 93:7 hexane/2-propanol at 228 nm, flow-rate: 1 mL/min): retention times; Rt = 28.14 min (major enantiomer, 135f) and Rt = 47.71 min (minor enantiomer, ent-135f). 1 Spectral data for 135f: Rf = 0.55 (1:1 EtOAc/hexane); H NMR (CDCl3, 500 MHz) δ 0.73 (t, J = 7.3 Hz, 3H), 0.92-1.00 (m, 2H), 1.04-1.11 (m, 2H), 2.92 (dq, J = 13.0, 6.5 Hz, 1H), 3.08 (dq, J = 13.7, 6.9 Hz, 1H), 3.86 (d, J = 4.9 Hz, 1H), 4.36 (d, J = 4.9 Hz, 1H), 5.88 (s, 1H), 7.55 (d, J = 8.7 Hz, 2H), 8.21 (d, J = 8.7 Hz, 2H); 13 C (CDCl3, 125 MHz) δ 13.45, 19.69, 31.35, 38.39, 56.50, 57.21, 123.57, 127.62, 140.29, 147.99, 164.97; IR (thin film) 3312 br, 2961 vs, 2934 s, 1655 vs, -1 + 1547 vs, 1518 vs, 1464 s, 1346 s cm ; HRMS (ESI-TOF) m/z 265.1179 [(M+H ); calcd. for C13H17N2O4 : 265.1188]; [α ]20 +42.2 (c 1.0, EtOAc) on 92% ee material (HPLC). D 768 O H N O Br 135g (2S,3S)-N-butyl-3-(4-bromophenyl)oxirane-2carboxamide 135g: Aldehyde 127g was reacted according to the general method B described above with (S)-VANOL as ligand. Purification of the crude epoxide by neutral alumina chromatography (17 mm × 300 mm column, 10:1 to 1:1 hexanes/ CH2Cl2 as eluent) afforded pure cis-epoxide 135g as a white solid (mp 109-110 ºC on 99% ee material) in 88% isolated yield (52.5 mg, 0.176 mmol); cis/trans: >100:1. β-ketoamide side product 136g: <1% yield. The optical purity of 135g was determined to be 99% ee by HPLC analysis (PIRKLE COVALENT (R,R) WHELK-O 1 column, 93:7 hexane/2-propanol at 228 nm, flow-rate: 1 mL/min): retention times; Rt = 15.09 min (major enantiomer, 135g) and Rt = 27.43 min (minor enantiomer, ent-135g). 1 Spectral data for 135g: Rf = 0.50 (1:1 EtOAc/hexane); H NMR (CDCl3, 500 MHz) δ 0.77 (t, J = 7.2 Hz, 3H), 0.92-0.99 (m, 2H), 1.04-1.10 (m, 2H), 2.86-2.92 (m, 1H), 3.13 (dq, J = 13.7, 6.9 Hz, 1H), 3.78 (d, J = 4.8 Hz, 1H), 4.25 (d, J = 4.8 Hz, 1H), 7.24 (d, J = 8.3 Hz, 2H), 7.47 (d, J = 8.4 Hz, 2H); 13 C (CDCl3, 151 MHz) δ 13.67, 19.77, 31.39, 38.39, 56.29, 57.57, 122.66, 128.33, 131.61, 132.33, 165.69; IR (thin film) 3300 br, 2957 s, 2928 s, 1653 vs, 1545 s, 1435 s, 1286 s -1 + cm ; HRMS (ESI-TOF) m/z 298.0449 [(M+H ); calcd. for C13H17BrNO2 : 298.0443]; [α ]20 D +20.7 (c 1.0, EtOAc) on 99% ee material (HPLC). 769 O H N Br O 135g' (2S,3S)-N-butyl-3-(3-bromophenyl)oxirane-2carboxamide 135g': Aldehyde 127g' was reacted according to the general method A described above with (S)-VANOL as ligand. Purification of the crude epoxide by neutral alumina chromatography (17 mm × 300 mm column, 10:1 to 1:1 hexanes/ CH2Cl2 as eluent) afforded pure cis-epoxide 135g' as a white solid (mp 74-75 ºC on 96% ee material) in 88% isolated yield (52.5 mg, 0.176 mmol); cis/trans: >100:1. β-ketoamide side product 136g': 4% yield. The optical purity of 135g' was determined to be 96% ee by HPLC analysis (PIRKLE COVALENT (R,R) WHELK-O 1 column, 93:7 hexane/2-propanol at 228 nm, flow-rate: 1 mL/min): retention times; Rt = 14.31 min (major enantiomer, 135g') and Rt = 27.29 min (minor enantiomer, ent-135g'). 1 Spectral data for 135g': Rf = 0.55 (1:1 EtOAc/hexane); H NMR (CDCl3, 500 MHz) δ 0.76 (t, J = 7.2 Hz, 3H), 0.97 (dqd, J = 14.9, 7.4, 2.9 Hz, 2H), 1.06-1.12 (m, 2H), 2.84-2.90 (m, 1H), 3.16 (dq, J = 13.7, 6.9 Hz, 1H), 3.77 (d, J = 4.8 Hz, 1H), 4.27 (d, J = 4.8 Hz, 1H), 5.88 (s, 1H), 7.20 (t, J = 7.8 Hz, 1H), 7.28 (d, J = 7.7 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.50 (s, 1H); 13 C (CDCl3, 125 MHz) δ 13.60, 19.71, 31.36, 38.34, 56.38, 57.28, 122.49, 125.28, 129.50, 129.95, 131.59, 135.46, 165.42; IR (thin film) 3304 br, 2959 vs, 2932 vs, 1658 vs, 1568 vs, 1541 vs, 1435 s, -1 + 1284 s cm ; HRMS (ESI-TOF) m/z 298.0442 [(M+H ); calcd. for C13H17BrNO2 : 298.0443]; [α ]20 –17.8 (c 1.0, EtOAc) on 96% ee material (HPLC). D 770 F O H N (2S,3S)-N-butyl-3-(4-bromo-2fluorophenyl)oxirane-2carboxamide 135x: Aldehyde 127x was reacted according O Br 135x to the general method B described above with (S)-VANOL as ligand. Purification of the crude epoxide by neutral alumina chromatography (17 mm × 300 mm column, 10:1 to 1:1 hexanes/ CH2Cl2 as eluent) afforded pure cis-epoxide 135x as a white solid (mp 86-87 ºC on 80% ee material) in 70% isolated yield (44.3 mg, 0.140 mmol); cis/trans: 39:1. β-ketoamide side product 136x: 9% yield. The optical purity of 135x was determined to be 80% ee by HPLC analysis (PIRKLE COVALENT (R,R) WHELK-O 1 column, 93:7 hexane/2propanol at 228 nm, flow-rate: 1 mL/min): retention times; Rt = 15.61 min (major enantiomer, 135x) and Rt = 23.23 min (minor enantiomer, ent-135x). 1 Spectral data for 135x: Rf = 0.68 (1:1 EtOAc/hexane); H NMR (CDCl3, 500 MHz) δ 0.83 (t, J = 7.3 Hz, 3H), 1.01-1.08 (m, 2H), 1.16 (dt, J = 14.8, 7.3 Hz, 2H), 2.98 (dq, J = 12.9, 6.4 Hz, 1H), 3.20 (dq, J = 13.7, 6.9 Hz, 1H), 3.87 (d, J = 4.7 Hz, 1H), 4.32 (d, J = 4.7 Hz, 1H), 5.91 (s, 1H), 7.24 (t, J = 8.0 Hz, 1H), 7.29-7.32 (m, 2H); 13 C (CDCl3, 125 MHz) δ 13.58, 19.74, 31.38, 38.40, 53.83, 53.86, 55.76, 119.24, 119.43, 120.09, 120.20, 122.87, 122.94, 127.16, 127.19, 129.17, 129.20, 160.06, 162.08, 165.29; IR (thin film) 3300 br, 2959 s, 2932 s, 1653 vs, 1547 vs, 1406 s -1 + cm ; HRMS (ESI-TOF) m/z 316.0364 [(M+H ); calcd. for C13H16BrFNO2 : 317.0348]; [α ]20 D +12.7 (c 1.0, EtOAc) on 80% ee material (HPLC). 771 O NC (2S,3S)-N-butyl-3-(4-cyanophenyl)oxirane-2- H N carboxamide 135y: Aldehyde 127y was reacted according O to the general method B described above with (S)-VANOL 135y as ligand. Purification of the crude epoxide by neutral alumina chromatography (17 mm × 300 mm column, 10:1 to 1:1 hexanes/ CH2Cl2 as eluent) afforded pure cis-epoxide 135y as a white solid (mp 72-73 ºC on 96% ee material) in 84% isolated yield (41.0 mg, 0.168 mmol); cis/trans: >100:1. β-ketoamide side product 136y: <1% yield. The optical purity of 135y was determined to be 96% ee by HPLC analysis (PIRKLE COVALENT (R,R) WHELK-O 1 column, 93:7 hexane/2-propanol at 228 nm, flow-rate: 1 mL/min): retention times; Rt = 38.97 min (major enantiomer, 135y) and Rt = 63.98 min (minor enantiomer, ent-135y). 1 Spectral data for 135y: Rf = 0.23 (1:1 EtOAc/hexane); H NMR (CDCl3, 600 MHz) δ 0.76 (t, J = 7.3 Hz, 3H), 0.93-0.99 (m, 2H), 1.04-1.09 (m, 2H), 2.87-2.93 (m, 1H), 3.08 (dq, J = 13.7, 6.9 Hz, 1H), 3.83 (d, J = 4.9 Hz, 1H), 4.32 (d, J = 4.9 Hz, 1H), 5.86 (s, 1H), 7.48 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 8.2 Hz, 2H); 13 C (CDCl3, 125 MHz) δ 13.54, 19.67, 31.30, 38.33, 56.40, 57.29, 112.49, 118.17, 127.39, 132.10, 138.41, 165.06; IR (thin film) 3312 br, 2959 s, 2934 s, 2229 s, -1 + 1664 vs, 1541 s, 1437 s cm ; HRMS (ESI-TOF) m/z 245.1283 [(M+H ); calcd. for C14H17N2O2 : 245.1290]; [α ]20 +41.0 (c 1.0, EtOAc) on 96% ee material (HPLC). D 772 O AcO H N O 135z 4-((2S,3S)-3-(butylcarbamoyl)oxiran-2-yl)phenyl acetate 135z: Aldehyde 127z was reacted according to the general method B described above with (S)-VANOL as ligand. Purification of the crude epoxide by neutral alumina chromatography (17 mm × 300 mm column, 10:1 to 1:1 hexanes/ CH2Cl2 as eluent) afforded pure cis-epoxide 135z as a white solid (mp 113-114 ºC on 97% ee material) in 82% isolated yield (45.5 mg, 0.164 mmol); cis/trans: >100:1. β-ketoamide side product 136z: 4% yield. The optical purity of 135z was determined to be 97% ee by HPLC analysis (PIRKLE COVALENT (R,R) WHELK-O 1 column, 80:20 hexane/2-propanol at 228 nm, flow-rate: 1 mL/min): retention times; Rt = 26.76 min (major enantiomer, 135z) and Rt = 46.04 min (minor enantiomer, ent-135z). 1 Spectral data for 135z: Rf = 0.34 (1:1 EtOAc/hexane); H NMR (CDCl3, 600 MHz) δ 0.76 (t, J = 7.2 Hz, 3H), 1.00 (dq, J = 14.7, 7.3 Hz, 2H), 1.07 (dtd, J = 14.5, 7.2, 2.7 Hz, 2H), 2.28 (s, 3H), 2.90 (dq, J = 12.9, 6.4 Hz, 1H), 3.09 (dq, J = 13.7, 6.9 Hz, 1H), 3.77 (d, J = 4.7 Hz, 1H), 4.29 (d, J = 4.7 Hz, 1H), 5.82 (s, 1H), 7.07 (d, J = 8.6 Hz, 2H), 7.37 (d, J = 8.3 Hz, 2H); 13 C (CDCl3, 125 MHz) δ 13.48, 19.70, 21.08, 31.19, 38.28, 56.27, 57.66, 121.64, 127.76, 130.74, 150.75, 165.83, 169.06; IR (thin film) 3310 br, 2957 s, 2930 s, 1757 vs, 1653 vs, 1545 vs, 1369 s, 1223 s -1 + cm ; HRMS (ESI-TOF) m/z 278.1395 [(M+H ); calcd. for C15H20NO4 : 278.1392]; [α ]20 D +14.5 (c 1.0, EtOAc) on 97% ee material (HPLC). 773 O (2S,3S)-N-butyl-3propyloxirane-2-carboxamide H N 135o: Aldehyde 127o was reacted according to the general method A O described above with (S)-VANOL as ligand. Purification of the 135o crude epoxide by neutral alumina chromatography (17 mm × 300 mm column, 10:1 to 1:1 hexanes/ CH2Cl2 as eluent) afforded pure cis-epoxide 135o as a white semi-solid in 65% isolated yield (24.1 mg, 0.130 mmol); cis/trans: nd. β-ketoamide side product 136o: 9% yield. The optical purity of 135o was determined to be 78% ee by HPLC analysis (PIRKLE COVALENT (R,R) WHELK-O 1 column, 97:3 hexane/2-propanol at 228 nm, flow-rate: 1 mL/min): retention times; Rt = 30.34 min (major enantiomer, 135o) and Rt = 37.02 min (minor enantiomer, ent135o). 1 Spectral data for 135o: Rf = 0.44 (1:1 EtOAc/hexane); H NMR (CDCl3, 600 MHz) δ 0.92 (t, J = 7.4 Hz, 3H), 0.95-0.97 (m, 3H), 1.34 (dq, J = 15.0, 7.5 Hz, 2H), 1.46-1.55 (m, 6H), 3.15-3.17 (m, 1H), 3.24 (dq, J = 13.3, 6.6 Hz, 1H), 3.32 (dq, J = 13.5, 6.7 Hz, 1H), 3.48 (d, J = 4.8 Hz, 1H), 6.13 (s, 1H); 13 C (CDCl3, 125 MHz) δ 13.63, 13.84, 19.41, 20.04, 29.64, 31.62, 38.55, -1 55.29, 58.39, 167.27; IR (thin film) 3306 br, 2961 s, 2934 s, 1653 vs, 1539 s, 1458 m cm ; + HRMS (ESI-TOF) m/z 186.1500 [(M+H ); calcd. for C10H20NO2 : 186.1494]; [α ]20 –1.9 (c D 1.0, EtOAc) on 78% ee material (HPLC). 774 O 6 (2S,3S)-N-butyl-3octyloxirane-2-carboxamide H N 135pʹ′: Aldehyde 127pʹ′ was reacted according to the general method A O 135p' described above with (S)-VANOL as ligand. Purification of the crude epoxide by neutral alumina chromatography (17 mm × 300 mm column, 10:1 to 1:1 hexanes/ CH2Cl2 as eluent) afforded pure cis-epoxide 135pʹ′ as a white semi-solid in 84% isolated yield (42.9 mg, 0.168 mmol); cis/trans: nd. β-ketoamide side product 136pʹ′: 6% yield. The optical purity of 135pʹ′ was determined to be 90% ee by HPLC analysis (PIRKLE COVALENT (R,R) WHELK-O 1 column, 97:3 hexane/2-propanol at 228 nm, flow-rate: 1 mL/min): retention times; Rt = 22.64 min (major enantiomer, 135pʹ′) and Rt = 27.43 min (minor enantiomer, ent-135pʹ′). 1 Spectral data for 135pʹ′: Rf = 0.32 (1:2 EtOAc/hexane); H NMR (CDCl3, 600 MHz) δ 0.85 (t, J = 7.1 Hz, 3H), 0.90 (t, J = 7.4 Hz, 3H), 1.21-1.27 (m, 8H), 1.28-1.35 (m, 4H), 1.40-1.53 (m, 6H), 3.11-3.14 (m, 1H), 3.21 (dq, J = 13.2, 6.6 Hz, 1H), 3.30 (dq, J = 13.5, 6.7 Hz, 1H), 3.46 (d, J = 4.8 Hz, 1H), 6.11 (s, 1H); 13 C (CDCl3, 125 MHz) δ 13.63, 14.04, 20.05, 22.61, 26.01, 27.64, 29.12, 29.30, 29.33, 31.63, 31.80, 38.55, 55.36, 58.57, 167.26; IR (thin film) 3312 br, 2957 s, -1 + 2938 s, 2857 m, 1661 vs, 1539 vs, 1458 m, cm ; HRMS (ESI-TOF) m/z 256.2271 [(M+H ); calcd. for C15H30NO2 : 256.2277]; [α ]20 +2.9 (c 1.0, EtOAc) on 90% ee material (HPLC). D 775 O (2R,3S)-N-butyl-3-(4-bromophenyl)oxirane-2- H N carboxamide 135g: A sample of trans-epoxide 135g was O Br obtained when aldehyde 127g was subjected to the reaction (2R,3S)-135g conditions given in the entry 4 of Table 8.3 in CHCl3. The optical purity of (2R,3S)-135g was determined to be 20% ee by HPLC analysis (PIRKLE COVALENT (R,R) WHELK-O 1 column, 93:7 hexane/2-propanol at 228 nm, flow-rate: 1 mL/min): retention times; Rt = 60.20 min (major enantiomer, (2R,3S)-135g) and Rt = 39.34 min (minor enantiomer, (2S,3R)-135g). 1 Spectral data for (2R,3S)-135g: Rf = 0.63 (1:1 EtOAc/hexane); H NMR (CDCl3, 500 MHz) δ 0.94 (t, J = 7.3 Hz, 3H), 1.37 (dq, J = 15.0, 7.5 Hz, 2H), 1.49-1.55 (m, 2H), 3.29 (qq, J = 13.2, 6.6 Hz, 2H), 3.47 (d, J = 2.0 Hz, 1H), 3.83 (d, J = 1.9 Hz, 1H), 6.19 (s, 1H), 7.14 (d, J = 8.6 Hz, 2H), 7.49 (d, J = 8.6 Hz, 2H); 13 C (CDCl3, 151 MHz) δ 13.69, 20.00, 31.56, 38.67, 58.54, 58.99, 123.06, 127.39, 131.85, 134.06, 166.94; IR (thin film) 3275 br, 2859 m, 2932 m, 1655 vs, 1564 -1 + m, 1439 w cm ; HRMS (ESI-TOF) m/z 298.0444 [(M+H ); calcd. for C13H17BrNO2 : 298.0443]. 8.9.5 One pot procedure for epoxidation reaction (Table 8.5) 1. * OH B(OPh)3 (3 equiv) DMSO (1 equiv) toluene, 25 ºC, 1 h OH then cooled to –60 ºC 59 (10 mol%) Ph 2. O H 127a CONHBu Ph 135a NHBu N2 128a –60 ºC, 24 h 776 O + Ph O O O NHBu 136a (2S,3S)-N-butyl-3-phenyloxirane-2-carboxamide 135a: To a flame-dried 10 mL round bottom flask filled with argon was added was added (S)-VANOL (9.0 mg, 0.02 mmol) and commercial B(OPh)3 (17.4 mg, 0.060 mmol), dimethyl sulfoxide 221a (1.42 µL, 0.020 mmol) and toluene (2 mL). The resulting mixture was stirred for 1 h at room temperature to give SULFOX-BOROX catalyst 432. After 1 h, the flask containing the catalyst was cooled to –60 °C for 10 min. To this solution was added benzaldehyde 127a (61 µL, 0.60 mmol, 3 equiv, freshly distilled). The resulting mixture was then stirred for 10 min at –60 °C. To this mixture was then added diazoacetamide 128a (28.3 mg, 0.200 mmol) and the resulting mixture was stirred for 24 h at – 60 °C. The reaction was quenched by the addition of Et3N (0.5 mL) and was then warmed to room temperature. The reaction mixture was then transferred to a 50 mL round bottom flask. The reaction flask was rinsed with EtOAc (3 mL × 2) and the rinse was added to the 50 mL round bottom flask. The resulting solution was then concentrated in vacuo followed by exposure to high vacuum (0.05 mm Hg) for 1 h to afford the crude epoxide as an off-white semi-solid. Purification of the crude epoxide by neutral alumina chromatography (17 mm × 300 mm column, 10:1 to 1:1 hexanes/ CH2Cl2 as eluent) afforded pure cis-epoxide 135a as a white solid in 75% isolated yield and 80% ee; cis/trans: 13:1. β-ketoamide side product 136a: 4% yield. 8.9.6 Epoxidation using catalyst 447 (Scheme 8.8) R catalyst 447 (10 mol%) O O + H 127g NHBu N2 toluene –60 °C, 24 h 128a R CONHBu 135g R = 4-Br-C6H4 777 O O O + R NHBu 136g BH3•Me2S (1 equiv) PhOH (1 equiv) (S)-VANOL Toluene, 100 °C, 1 h 59 then 0.5 mm Hg (10 mol%) 100 °C, 0.5 h PhB(OH)2 (2 equiv) DMSO Toluene, 100 °C, 1 h then 0.5 mm Hg 100 °C, 0.5 h 1h + [DMSO-H] Ph O –O B B O * O O B Ph catalyst 447 (2S,3S)-N-butyl-3-(4-bromophenyl)oxirane-2-carboxamide 135g: Preparation of the precatalyst stock solution : To a 25 mL flame-dried home-made Schlenk flask , prepared from a single-necked 25 mL pear-shaped flask that had its 14/20 glass joint replaced with a high vacuum threaded Teflon valve, equipped with a stir bar and flushed with argon was added (S)VANOL (26.3 mg, 0.06 mmol) and PhOH (5.7 mg, 0.06 mmol, freshly sublimed). Under an argon flow through the side-arm of the Schlenk flask, dry toluene (2 mL) was added through the top of the Teflon valve to effect dissolution. After the addition of the toluene, BH3•Me2S (30 µL, 0.06 mmol, 2 M in toluene) was added. The flask was sealed by closing the Teflon valve, and then placed in a 100 ºC oil bath for 1 h. After 1 h, a vacuum (0.5 mm Hg) was carefully applied by slightly opening the Teflon valve to remove the volatiles. After the volatiles were removed completely, a full vacuum was applied and maintained for a period of 30 min at a temperature of 100 ºC (oil bath). The flask was then allowed to cool to room temperature and opened to argon through the side-arm of the Schlenk flask. To this flask was added PhB(OH)2 (14.6 mg, 0.120 mmol) and toluene (2 mL). The flask was sealed by closing the Teflon valve, and then placed in a 100 ºC oil bath for 1 h. After 1 h, a vacuum (0.5 mm Hg) was carefully applied by slightly opening the Teflon valve to remove the volatiles. After the volatiles were removed completely, a full vacuum was applied and maintained for a period of 30 min at a temperature of 100 ºC (oil bath). The flask was then allowed to cool to room temperature and 778 opened to argon through the side-arm of the Schlenk flask. This was then completely dissolved in dry toluene (3 mL) under an argon flow through side-arm of the Schlenk flask to afford the stock solution of the pre-catalyst. An aliquot of 1mL of the pre-catalyst was then transferred to a 10 mL flame-dried home-made Schlenk flask equipped with a stir bar and flushed with argon. Asymmetric epoxidation protocol: To the flask containing the pre-catalyst (1 mL aliquot from 0.02 M stock solution) was added the dimethyl sulfoxide 221a (1.42 µL, 0.020 mmol) under an argon flow through side-arm of the Schlenk flask. The resulting mixture was stirred for 1 h at room temperature to give the catalyst 447. The rest of the procedure was similar to method B (for solid aldehydes) discussed earlier. Purification of the crude epoxide by neutral alumina chromatography (17 mm × 300 mm column, 10:1 to 1:1 hexanes/ CH2Cl2 as eluent) afforded pure cis-epoxide 135g in 85% isolated yield and 90% ee; cis/trans: 55:1. β-ketoamide side product 136g: 1.4% yield. 8.9.7 Epoxidation using the DIAZO-BOROX catalyst 448a (Table 8.8) R catalyst 447 (10 mol%) O O + H 127g NHBu N2 toluene –60 °C, 24 h 128a O O R CONHBu 135g O + R NHBu 136g R = 4-Br-C6H4 BH3•Me2S (3 equiv) PhOH (2 equiv) H2O (3 equiv) (S)-VANOL Toluene, 100 °C, 1 h 59 then 0.5 mm Hg (10 mol%) 100 °C, 0.5 h pre-catalyst Diazo 128a –60 °C 779 + [Diazo-H] OPh O –O B B O * O O B OPh catalyst 448a (2S,3S)-N-butyl-3-(4-bromophenyl)oxirane-2-carboxamide 135g: Preparation of the precatalyst stock solution : same as discussed earlier for method A or method B. Asymmetric epoxidation protocol: The flask containing the pre-catalyst was cooled to –60 °C for 10 min. Meanwhile, to a separate 10 mL flame-dried round bottom flask was added diazoacetamide 128a (28.23 mg, 0.2000 mmol) and dry toluene (1.5 mL). To the falsk containing the pre-catalyst was added pre-made solution of diazoacetamide 128a. The flask containing the diazoacetamide 128a was then rinsed with toluene (0.5 mL) and the rinse was then transferred to the flask containing the catalyst at –60 °C. This was then followed by closing the Teflon valve and stirring the resulting mixture for 10 min at –60 °C. The rest of the procedure was similar to method B (for solid aldehydes) discussed earlier. Purification of the crude epoxide by neutral alumina chromatography (17 mm × 300 mm column, 10:1 to 1:1 hexanes/ CH2Cl2 as eluent) afforded pure cis-epoxide 135g in 86% isolated yield and 91% ee; cis/trans: 56:1. β-ketoamide side product 136g: 2% yield. 8.9.8 NMR analysis of boroxinate catalysts 432 and 448a (Figure 8.4) BH3•Me2S (3 equiv) + [B-H] PhOH (2 equiv) OPh O B H2O (3 equiv) B (S)-VANOL O – preB O * 59 Toluene, 100 °C, 1 h catalyst temp O O B (0.1 mmol) d8-toluene then 0.5 mm Hg OPh 100 °C, 0.5 h 432 (B = 221a) 448a (B = 128a) 1 Entry 1, Figure 8.4A: H NMR of pure VANOL (S)-59 in d8-toluene 780 Entry 2, Figure 8.4A: To a 25 mL flame-dried home-made Schlenk flask (see Figure 2.26) equipped with a stir bar and flushed with argon was added (S)-VANOL (44 mg, 0.1 mmol) and BH3•Me2S (150 µL, 0.3 mmol, 2.0 M in toluene), PhOH (18.8, 0.2 mmol) and H2O (5.4 µL, 0.3 mmol). Under an argon flow through the side-arm of the Schlenk flask, dry toluene (2 mL) was added through the top of the Teflon valve to effect dissolution. The flask was sealed by closing the Teflon valve, and then placed in an 100 ºC oil bath for 1 h. After 1 h, a vacuum (0.5 mm Hg) was carefully applied by slightly opening the Teflon valve to remove the volatiles. After the volatiles were removed completely, a full vacuum was applied and maintained for a period of 30 min at a temperature of 100 ºC (oil bath). The flask was then allowed to cool to room temperature and opened to argon through the side-arm of the Schlenk flask. To the flask containing the pre-catalyst was d8-toluene (1 mL) under an argon flow through side-arm of the Schlenk flask. The reaction mixture was then stirred for 10 min. The resulting solution was then 1 directly transferred to a quartz NMR tube and was subjected to H NMR and 11 B NMR analysis. Entry 3, Figure 8.4A: 1.0 equiv of DMSO 221a and d8-toluene (1 mL) was added to the precatalyst (as shown in entry 2) for 10 min at 25 °C. Entry 4, Figure 8.4A: same as entry 3 except p-bromobenzaldehyde 127g used in place of DMSO. Entry 5, Figure 8.4A: 1.0 equiv of DMSO 221a was added to the entry 4 for 10 min at 25 °C. Entry 6, Figure 8.4A: same as entry 3 except diazoacetamide 128a used in place of DMSO. Entry 7, Figure 8.4A: 1 mL of d8-toluene was added to the pre-catalyst followed by the addition of 1.0 equiv of diazoacetamide 128a as a solution in d8-toluene (1 mL) for 10 min at 25 781 °C. Entry 8, Figure 8.4A: 1 mL of d8-toluene was added to the pre-catalyst and the resulting solution was cooled to –60 ºC. Thereafter, a pre-cooled (–60 ºC) solution of 1.0 equiv of diazoacetamide 128a in d8-toluene (1 mL) was added and the NMR was taken at –60 ºC. Entry 9, Figure 8.4A: 1 mL of d8-toluene was added to the pre-catalyst and the resulting solution was cooled to –60 ºC. Thereafter, the NMR was taken at –60 ºC. 8.9.9 Gram scale asymmetric catalysis and KIE studies (Scheme 8.9-8.11) R catalyst (10 mol%) O O + H 127g (6.0 mmol) NHBu N2 R toluene –60 °C, 24 h 128a (4.8 mmol) R = 4-Br-C6H4 catalyst 432 (with DMSO) 448a (without DMSO) O O CONHBu R 135g %ee %ee %yield before 1st 1st recryst Crop Crop 135g 135g 135g 135g 90 79 NHBu 136g %y 78 70 O + 99 97 65 60 c:t %y 136g 30:1 15:1 5 13 (2S,3S)-N-butyl-3-(4-bromophenyl)oxirane-2-carboxamide 135g: Preparation of the precatalyst stock solution : To a 100 mL flame-dried home-made Schlenk flask , prepared from a single-necked 100 mL pear-shaped flask that had its 14/20 glass joint replaced with a high vacuum threaded Teflon valve, equipped with a stir bar and flushed with argon was added (S)VANOL (632 mg, 1.44 mmol) and PhOH (271 mg, 2.18 mmol, freshly sublimed). Under an argon flow through the side-arm of the Schlenk flask, dry toluene (16 mL) was added through 782 the top of the Teflon valve to effect dissolution. After the addition of the toluene, BH3•Me2S (2.16 mL, 4.32 mmol, 2 M in toluene) and water (78.0 µL, 4.32 mmol) was added. The flask was sealed by closing the Teflon valve, and then placed in a 100 ºC oil bath for 1 h. After 1 h, a vacuum (0.5 mm Hg) was carefully applied by slightly opening the Teflon valve to remove the volatiles. After the volatiles were removed completely, a full vacuum was applied and maintained for a period of 30 min at a temperature of 100 ºC (oil bath). The flask was then allowed to cool to room temperature and opened to argon through the side-arm of the Schlenk flask. This was then completely dissolved in dry toluene (72 mL) under an argon flow through side-arm of the Schlenk flask to afford the stock solution of the pre-catalyst. An aliquot of 24 mL of the pre-catalyst was then transferred to a 250 mL flame-dried round bottom flask equipped with a stir bar and flushed with argon. Asymmetric epoxidation protocol (with DMSO): To the flask containing the pre-catalyst (24 mL aliquot from 0.02 M stock solution) was added the dimethyl sulfoxide 221a (37.5 µL, 0.48 mmol). The resulting mixture was stirred for 1 h at room temperature to give SULFOX-BOROX catalyst 432. Meanwhile, to a separate 100 mL flame-dried round bottom flask was added diazoacetamide 128a (677.6 mg, 4.800 mmol) and dry toluene (36 mL). After 1 h, the flask containing the catalyst was cooled to –60 °C for 10 min. To this solution was added pre-made solution of diazoacetamide 128a. The flask containing the diazoacetamide 128a was then rinsed with toluene (12 mL) and the rinse was then transferred to the flask containing the catalyst at –60 °C. This was then followed by the stirring of the resulting mixture for 10 min at –60 °C. Meanwhile, to a separate 50 mL flame-dried round bottom flask was added aldehyde 127g (1.11 g, 6.00 mmol, 1.2 equiv, freshly purified) and dry toluene (24 mL). To the mixture containing 783 diazoacetamide 128a and catalyst was then added a pre-made solution of aldehyde 127g and the resulting mixture was stirred for 24 h at –60 °C. The reaction was quenched by the addition of Et3N (4 mL) and was then warmed to room temperature. The reaction mixture was then transferred to a 500 mL round bottom flask. The reaction flask was rinsed with EtOAc (50 mL × 2) and the rinse was added to the 500 mL round bottom flask. The resulting solution was then concentrated in vacuo followed by exposure to high vacuum (0.05 mm Hg) for 1 h to afford the crude epoxide as an off-white semi-solid. The unreacted p-bromobenzaldehyde 127g (148 mg, 0.8 mmol) was recovered by flash silica gel column chromatography followed by the sublimation. The sample of the aldehyde was further subjected to the KIE studies. The remaining crude epoxide was flushed through column using EtOAc. Purification of the crude epoxide by neutral alumina chromatography (30 mm × 300 mm column, 10:1 to 1:1 hexanes/ CH2Cl2 as eluent) afforded pure cis-epoxide 135g as a white solid (mp 109-110 ºC on 99% ee material) in 78% isolated yield (1.12 g, 3.74 mmol) and 90% ee; cis/trans: 30:1. β-ketoamide side product 136g: 5% yield. The ee of the epoxide was increased to 99% ee with a single st recrystallization (1:9 EtOAc/hexanes). The yield of the 1 crop was 65%. Asymmetric epoxidation protocol (without DMSO): The same reaction in the absence of the DMSO resulted cis-epoxide 135g as a white solid (mp 109-110 ºC on 99% ee material) in 70% isolated yield (1.00 g, 3.36 mmol) and 79% ee; cis/trans: 15:1. β-ketoamide side product 136g: 13% yield. The ee of the epoxide was increased to 97% ee with a single recrystallization (1:9 st EtOAc/hexanes). The yield of the 1 crop was 60%. 784 REFERENCES 785 REFERENCES (1) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974-5976. (2) Zhang, W.; Loebach, J. L.; Wilson, S. R.; Jacobsen, E. N. J. Am. Chem. Soc. 1990, 112, 2801-2803. (3) Irie, R.; Noda, K.; Ito, Y.; Katsuki, T. Tetrahedron Lett. 1991, 32, 1055-1058. (4) Tu, Y.; Wang, Z.-X.; Shi, Y. J. Am. Chem. Soc. 1996, 118, 9806-9807. (5) (a) Matsumoto, K.; Katsuki, T. In Catalytic Asymmetric Synthesis, 3rd Ed.; Ojima, I., Ed.; Wiley-VCH: New York, 2010, p 839. (b) Wong, O. A.; Shi, Y. Chem. Rev. 2008, 108, 39583987. (c) Matsumoto, K.; Sawada, Y.; Katsuki, T. Pure Appl. Chem. 2008, 80, 1071-1077. (d) Aziridines and Epoxides in Organic Synthesis; Yudin, A. K., Ed.; Wiley-VCH: Weinheim, 2006. (6) Tokunaga, M.; Larrow, J. F.; Kakiuchi, F.; Jacobsen, E. N. Science 1997, 277, 936-938. (7) (a) Katsuki, T. In Comprehensive Asymmetric Catalysis, 1st Ed.; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: New York, 1999. (b) Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis, 2nd Ed.; Ojima, I., Ed.; Wiley-VCH: New York, 2000. (c) Li, Z.; Yamamoto, H. J. Am. Chem. Soc. 2010, 132, 7878-+. (d) Zhang, W.; Yamamoto, H. J. Am. Chem. Soc. 2007, 129, 286-287. (e) Jacobsen, E. N.; Wu, M. H. E. In Comprehensive Asymmetric Catalysis, 2nd Ed.; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: New York, 1999, Vol. Vol 2, p 649-677. (8) (a) Aggarwal, V. K.; Wang, M. F. Chem. Commun. 1996, 191-192. (b) Yang, D.; Wong, M.K.; Yip, Y.-C.; Wang, X.-C.; Tang, M.-W.; Zheng, J.-H.; Cheung, K.-K. J. Am. Chem. Soc. 1998, 120, 5943-5952. (c) Denmark, S. E.; Matsuhashi, H. J. Org. Chem. 2002, 67, 3479-3486. (d) Page, P. C. B.; Buckley, B. R.; Heaney, H.; Blacker, A. J. Org. Lett. 2005, 7, 375-377. (9) (a) Nishikawa, Y.; Yamamoto, H. J. Am. Chem. Soc. 2011, 133, 8432-8435. (b) Shibasaki, M.; Kanai, M.; Matsunaga, S. Aldrichimica Acta 2006, 39, 31–39. (10) (a) Juliá, S.; Masana, J.; Vega, J. C. Angew. Chem., Int. Ed. 1980, 19, 929-931. (b) Ooi, T.; Ohara, D.; Tamura, M.; Maruoka, K. J. Am. Chem. Soc. 2004, 126, 6844-6845. (c) Lattanzi, A. Org. Lett. 2005, 7, 2579-2582. (d) Marigo, M.; Franzén, J.; Poulsen, T. B.; Zhuang, W.; 786 Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 6964-6965. (e) Lee, S.; MacMillan, D. W. C. Tetrahedron 2006, 62, 11413-11424. (11) (a) Liu, Y.; Provencher, B. A.; Bartelson, K. J.; Deng, L. Chem. Sci. 2011, 2, 1301-1304. (b) Ku, J.-M.; Yoo, M.-S.; Park, H.-g.; Jew, S.-s.; Jeong, B.-S. Tetrahedron 2007, 63, 8099-8103. (c) Arai, S.; Shioiri, T. Tetrahedron 2002, 58, 1407-1413. (d) Arai, S.; Shirai, Y.; Ishida, T.; Shioiri, T. Tetrahedron 1999, 55, 6375-6386. (e) Arai, S.; Shirai, Y.; Shioiri, T.; Ishida, T. Chem. Commun. 1999, 49-50. (f) Arai, S.; Shioiri, T. Tetrahedron Lett. 1998, 39, 2145-2148. (g) Arai, S.; Ishida, T.; Shioiri, T. Tetrahedron Lett. 1998, 39, 8299-8302. (12) (a) Aggarwal, V. K.; Alonso, E.; Hynd, G.; Lydon, K. M.; Palmer, M. J.; Porcelloni, M.; Studley, J. R. Angew. Chem., Int. Ed. 2001, 40, 1430-1433. (b) Aggarwal, V. K.; Alonso, E.; Bae, I.; Hynd, G.; Lydon, K. M.; Palmer, M. J.; Patel, M.; Porcelloni, M.; Richardson, J.; Stenson, R. A.; Studley, J. R.; Vasse, J.-L.; Winn, C. L. J. Am. Chem. Soc. 2003, 125, 1092610940. (c) Aggarwal, V. K.; Winn, C. L. Acc. Chem. Res. 2004, 37, 611-620. (13) (a) He, L.; Liu, W.-J.; Ren, L.; Lei, T.; Gong, L.-Z. Adv. Synth. Catal. 2010, 352, 11231127. (b) Liu, W. J.; Lv, B. D.; Gong, L. Z. Angew. Chem., Int. Ed. 2009, 48, 6503-6506. (14) (a) Li, W.; Wang, J.; Hu, X.; Shen, K.; Wang, W.; Chu, Y.; Lin, L.; Liu, X.; Feng, X. J. Am. Chem. Soc. 2010, 132, 8532-8533. (b) Hashimoto, T.; Miyamoto, H.; Naganawa, Y.; Maruoka, K. J. Am. Chem. Soc. 2009, 131, 11280-11281. (c) Trost, B. M.; Malhotra, S.; Fried, B. A. J. Am. Chem. Soc. 2009, 131, 1674-+. (d) Hashimoto, T.; Naganawa, Y.; Maruoka, K. J. Am. Chem. Soc. 2008, 130, 2434-2435. (e) Hasegawa, K.; Arai, S.; Nishida, A. Tetrahedron 2006, 62, 13901401. (f) Dudley, M. E.; Morshed, M. M.; Brennan, C. L.; Islam, M. S.; Ahmad, M. S.; Atuu, M.-R.; Branstetter, B.; Hossain, M. M. J. Org. Chem. 2004, 69, 7599-7608. (g) Yao, W.; Wang, J. Org. Lett. 2003, 5, 1527-1530. (h) Jiang, N.; Wang, J. B. Tetrahedron Lett. 2002, 43, 12851287. (i) Mahmood, S. J.; Hossain, M. M. J. Org. Chem. 1998, 63, 3333-3336. (j) Holmquist, C. R.; Roskamp, E. J. J. Org. Chem. 1989, 54, 3258-3260. (k) Zhu, Z.; Espenson, J. H. J. Am. Chem. Soc. 1996, 118, 9901-9907. (l) Zhu, Z.; Espenson, J. H. J. Org. Chem. 1995, 60, 70907091. (m) Curini, M.; Epifano, F.; Marcotullio, Maria C.; Rosati, O. Eur. J. Org. Chem. 2002, 1562-1565. (15) Huang, L.; Wulff, W. D. J. Am. Chem. Soc. 2011, 133, 8892-8895. (16) Desai, A. A.; Wulff, W. D. J. Am. Chem. Soc. 2010, 132, 13100-13103. (17) Li, X.; Burrell, C. E.; Staples, R. J.; Borhan, B. J. Am. Chem. Soc. 2012, 134, 9026-9029. 787 (18) Mukherjee, M.; Gupta, A. K.; Lu, Z.; Zhang, Y.; Wulff, W. D. J. Org. Chem. 2010, 75, 5643-5660. (19) Hasegawa, T.; Aoyama, H.; Omote, Y. J. Chem. Soc., Perkin Trans. 1 1979, 963-969. (20) Vetticatt, M. J.; Desai, A. A.; Wulff, W. D. J. Am. Chem. Soc. 2010, 132, 13104-13107. (21) Gaussian 03, Revision D.01 M. J. Frisch, G. W. T., H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman, J. A. Montgomery, Jr., T. Vreven, K. N. Kudin, J. C. Burant, J. M. Millam, S. S. Iyengar, J. Tomasi, V. Barone, B. Mennucci, M. Cossi, G. Scalmani, N. Rega, G. A. Petersson, H. Nakatsuji, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, M. Klene, X. Li, J. E. Knox, H. P. Hratchian, J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R. E. Stratmann, O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli, J. W. Ochterski, P. Y. Ayala, K. Morokuma, G. A. Voth, P. Salvador, J. J. Dannenberg, V. G. Zakrzewski, S. Dapprich, A. D. Daniels, M. C. Strain, O. Farkas, D. K. Malick, A. D. Rabuck, K. Raghavachari, J. B. Foresman, J. V. Ortiz, Q. Cui, A. G. Baboul, S. Clifford, J. Cioslowski, B. B. Stefanov, G. Liu, A. Liashenko, P. Piskorz, I. Komaromi, R. L. Martin, D. J. Fox, T. Keith, M. A. Al-Laham, C. Y. Peng, A. Nanayakkara, M. Challacombe, P. M. W. Gill, B. Johnson, W. Chen, M. W. Wong, C. Gonzalez, and J. A. Pople, Gaussian, Inc., Wallingford CT, 2004 (22) Singleton, D. A.; Thomas, A. A. J. Am. Chem. Soc. 1995, 117, 9357-9358. (23) Ouihia, A.; Rene, L.; Guilhem, J.; Pascard, C.; Badet, B. J. Org. Chem. 1993, 58, 16411642. (24) Doyle, M. P.; Kalinin, A. V. J. Org. Chem. 1996, 61, 2179-2184. (25) Blankley, C. J.; Sauter, F. J.; House, H. O. Org. Synth. 1969, 49, 22. (26) García, M. J.; Rebolledo, F.; Gotor, V. Tetrahedron 1994, 50, 6935-6940. (27) Neo, A. G.; Delgado, J.; Polo, C.; Marcaccini, S.; Marcos, C. F. Tetrahedron Lett. 2005, 46, 23-26. 788 CHAPTER 9   IS IT REALLY A LEWIS ACID CATALYED ASYMMETRIC IMINO-ALDOL REACTION? - PROBING THE NATURE OF THE ACTIVE SITE VIA NMR SPECTROSCOPY, COMPUTATIONAL STUDIES AND SUBSTRATE AND CATALYST MODIFICATIONS Another year; another reaction. I think that we should pursue it a little more! -William D. Wulff 9.1 Introduction 1 Out of all catalytic asymmetric reactions, the Mannich reaction and Mannich-type 2 reactions are some of the most important and useful reactions. One of the Mannich-type reactions is the reaction of an enolate or enolate equivalent with an aldimine. This reaction provides an easy access to the optically active β-amino esters or ketones, which can easily be 3 transformed into β-amino acids, β-amino-alcohols, β-lactams etc. In the 90’s, several examples of enantioselective Mannich-type reactions using a stoichiometric amount of an activator for the imines were reported. 4 However, in last decade or so, various kinds of asymmetric catalysis have been utilized for the realization of this reaction. This includes a variety of chiral Lewis acid 2a,2e 5 and Brønsted acid mediated asymmetric reactions. Specifically, one of the early examples involving chiral Lewis acids was reported by Kobayashi and co-workers in 1997. 6 They reported the first asymmetric Mannich type reaction between imine 458 and ketene silyl acetal 460 using a catalyst derived from Zr(OtBu)4 463b, NMI 464 and (R)-6,6ʹ′-Br2-BINOL 459. 789 In due course of time, they reported several modifications of this catalytic system for the same reaction. 2a Within four years of the first example, the Wulff group reported an unusually robust and temperature independent catalytic system which provided higher selectivities by employing 7 vaulted biaryl ligand (S)-VAPOL 59 rather than the linear biaryl ligands 55 and 459. A list of various ligands and imines screened for imino-aldol reaction are presented in Figure 9.1. Figure 9.1 Ligands and imines used in the imino-aldol reaction. OMe N OH N R N R 455 OH N R 456 R 458 457 Br OH OH OH OH Ph Ph OH OH Br (R)-BINOL 55 (R)-6,6-Br2-BINOL 459 (S)-VAPOL 58 Based on the initial CPK models, Wulff and cowerkers installed two methyl groups at the 3 and 5 positions of the phenyl ring of the imine 457, thereby, transforming it to the imine 458 (Figure 9.1). Excellent results were obtained utilizing imine 458 and also, it was found to be 7 independent of the temperature (Table 9.1). More importantly, they were able to employ a 790 catalyst loading as low as up to 2 mol% (Table 9.1, entries 7 and 9). The only data from Table 9.1 that comes from the present dissertation is entry 6 (solvent = CH2Cl2). Table 9.1 Imino-aldol reaction between imine 457/458 with ketene acetal 460 using various ligands. Zr(OiPr)4: NMI:Ligand R R OH (1.0:1.2:2.2) OTMS Ph N R + OMe OH 457a (R=H) 458a (R=Me) Catalyst (2–20 mol %) R NH O solvent, T °C, time h Ph OMe 461a (R=H) 462a (R=Me) 460 Solvent Imine # 1 d 2 3 4 d 5 6 Cat (mol%) T (°C) Ester 457a 457a 457a 457a 457a 55 55 58 55 459 20 10 20 20 10 –45 –45 –45 25 25 461a 461a 461a 461a 461a 457a 58 20 25 CH2Cl2 Yield ee Time b c (h) (%) (%) 80 36 19 87 86 19 50 80 10 100 28 4 87 48 4 461a 78 e 457a 7 8 9 10 L d 58 2 40 461a – 84 – 458a 458a 458a 459 58 58 10 20 2 25 25 100 462a 462a 462a – – – – – – Toluene Yield ee Time b c (h) (%) (%) – – – – – – 92 91 20 – – – 95 62 18 18 94 – 100 – – – 93 100 95 89 f,g 15 g,h 6 86 47 98 98.5 18 15 5 a Unless otherwise specified, all reactions were performed with 0.25 mmol of imine 457/458 in toluene (0.125 M in imine) with 1.2 equiv of 460 and 10, 20 or 2 mol% of the catalyst at T i i °C. The catalyst was prepared from Zr(O Pr)4/ PrOH 463a, ligand 55/58/459 (2.2 equiv) and NMI 464 (1.2 equiv) in CH2Cl2 (entries 1, 2, 4, 5 and 8) or toluene (entries 3, 6, 7, 9 and 10) at 25 °C for 1h. L = Ligand. used. e 15:1 CH2Cl2: toluene. b f Isolated Yield. 0.5 M in imine. 791 c g Determined by HPLC. 15:1 toluene:CH2Cl2. h d t Zr(O Bu)4 463b 1.0 M in imine. Our catalyst was prepared by the reaction of 2.2 equivalents of (S)-VAPOL 58 with 1 equiv of Zr(iPrO)4 463a and 1.2 equiv of N-methylimidazole (NMI) 464 at room temperature for 1 h. In dichloromethane, it was found that (S)-VAPOL 58 and (R)-6,6ʹ′-Br2-BINOL 459 were superior to (R)-BINOL 55 at –45 °C (Table 9.1, entries 1-3). At 25 °C, while asymmetric induction in the case of VAPOL remains almost unchanged (84% ee, Table 9.1, entry 6), it decreased quite sharply in the case of (R)-6,6ʹ′-Br2-BINOL 459 (48% ee, Table 9.1, entry 5). When the solvent is changed to toluene, the induction increases in both cases at room temperature. However, (S)-VAPOL 58 proved still to be the best ligand for this reaction in toluene at room temperature (89% ee vs 62% ee, Table 9.1 entries 6 vs. 5). In fact, quantitative yield was obtained with only a small drop-off in the asymmetric induction (86% ee), when the reaction was performed at 40 °C with 2 mol% catalyst loading. Additionally, almost optically pure β-amino ester was obtained employing imine 458a independent of temperature (entries 910). However, only 47% ee was observed when (R)-6,6ʹ′-Br2-BINOL 459 was used as the ligand in the case of the imine 458a (entry 8). Thus, the catalyst generated from VAPOL is far more efficient than the catalyst generated from (R)-BINOL 55 or its derivative 459 as low temperature is not necessary for attaining high asymmetric inductions. 9.2 Proposed catalytic cycle of imino-aldol reaction In the year 2001, Wulff proposed a mechanism for the imino-aldol reaction and this is presented in Scheme 9.1. Initially, the proposed catalytic cycle I involved a catalyst bearing two VAPOL ligands on one zirconium and o-hydroxyphenylimine 457 is coordinated to the 792 zirconium. Based on the initial space-filling CPK models, we found that the binding of the two VAPOL units to one zirconium atom is possible only with a facial arrangement of the four oxygen atoms as illustrated by structure 465 in Scheme 9.1. Also, two NMIs are proposed to be coordinating at the axial positions. Thereafter, the imine is proposed to replace one of the NMI at one of the apical position. This would lead to imine-catalyst complex 466 where a phenol exchange has occurred. Subsequent attack of ketene acetal 460 would give 467 first, and then 468, whose trimethylsilylated oxygen atom attacks the Zr center to afford the product 469. Subsequent hydrolysis would furnish the β-amino ester 461. Scheme 9.1 Proposed catalytic cycles of imino-aldol reaction using (S)-VAPOL 58 (A, B, C) and (R)-6,6ʹ′-Br2-BINOL 459 (D) as the ligands. (A) Catalytic cycle I (B) Catalytic cycle II (C) Catalytic cycle III (D) Catalytic cycle IIIʹ′ A OTMS Zr(OiPr)4 463a OH + OH (S)-58 N OH O R O 457 N OH O O NMI OMe 460 R Zr N NMI 464 NMI iPrOH O O O O Cycle I O O NH O OMe NMI O OMe O OTMS HN O Zr NH O R OH O O + H3O 461 N – R Zr NMI 465 OH + TMS O OMe 466 Zr R N OMe NMI 468 469 793 OTMS O O R 467 Scheme 9.1 cont’d B OTMS Zr(OiPr)4 463a OH + N OH R O O 457 N OMe 460 R Zr N 464 OH (S)-58 – + N H O NMI TMS NMI NMI iPrOH O O 470 O O Zr OMe O Cycle II O O + O O NMI OH NH O OMe TMS + H3O OTMS 461 O NH O R R Zr 465 R – N H O +N O H – O Zr OMe NMI 471 R O O OMe O O O NMI 472 469 C OTMS OH Zr(OiPr)4 463a + OH (S)-58 N OH N O R Zr 457 N O 464 NMI – iPrOH O O O O O Zr isomerise Zr R NMI O O O O N O 474 NMI O O N– R 475 OH O OTMS + H3O NH O OMe 461 O + TMS O MeO 465 R HO Zr Cycle III NMI 473 NMI OMe 460 O HO Zr O O TMS O MeO NH O R O HO OMe 469 N R 476 794 Scheme 9.1 cont’d D OTMS OH Zr(OtBu)4 463b + N OH N Zr 457 N OH (S)-459 464 O – tBuOH 474' O O O O O Zr isomerise Zr R NMI O O O O N O NMI NMI O O N– R 475' OH O OTMS + H3O NH O OMe 461 O + TMS O MeO 465' R HO Zr Cycle III' NMI 473' NMI OMe 460 O HO O R Zr O O TMS O MeO NH O R O HO OMe 469 N R 476' During recent mechanistic investigations, we envisioned another catalytic cycle with a different mode of activation of the imine (Scheme 9.1B). This involves the presence of the imine–catalyst complex 470 where the imine is protonated and is hydrogen bonded to the oxygen of the ligand 58. As the imine is covalently bonded to zirconium after phenol exchange, this type of interaction would fall in the category of Lewis acid assisted Brønsted acid catalysis. Another plausible mechanism was proposed by Kobayashi and coworkers and involves (R)-6,6ʹ′Br2-BINOL 459 as the ligand. It excludes the presence of NMI in the transition states (Catalytic cycle IIIʹ′, Scheme 9.1D and Scheme 9.2B). The catalyst is generated from a mixture of Zr(OtBu)4 463b, NMI 464 and (R)-6,6ʹ′-Br2-BINOL 459. 795 In this mechanism, it has been assumed that step one involves the isomerization of complex 465', where there are two NMI groups that are trans to each other (Catalytic cycle III, Scheme 9.2B), to 473' where the NMI groups are cis to each other. The second step involves the exchange of the NMI groups by the imine 457 leading to the formation of the imine-catalyst complex 474'. The coordination of the hydroxyl group to the zirconium atom indicates the importance of the hydroxyl group. Subsequent attack of ketene acetal 460 would give 475' then 476', which is followed by the final release of the product 461. A similar kind of mechanism can also be assumed for the reaction involving (S)-VAPOL 58 as the ligand (Catalytic cycle III, Scheme 9.1C). Various techniques such as NMR studies and theoretical calculations were then used to determine the most probable catalytic cycle and to support the proposed intermediates of the corresponding catalytic cycle. The details are discussed below. 9.3 NMR experiments: In support of the intermediate 465, a clean spectrum was observed when a catalyst derived from Zr(iPrO)4, 2 equiv of (S)-VAPOL 58 and 2 equiv of N-methyl imidazole 464 was subjected 1 1 to H NMR analysis. The observed H NMR spectrum with a single bay proton doublet at δ = 11.33 ppm clearly indicates the presence of a C2-symmetric species 465 bearing two mutually trans NMI ligands bound to zirconium. Thereafter, another NMR experiment was performed to gain an insight into the interaction of the imine with the catalyst. This provides some information about the phenol exchange. An excess amount of imine 457a (2 equiv) was added to the catalyst that was generated from 1 equiv of Zr(iPrO)4 463a, 2 equiv of VAPOL 58 and 2 796 equiv of N-methyl imidazole 464 in d8-toluene. Non-equivalent phenanthrene units were 1 observed in the H NMR spectrum. In fact, the appearance of new bay protons at δ = 11.4 and δ = 11.8 ppm indicated the loss of C2 symmetry and supported the proposal of phenol exchange resulting from the addition of the imine to the catalyst. Another piece of evidence comes from the fact that the reaction of imine 456a (R = Ph) gave the racemic product in 5% yield only 7 (Figure 9.1). Also, a similar observation has been made for the catalyst derived from (R)-6,6ʹ′- Br2-BINOL 459 where the imines 455a (R = Ph) and 456a (R = Ph) gave good yields but only in 5% ee. 9.4 6 DFT calculations Intrigued by the observations from the NMR experiments on the catalyst for the imino- aldol reaction, we decided to investigate the catalyst and catalytic cycle further using computational chemistry. Specifically, the nature of the active site and subsequent transition state of the imino-aldol reaction were point of interests in these theoretical calculations. The possibility of hydrogen bonding in 470 (Scheme 9.1) motivated us to study the mechanism of the reaction in detail. The catalytic asymmetric imino-aldol reaction is a challenging system to examine computationally due to the size of the system which includes two VAPOL units and the zirconium atom (with d-orbitals). The number of atoms is more than 125 in each of the reactions studied computationally. Hence, in order to reduce the computational cost, the hybrid DFT:HF ONIOM method was employed to obtain quality results. It must be noted that it is not ‡ reasonable to expect quantitative matches of experimental and theoretical ΔΔG given the size of the experimental system and the errors associated with each of the methods. 797 The ‘extrapolated energy’ from the ONIOM calculation gives an initial measure of the relative energy of the transition state structures. Thereafter, following the common approach, one can then perform a single point energy calculation on the ONIOM optimized geometries using the DFT method with a larger basis set for the whole system. All calculations were performed with 8 the Gaussian ʹ′03. Geometries and transition states were fully optimized and characterized by frequency using B3LYP or hybrid density functional theory (BHandHLYP) with the LanL2DZ or DGDZVP basis sets for the high level and HF with STO-3G basis set for the low level in ONIOM calculations. Free energies (298.15 K, 1 atm) and natural charges from the natural population analysis were also computed for the gas phase. As the reaction was performed in toluene, one does not expect much stabilization from toluene for the charged intermediates/transition states along the reaction coordinate. In the continuum solvation model, the single-point energy calculations with the self-consistent reaction field (SCRF) calculation based on the polarizable continuum model (PCM, ε = 2.379 for toluene) were carried out at the high level for the one used for geometry optimization in ONIOM calculations. 9.4.1 Catalytic cycle I verses catalytic cycle II As stated earlier, there are two possible kinds of imine-catalyst complexes and these are 466a and 470a. These two complexes 466a and 470a were computed using ONIOM (B3LYP/LanL2DZ:HF/STO-3G) calculations. The division of layers for the ONIOM calculations is illustrated by the color scheme given in Figure 9.2. The choice of the basis sets for the higher level calculations were made after carefully considering the available options for the zirconium atom in Gaussian ʹ′03. All distances in the fully optimized structures are reported in angstroms. The reported energies are the free energies (ΔΔG) of fully optimized geometries from the ONIOM calculations. 798 Figure 9.2 Division of layers for the ONIOM calculations ONIOM(B3LYP/LanL2DZ:HF/ STO-3G) and ONIOM(BHandHLYP/DGDZVP:HF/STO-3G) level. O O Zr O N d1 Ph H O1 O2 d2 NMI 466a O d N O3 3 H Ph d4 O4 Zr O O NMI 470a Red = B3LYP/LanL2DZ OTMS or BHandHLYP/DGDZVP OMe Green = HF/STO-3G 460 Interestingly, the imine-catalyst complex 470a was found to be the preferred complex as the other complex 466a was found to be +38.0 Kcal/mol higher in energy (Figure 9.3). The huge difference in energy suggests that the complex 466a is highly unfavorable. In complex 466a, the proposed hydrogen bonding (d1 = 2.87 Å, Figure 9.3) between nitrogen of imine and the proton attached to O1 is found to be a very weak interaction and in fact the bond angle (98º) is far away 799 from linear. The preference for the imine-catalyst complex 470a suggests that a Lewis acid assisted Brønsted acid catalysis might be a plausible mechanism in this case. There is a probability of a weak hydrogen bonding (d4) existing in the case of complex 470a with a 4 4 calculated bond distance of 2.53 Å (d4, O -H, Figure 9.3) and bond angle of 169.6º (∠O HN, Figure 9.3). In order to refine the analysis, we subjected the both complexes to geometry optimization using hybrid density functional (BHandHLYP) with DGDZVP basis set. BHandHLYP is considered to be a better method than B3LYP for the case of hydrogen bonding and other non-covalent interactions. 9 In this case, the bond distance (d4) and bond angle were 4 4 determined to be 2.32 Å (d4, O -H, Figure 9.3) and 179.6º (∠O HN, Figure 9.3) respectively. This indicated the presence of a hydrogen bond of moderate strength. Another weak interaction 3 was found to be operating between O and the H attached to nitrogen of imine (d3 = 2.31 Å, Figure 9.3). It must be noted that complex 466a is +29 Kcal/mol higher in energy as compared to complex 470a even at the higher level of calculations (ONIOM(BHandHLYP/DGDZVP:HF/STO-3G), Figure 9.3). Figure 9.3 Calculated 3D structures and relative energies of the imine-catalyst complexes 466a and 470a at ONIOM(B3LYP/LanL2DZ:HF/STO-3G) ONIOM(BHandHLYP/DGDZVP:HF/STO-3G) level. level and The structures are visualized by the Mercury program (C, gray; O, red; N, blue; Zr, yellow; H, white). Hydrogen atoms are omitted (except N-H) and the ligand is given in green color for clarity. Free energies and bond lengths are in Kcal/mol and Å respectively. Some interactions are highlighted: d1 = 2.87 Å, d2 = 3.02 800 Figure 9.3 cont’d Å, d3 = 2.21 Å and d4 = 2.53 Å with ONIOM(B3LYP/LanL2DZ:HF/STO-3G) and d1 = 2.95 Å, d2 = 2.97 Å, d3 = 2.31 Å and d4 = 2.32 Å with ONIOM(B3LYP/LanL2DZ:HF/STO-3G) O 1 d3 d1 d2 O O 3 d4 2 O 466a ΔΔG = +38 4 470a ΔΔG = 0 Although the imine-catalyst complex 466a is highly unlikely to be a viable intermediate, we decided to compute the transition states for the reaction of ketene acetal 460 with both complexes 466a and 470a. More unstable intermediates tend to be also much more reactive and therefore, it is important to explore reactivity and compare the activation barriers for reaction of both complexes. Transition states for the key carbon-carbon bond-forming step of the reactions between 466a and 460 and 470a and 460 were located by scanning the coordinates at the ONIOM(B3LYP/LanL2DZ:HF/STO-3G) level. All distances are reported in angstroms, and all ‡ reported energies are ΔΔG of fully optimized geometries from the ONIOM calculations. Also, 801 it must be noted that the ketene acetal 460 was calculated at B3LYP/LanL2DZ level of theory. Figure 9.4 Free Energy diagram for the transition states TS0-477-Si and TS1-478-Si at ONIOM(B3LYP/LanL2DZ:HF/STO-3G) level. Energy in parenthesis is enthalpy. B3LYP/LANL2DZ:HF/STO-3g 98.5 (80.5) TS0-477-Si ΔG (ΔH) (kcal/mol) 60.5 (41.5) 68.2 (67.4) 38.0 (39.0) 30.3 (13.1) Reactants 466a + 460 TS1-478-Si 0.0 Reactants 470a + 460 (R) - 461a Mannich product 58 + 463a + 464 + 457a 466a or 470a (R) - 461a Mannich product Reaction Coordinate The DFT calculations at B3LYP/LanL2DZ level of theory revealed that a direct coordination of N of imine to the zirconium atom in complex 466 is highly unfavorable as a high energy barrier of +60.5 kcal/mol was found in the case of the corresponding transition state (TS0 477-Si, Figure 9.4 and 9.5) leading to favored enantiomer (R). The fact that the calculated barrier for TS1-478-Si (470→471) is approximately three times lower than the barrier for TS0477-Si (466→467) strongly supports the catalytic cycle II (Figure 9.4 and 9.5). 802 Figure 9.5 Calculated 3D structures of the TS0-477-Si and TS1-478-Si at ONIOM(B3LYP/LanL2DZ:HF/STO-3G) level. The structures are visualized by the Mercury program (C, gray; O, red; N, blue; Zr, yellow; Si = light blue). Hydrogen atoms are omitted (except N-H) and the ligand is given in green color for clarity. Bond lengths are in Å. Some interactions are highlighted: d1 = 3.55 Å, d2 = 3.07 Å, d5 = 1.95 Å, d3 = 2.17 Å, d4 = 2.97 Å and d6 = 2.08 Å. d6 d2 d1 d3 d5 TS0-477-Si d4 TS1-478-Si The computations discussed above were performed with four different orientations of attack by the ketene acetal and the data presented above was for the lowest energy orientation of the four. The discussion of the other possible transition states is given below. 9.4.2 Various transition states for catalytic cycle II As discussed above, four transition states (including TS1-478-Si) were located for one particular enantiomer by employing the different orientations and conformations of silyl ketene 803 acetal 460 (Figure 9.6A). The lowest energy transition state leading to the favored enantiomer (R) was found to be TS1-478-Si when it was subjected to ONIOM(BHandHLYP/DGDZVP:HF/STO-3G) level of calculations. The key observation in the favored structure is that the hydrogen bonding (d4) is further weakened due to increase in the bond distance from 2.3 to 2.9 Å (Figure 9.6). Nonetheless, a weak interaction is still operational providing the R enantiomer as the major product. Also, it must be noted that the Re face of the imine 457a is completely shielded by the (S)-VAPOL 58. The carbon-carbon bond distance for transition state TS1-478-Si is 2.08 Å (Figure 9.5). Interestingly, TS3-480-Re which leads to lowest energy structure for minor enantiomer was found to have no hydrogen bonding as the OH distance was ~ 4 Å. The energy difference between favored transition state TS1-479-Si and disfavored transition state TS3-480-Re was determined to be +1.8 Kcal/mol (Figure 9.6). The absence of the hydrogen bonding is probably due to the steric hindrance between the methyl groups of ketene acetal 460 and the phenanthrene ring of the (S)-VAPOL 58. Figure 9.6 (A) Different conformations and orientations of silyl ketene acetal 460 used for calculations. (B) Calculated 3D structures and relative free energies of TS1-478 to TS4-481 at ONIOM(BHandHLYP/DGDZVP:HF/STO-3G) level. The structures are visualized by the Mercury program (C, gray; O, red; N, blue; Zr, yellow; Si = light blue). Hydrogen atoms are omitted (except N-H) and the ligand is given in green color for clarity. Free energies and bond 3 lengths are in kcal/mol and Å respectively. Some interactions are highlighted: d3 (O –H), d4 4 (O –H) and d6 (C–C). (C) Space-filling rendition of TS1-478-Si and TS3-480-Re with top and side-view with hydrogens showing. 804 Figure 9.6 cont’d A P N N R O Me O P N R Me TMS (For TS1-478) O P N R TMS O TMS (For TS2-479) O P R O Me O O TMS Me (For TS4-481) (For TS3-480) B d6 d6 d3 d3 d4 d4 TS1-478-Si TS1-478-Re ‡ ‡ ΔΔG = +0.0 ΔΔG = +2.2 d3 = 2.16 Å, d4 = 2.99 Å and d6 = 2.09 Å d3 = 2.24 Å, d4 = 3.98 Å and d6 = 2.09 Å 805 Figure 9.6 cont’d d6 d6 d3 d3 d4 d4 TS2-479-Si TS2-479-Re ‡ ‡ ΔΔG = +1.9 ΔΔG = +2.8 d3 = 2.15 Å, d4 = 2.99 Å and d6 = 2.09 Å d3 = 2.21 Å, d4 = 3.94 Å and d6 = 2.15 Å d6 d6 d3 d4 d3 d4 TS3-480-Si TS3-480-Re ‡ ‡ ΔΔG = +0.1 ΔΔG = +1.8 d3 = 2.17 Å, d4 = 2.93 Å and d6 = 2.09 Å d3 = 2.24 Å, d4 = 3.96 Å and d6 = 2.08 Å 806 Figure 9.6 cont’d d6 d6 d3 d3 d4 d4 TS4-481-Si TS4-481-Re ‡ ‡ ΔΔG = +0.5 ΔΔG = +7.1 d3 = 2.18 Å, d4 = 3.09 Å and d6 = 2.15 Å d3 = 2.16 Å, d4 = 3.89 Å and d6 = 2.16 Å C Top view TS1-478-Si ‡ ΔΔG = +0.0 807 Side view Figure 9.6 cont’d Top view TS3-480-Re Side view ‡ ΔΔG = +1.8 Further, the single point energies with the self-consistent field (SCRF) calculation based on the polarizable continuum model (PCM, ε = 2.379 for toluene) were calculated at BHandHLYP/DGDZVP level of theory and the TS3-480-Re was found to be +1.1 kcal/mol ‡ (ΔΔGsol ) higher in energy as compared to TS1-478-Si. 9.5 Catalyst modifications After location of the transition states for the zirconium mediated imino-aldol reaction, it was decided to experimentally test them via some modified catalytic systems. According to the calculated transition states, the third ring C in (S)-VAPOL 58 is extremely important. Hence, it would be interesting to screen the reaction in the absence of the ring C. Subsequently, we examined some ligands like (S)-VANOL 59 and (S)-ISOVAPOL 197 where either the third ring 808 is removed or shifted (Figure 9.7). As predicted, a sharp decrease in ee was observed in both cases as compared to (S)-VAPOL 58 (entries 2 and 3, Table 9.2). Figure 9.7 Various ligands used for imino-aldol reaction. B C A Ph Ph OH OH 58 Remove extra ring Add extra methyl Shift extra ring C' Me B B B C A A Ph Ph OH OH Ph Ph A Ph Ph OH OH OH OH Me 59 482 197 In an attempt to increase the asymmetric induction based on the computational findings and initial CPK model study, Kostas Rampalokos, a former group member, prepared (S)-8,8ʹ′Me2-VAPOL 482. Although it did not improve the asymmetric induction, it did give essentially the same results as (S)-VAPOL 58. Hence the results obtained further supports the proposed 809 mechanism. The details of the screening of the ligands at various temperatures are given in Table 9.2. Table 9.2 Imino-aldol reaction between imine 457a with keten acetal 460 using various ligands. Zr(OiPr)4: NMI:Ligand OH (1.0:1.2:2.2) OTMS Ph + N OMe OH 457a Catalyst (20 mol %) NH O Toluene, T °C, 24h Ph OMe 461a 460 Temperature # Yield (%) 1 2 3 4 25 °C –45 °C Ligand (S)-VAPOL 58 (S)-8,8ʹ′-Me2-VAPOL 482 (S)-ISOVAPOL 197 (S)-VANOL 59 b 92 90 58 53 ee (%) 91 91 06 –18 c Yield (%) 95 97 63 71 b ee (%) c 89 86 71 51 a Unless otherwise specified, all reactions were run with 0.25 mmol of imine 457a in toluene (0.125 M in imine) with 1.2 equiv of 460 and 20 mol% of the catalyst at T °C. The catalyst was prepared from Zr(OiPr)4/iPrOH, ligand (1.2 equiv) and NMI (1.2 equiv) in toluene at 25 °C for 1 h. 9.6 b Isolated Yield. c Determined by HPLC. Imine modifications Based on initial studies with CPK models, there were some modifications done in the structure of the imine 457. A new imine 458 was prepared by installing two methyl groups at 3 and 5 position of the phenyl ring of the imine 457 (Figure 9.1). Excellent results were obtained with imine 458a (Table 9.1, entries 8-10) and also the asymmetric inductions were found to be independent of temperature. Hence, we decided to locate and analyze the transition states where 810 the imine 458a was used in the reaction. The calculated transition structures are shown in Figure 9.8. Figure 9.8 Calculated 3D structures and relative free energies of (A) TS-483-Si and (B) TS-483Re at ONIOM(BHandHLYP/DGDZVP:HF/STO-3G) level. The structures are visualized by the Mercury program (C, gray; O, red; N, blue; Zr, yellow; Si, light blue; H, white). Hydrogen atoms are omitted (except N-H) and the ligand is given in green color for clarity. Free energies 3 and bond lengths are in kcal/mol and Å respectively. Some interactions are highlighted: d3 (O – 4 H), d4 (O –H) and d6 (C–C). Space-filling rendition of TS-483-Si and TS-483-Re with top and side-view with hydrogens showing. The ortho methyl group is shown in magenta color in the space filling models. A d6 d3 d4 Top view 811 Figure 9.8 cont’d Side view-A Side view-B TS-483-Si ‡ ΔΔG = +0.0 d3 = 2.23 Å, d4 = 2.84 Å and d6 = 2.09 Å B d6 d3 d4 Top view 812 Figure 9.8 cont’d Side view-A Side view-B TS-483-Re ‡ ΔΔG = +4.4 d3 = 2.23 Å, d4 = 2.92 Å and d6 = 2.05 Å As stated earlier, based on initial CPK models, it was predicted that rocking the imine down into the cleft should provide a conformation that provides a greater facial selectivity of attack on the imine since it should provide greater shielding of the Re-face by the phenanthrene unit on the right side of the molecule. The methyl group at the ortho position should be sufficient to push the imine down into the cleft, thus increasing the selectivity of the reaction. This was indeed observed in the calculated transition states (Figure 9.8). The ortho methyl group is given in the magenta color in the side-view-A of both transition states (TS-483-Si and TS-483Re). As shown in Figure 9.8, this methyl group makes close contacts with the floor of the cleft even when the imine is rotated down into the cleft and results in greatly restricted movement 813 about the Zr–O–C unit to the imine moiety. Another important interaction is π-π stacking between the phenanthrene unit of the ligand and the phenyl ring of the imine 458a (Figure 9.8). Last but not least, the TS for favored enantiomer is found to be +4.4 kcal/mol lower than the disfavored TS. In all, the calculated transition states also support the concept of the modified imines 458. Figure 9.9 Free Energy diagram of transition states for imines 457a and 458a at ONIOM(BHandHLYP/DGDZVP:HF/STO-3G) level for catalytic cycle II. Energy in parenthesis is enthalpy. BHandHLYP/DGDZVP::HF/STO-3g Ph Ph N 37.7 (20.9) 33.1 (17.5) TS-483-Re ΔG (ΔH) (kcal/mol) TS1-478-Re TS3-480-Si N OH imine 458a OH imine 457a 33.3 (15.8) 31.2 (14.6) TS-483-Si 0.0 0.0 Reactants Reactants 470a + 460 470a'' + 460 (R) - 461a or (S) - 461a 58 + 463a + 464 + 457a 470a 58 + 463a + 464 + 458a 470a'' Reaction Coordinate 814 (R) - 462a or (S) - 462a An energy diagram showing the energy barriers in the reactions of the imines 457a and 458a for the final optimized transition states for the carbon-carbon bond forming step is presented in Figure 9.9. Finally, a new mechanism has been established with the aid of NMR spectroscopy, computational studies and substrate and catalyst modifications. The observed mechanism is unprecedented and hopefully will lead to new applications to the field of asymmetric catalysis. 9.7 Examination of the catalytic cycle III for (S)-VAPOL 58 At this point, we were curious as to whether the proposed catalytic cycle III holds true for the imino-aldol reaction using (S)-VAPOL 58 (Scheme 9.1C). Hence, we located two transition states for the carbon-carbon bond forming step in catalytic cycle III (474→475) using ONIOM(BHandHLYP/DGDZVP:HF/STO-3G) level of theory. The new optimized transition states (TS-484-Si and TS-484-Re) are presented in Figure 9.10. Interestingly, the calculated results are not consistent with the experimental results. Hence, it is likely that the proposed catalytic cycle III is not favored in the case of (S)-VAPOL 58. An important feature to be noted is the elongated bond distance between Zr and N of the imine (d8 = 2.43–2.39 Å). This probably is due to steric compulsions and leads to a weak coordination. Figure 9.10 Calculated 3D structures and relative free energies of TS-484-Si and TS-484-Re at ONIOM(BHandHLYP/DGDZVP:HF/STO-3G) level. The structures are visualized by the Mercury program (C, gray; O, red; N, blue; Zr, yellow; Si, light blue; H, white). Hydrogen 2 atoms are omitted (except O-H and sp -C-H of imine) and the ligand is given in green color for clarity. Free energies and bond lengths are in kcal/mol and Å respectively. Some bond distances 815 Figure 9.10 cont’d are highlighted: d7 (Zr–O), d8 (Zr–N) and d9 (C–C). d9 d7 d7 d9 d8 d8 TS-484-Si TS-484-Re ‡ ‡ ΔΔG = +10.0 d7 = 2.28 Å, d8 = 2.43 Å and d9 = 2.02 Å 9.8 ΔΔG = +0.0 d7 = 2.31 Å, d8 = 2.39 Å and d9 = 2.04 Å Case of BINOL derivative 459 In the preceding sections, we found evidence for a new mechanism for the imino-aldol reaction catalyzed by a zirconium compound incorporating the using the (S)-VAPOL ligand 58 (Catalytic cycle II, Scheme 9.1B). This reaction was originally reported by Kobayashi and 6 coworkers where they used (R)-6,6ʹ′-Br2-BINOL 459 as the ligand. As stated earlier (Catalytic cycle III', Scheme 9.1D), Kobayashi and coworkers proposed another plausible mechanism, which excludes the presence of NMI in the transition states (Catalytic cycle III', Scheme 9.1D and 9.2B). The catalyst was generated from a mixture of Zr(OtBu)4 463b, NMI 464 and (R)6,6ʹ′-Br2-BINOL 459. In this mechanism, it has been assumed that step one involves an isomerization of complex 465' in which there are two NMI groups trans to each other (Catalytic 816 cycle III', Scheme 9.2B). Complex 465' isomerizes to 473' in which the two NMI groups are cis to each other. The second step involves the exchange of the NMI groups by the imine 457 leading to the formation of the imine-catalyst complex 474'. The coordination of the hydroxyl group to the zirconium atom indicates the importance of the hydroxyl group. Subsequent attack of ketene acetal 460 would give 475' then 476', which is followed by the final release of the product 461 in the form of its silylated derivative 469. The obvious question then arises as to whether the mechanism of the reaction can change depending on the ligand used (Catalytic cycle II' vs III', Scheme 9.2). Hence, we decided to gather more information about the transition states for the reaction involving catalysts derived from for BINOL derivative 459 by examining both catalytic cycles II' and III'. Scheme 9.2 Proposed catalytic cycles of imino-aldol reaction using (R)-6,6ʹ′-Br2-BINOL 459 as the ligand. (A) Catalytic cycle II' (B) Catalytic Cycle III' A OTMS OH Zr(OtBu)4 463b + N OH R O O 457 N N OH (R)-459 464 NMI O TMS + O 470' Zr OMe O Cycle II' O O OMe 8 R NMI O O – Zr O NMI tBuOH + N H O O NMI OH 465' NH O R TMS OMe + H3O OTMS 9 O NH O R +N O H O – Zr O O OMe NMI 472' 469 817 OMe R O O O R – Zr N H O NMI 471' Scheme 9.2 cont’d B OTMS OH Zr(OtBu)4 463b + N OH N O R Zr 457 N OH (S)-459 464 O NMI – tBuOH O O O O O Zr isomerise Zr R NMI O O O O N O 474' NMI O O + TMS O MeO O N– R 475' 465' OH O OTMS + H3O NH O R HO Zr Cycle III' NMI 473' NMI OMe 460 O HO OMe Zr O O TMS O MeO NH O R 461 O HO OMe 469 N R 476' In this case, the division of layers for ONIOM calculations is shown in Figure 9.11. Figure 9.11 Division of layers for the ONIOM calculations ONIOM(B3LYP/LanL2DZ:HF/ STO-3G) and ONIOM(B3LYP/DGDZVP:B3LYP/LanL2MB) level. O N O3 d3 H Ph d4 4 O Zr O O NMI 470a' 818 Figure 9.11 cont’d O O O HO d7 Zr d8 N O R 474a' Red = B3LYP/LanL2DZ or B3LYP/DGDZVP OTMS Green = HF/STO-3G or OMe B3LYP/LanL2MB 460 Four different orientations of the ketene acetals were taken into consideration. Subsequently, four transition states (TS1-485 to TS4-488) were located for one particular enantiomer depending upon the different orientations and conformations of silyl ketene acetal 460 (Figure 9.12). The method ONIOM(B3LYP/LanL2DZ:HF/STO-3G). used for above calculations is The lowest energy transition states for S and R enantiomers were then carefully examined (TS1-485-Re and TS3-487-Si, Figure 9.12). Interestingly, the observed theoretical results were not consistent with the experimental observations. The lowest energy transition state (TS3-487-Si) leading to the favored enantiomer was found to be higher in energy by +0.5 kcal/mol than the lowest energy transition state (TS1485-Re) leading to the disfavored enantiomer (Figure 9.12). 819 Figure 9.12 (A) Different conformations and orientations of silyl ketene acetal 460 used for calculations. (B) Calculated 3D structures and relative free energies of TS1-485 to TS4-488 at ONIOM(B3LYP/LanL2DZ:HF/STO-3G) level. The structures are visualized by the Mercury program (C, gray; O, red; N, blue; Zr, yellow; Si, light blue; Br, magenta; H, white). Hydrogen atoms are omitted (except N-H) and the ligand is given in green color for clarity. Free energies 3 and bond lengths are in kcal/mol and Å respectively. Some interactions are highlighted: d3 (O – 4 H), d4 (O –H) and d6 (C–C). A N P N R O Me O P N R Me TMS (For TS1-485) O P N R TMS O TMS O R O Me O O TMS (For TS3-487) (For TS2-486) P Me (For TS4-488) B d6 d6 d3 d3 d4 d4 TS1-485-Si TS1-485-Re ‡ ‡ ΔΔG = +0.9 ΔΔG = +0.0 d3 = 2.42 Å, d4 = 2.17 Å and d6 = 2.09 Å d3 = 2.21 Å, d4 = 2.46 Å and d6 = 2.18 Å 820 Figure 9.12 cont’d d6 d6 d3 d3 d4 d4 TS2-486-Si TS2-486-Re ‡ ‡ ΔΔG = +2.1 ΔΔG = +2.9 d3 = 2.40 Å, d4 = 2.21 Å and d6 = 2.06 Å d3 = 2.26 Å, d4 = 2.35 Å and d6 = 2.11 Å d6 d6 d3 d4 d3 d4 TS3-487-Si TS3-487-Re ‡ ‡ ΔΔG = +0.5 ΔΔG = +0.4 d3 = 2.40 Å, d4 = 2.23 Å and d6 = 2.09 Å d3 = 2.24 Å, d4 = 2.35 Å and d6 = 2.12 Å 821 Figure 9.12 cont’d d6 d6 d3 d4 d3 d4 TS4-488-Re TS4-488-Si ‡ ‡ ΔΔG = +3.9 ΔΔG = +1.6 d3 = 2.42 Å, d4 = 2.16 Å and d6 = 2.10 Å d3 = 2.22 Å, d4 = 2.42 Å and d6 = 2.12 Å We then decided to include the DFT in the lower level of the ONIOM calculations. Subsequently, the transition states TS1-485 and TS3-487 were subjected to the higher level calculations, i.e. ONIOM(B3LYP/DGDZVP:B3LYP/LanL2MB) (Figure 9.13). However, there was no change in the outcome. Therefore, it is likely that there is a difference in the mechanism of the imino-aldol reaction depending on the type of the ligand employed. Consequently, the catalytic cycle IIʹ′ (Scheme 9.2A) in the case of (R)-6,6ʹ′-Br2-BINOL 459 was not supported by the above described computational analysis since it predicts the wrong enantiomer of the product. Figure 9.13 Calculated relative free energies of TS1-485-Si, TS1-485-Re, TS3-487-Si and TS3487-Re, at ONIOM(B3LYP/DGDZVP: B3LYP/LanL2MB) level. Free energies and bond 822 Figure 9.13 cont’d 3 lengths are in kcal/mol and Å respectively. Some interactions are highlighted: d3 (O –H), d4 4 (O –H) and d6 (C–C). TS1-485-Si TS1-485-Re ‡ ‡ ΔΔG = +1.3 ΔΔG = +0.0 d3 = 2.42 Å, d4 = 2.17 Å and d6 = 2.09 Å d3 = 2.21 Å, d4 = 2.46 Å and d6 = 2.18 Å TS3-487-Si TS3-487-Re ‡ ‡ ΔΔG = +1.3 ΔΔG = +0.2 d3 = 2.40 Å, d4 = 2.21 Å and d6 = 2.06 Å d3 = 2.26 Å, d4 = 2.35 Å and d6 = 2.11 Å Next, we decided to computationally examine the original proposed mechanism by Kobatashi i.e. catalytic cycle IIIʹ′ (Scheme 9.2B). The division of layers for ONIOM calculations is already shown in Figure 9.11. Similar to the approach for catalytic cycle IIʹ′, four different orientations of ketene acetal 460 were examined (Figure 9.14). Three transition states were located and the transition state with the fourth orientation failed to converge irrespective of the method utilized (Figure 9.14). Interestingly, the lowest energy transition state (TS1-489-Si) leading to the favored enantiomer was found to be 0.9 kcal/mol higher in energy than the lowest energy transition state (TS1-489-Re) leading to the disfavored enantiomer using ONIOM(B3LYP/LanL2DZ:HF/STO-3G) level of calculations (Figure 9.14). This suggested that either the catalytic cycle IIIʹ′ does not hold true for the reaction, or the level of calculations is not appropriate. Hence we decided to perform the calculations using DFT in the lower layer and the results are presented in Figure 9.15. 823 Figure 9.14 (A) Different conformations and orientations of silyl ketene acetal 460 used for calculations. (B) Calculated 3D structures and relative free energies of TS1-489 to TS4-492 at ONIOM(B3LYP/LanL2DZ:HF/STO-3G) level. The structures are visualized by the Mercury program (C, gray; O, red; N, blue; Zr, yellow; Si, light blue; Br, magenta; H, white). Hydrogen 2 atoms are omitted (except O-H and sp -C-H of imine) and the ligand is given in green color for clarity. Free energies and bond lengths are in kcal/mol and Å respectively. Some bond distances are highlighted: d7 (Zr–O), d8 (Zr–N) and d9 (C–C). A N P N R O Me O P N R Me TMS O N R TMS O TMS (For TS2-490) (For TS1-489) P O P R O Me O O TMS Me (For TS4-492) (For TS3-491) B d9 d7 d7 d9 d8 d8 TS1-489-Si TS1-489-Re ‡ ‡ ΔΔG = +0.9 ΔΔG = +0.0 d7 = 2.25 Å, d8 = 2.32 Å and d9 = 2.11 Å d7 = 2.23 Å, d8 = 2.31 Å and d9 = 2.13 Å 824 Figure 9.14 cont’d d9 d9 d7 d7 d8 d8 TS2-490-Si TS2-490-Re ‡ ‡ ΔΔG = +3.7 ΔΔG = +5.3 d7 = 2.24 Å, d8 = 2.33 Å and d9 = 2.12 Å d7 = 2.24 Å, d8 = 2.29 Å and d9 = 2.06 Å d9 d7 d9 d7 d8 d8 TS3-491-Re TS3-491-Si ‡ ‡ ΔΔG = +1.7 ΔΔG = +2.0 d7 = 2.24 Å, d8 = 2.32 Å and d9 = 2.12 Å d7 = 2.23 Å, d8 = 2.31 Å and d9 = 2.11 Å TS4-492-Si TS4-492-Re (no convergence achieved) (no convergence achieved) 825 As stated in last paragraph, TS1-489 and TS3-491 were subjected to ONIOM(B3LYP/DGDZVP:B3LYP/LanL2MB) level of calculations (Figure 9.15). The lowest energy transition state leading to the favored enantiomer (R) was found to be TS1-489-Si. Similarly, TS3-491-Re was found to be the lowest transition state leading to the disfavored enantiomer (S). The observed results with the higher level calculations were found to be consistent with the experimental results. The energy difference between favored transition state TS1-489-Si and disfavored transition state TS3-491-Re was determined to be +1.8 Kcal/mol (Figure 9.15). Also, it must be noted that the Re face of the imine 457a is completely shielded by the naphthalene unit of the (R)-6,6ʹ′-Br2-BINOL 459. Additionally, there is a possible π-π stacking interaction between the phenyl ring of imine and one of the naphthalene rings of the ligand 459. The reason that the (S)-enantiomer is unfavorable is probably due to the steric hindrance between the methyl groups of ketene acetal 460 and the naphthalene ring of the ligand 459 (Figure 9.15). Figure 9.15 (A) Calculated relative free energies of TS1-489-Si, TS1-489-Re, TS3-491-Si and TS3-491-Re, at ONIOM(B3LYP/DGDZVP:B3LYP/LanL2MB) level. Free energies and bond lengths are in kcal/mol and Å respectively. Some bond distances are highlighted: d7 (Zr–O), d8 (Zr–N) and d9 (C–C). (B) Calculated 3D structures and relative free energies of TS1-489-Si and TS3-491-Re at ONIOM(B3LYP/DGDZVP:B3LYP/LanL2MB) level. The structures are visualized by the Mercury program (C, gray; O, red; N, blue; Zr, yellow; Si, light blue; Br, 2 magenta; H, white). Hydrogen atoms are omitted (except O-H and sp -C-H of imine) and the 826 Figure 9.15 cont’d ligand is given in green color for clarity. Free energies and bond lengths are in kcal/mol and Å respectively. Some bond distances are highlighted: d7 (Zr–O), d8 (Zr–N) and d9 (C–C). A TS1-489-Si TS1-489-Re ‡ ‡ ΔΔG = +0.0 ΔΔG = +1.9 d7 = 2.33 Å, d8 = 2.35 Å and d9 = 1.99 Å d7 = 2.30 Å, d8 = 2.34 Å and d9 = 2.04 Å TS3-491-Si TS3-491-Re ‡ ‡ ΔΔG = +0.9 ΔΔG = +1.8 d7 = 2.34 Å, d8 = 2.32 Å and d9 = 2.03 Å d7 = 2.27 Å, d8 = 2.33 Å and d9 = 2.01 Å B d7 d9 d8 TS1-489-Si ‡ ΔΔG = +0.0 d7 = 2.33 Å, d8 = 2.35 Å and d9 = 1.99 Å 827 Figure 9.15 cont’d d9 d7 d8 TS3-491-Re ‡ ΔΔG = +1.8 d7 = 2.27 Å, d8 = 2.33 Å and d9 = 2.01 Å 9.9 Conclusions In this chapter, the active site of the catalytic asymmetric imino-aldol reaction has been probed via NMR spectroscopy, computational studies and substrate and catalyst modifications. In the literature, two mechanisms have been proposed. One of them involves the presence of imidazole in the transition state whereas the other one assumes no role of imidazole in the transition state. Both reactions were assumed to be Lewis acid catalyzed reactions. We found that the reaction is actually a Lewis acid assisted Brønsted acid catalyzed reaction (Scheme 9.1, Catalytic cycle II) when (S)-VAPOL ligand is used and a Lewis acid catalyzed reaction (Scheme 9.2, Catalytic cycle III') when (R)-6,6'-Br2-BINOL ligand is utilized. The transition states were located using ONIOM level calculations. 828 APPENDIX 829 9.10 Experimental 9.10.1. General Information .........................................................................................................831 9.10.2. Synthesis of imine 457a ...................................................................................................831 9.10.3. General procedure for imino-aldol reaction between 457a and 460 (Table 9.1-9.2) ......832 9.10.4. DFT Calculations .............................................................................................................834 830 9.10.1 General Information Same as Chapter 2 9.10.2 Preparation of imine 457a O ZnCl2 + H2N 127a benzene reflux, 5 h OH N OH 457a 126x (E)-2-(benzylideneamino)phenol 457a: To a 250 mL flame-dried round bottom flask filled with argon was added 2-aminophenol 126x (2.18 g, 20.0 mmol), benzaldehyde 127a (2.02 mL, 20 mmol), ZnCl2 (100 mg, 0.73 mmol) and dry benzene (100 mL). The reaction mixture was refluxed with a Dean-Stark trap for 5 h, and then cooled to room temperature. The reaction mixture was filtered through Celite and the Celite bed was washed with benzene (10 mL × 3) and then the filtrate was concentrated by rotary evaporation to give the crude imine as a yellow solid. Crystallization (ethanol) and collection of the first crop afforded 457a as yellow crystals (mp. 91-92 °C) in 85% isolated yield (3.35 g, 17.0 mmol). 1 Spectral data for 457a: H NMR (CDCl3, 300 MHz) δ 6.92 (ddd, J = 7.9, 7.4, 1.4 Hz, 1H), 7.02 (dd, J = 8.1, 1.4 Hz, 1H), 7.21-7.18 (m, 1H), 7.25 (s, 1H), 7.32 (dd, J = 7.9, 1.5 Hz, 1H), 7.537.47 (m, 3H), 7.95-7.91 (m, 2H), 8.71 (s, 1H); 13 C (CDCl3, 75 MHz) δ 114.90, 115.62, 118.54, 128.69, 128.81, 129.41, 131.39, 135.41, 135.73, 151.10, 151.22. These spectral data match those previously reported for this compound. 10 831 9.10.3 General procedure for the imino-aldol reaction (Table 9.1-9.2) Zr(OiPr)4: NMI:(S)-VAPOL OH (1.0:1.2:2.2) OTMS Ph + N OH 457a OMe Catalyst (20 mol %) toluene, T °C, 24 h NH O Ph OMe 461a 460 (a) At room temperature (25 ºC): (R)-methyl 3-((2-hydroxyphenyl)amino)-2,2-dimethyl-3-phenylpropanoate 461a: To a 10 mL flame-dried round bottom flask were added (S)-VAPOL (59.25 mg, 0.1100 mmol) and i i Zr(O Pr)4• PrOH (19.38 mg, 0.0500 mmol) in toluene (0.9 mL). To this solution was added 1methylimidazole (4.78 µL, 0.060 mmol) in toluene (0.1 mL) at room temperature. The mixture was stirred for 1 h at the same temperature. A solution of imine 457a (49.31 mg, 0.2500 mmol) in toluene (1 mL) was added to the flask containing the catalyst and the mixture was stirred for an additional 5 min. This was then followed by the addition of the silyl ketene acetal 460 (62 µL, 0.3 mmol). The resulting reaction mixture was stirred for 24 h at room temperature. Aqueous NaHCO3 (2 mL) was added to quench the reaction. The mixture was extracted with CH2Cl2 (10 mL × 2). The combined organic layer was concentrated in vacuo to give the crude product. The crude product was then treated with a mixture of THF and aqueous 1N HCl (11 mL, 10:1, v/v) at 0 ºC for 30 min. The hydrolysis was quenched with aqueous NaHCO3 (2 mL) and then extracted with ethyl acetate (10 mL × 2). The combined organic layer was washed with brine and dried with anhydrous MgSO4 and concentrated in vacuo to give the crude product 832 461a. Purification of the crude product by silica gel column chromatography (20 × 280 mm, 5:1 hexanes/EtOAc as eluent) afforded pure ester 461a in 95% yield (71 mg, 0.24 mmol). The optical purity of 461a was determined to be 89% ee by HPLC analysis (Daicel Chiralpak AD, 90:10 Hexanes/i-PrOH at 222 nm, flow rate: 1.0 mL/min): retention times; Rt = 8.47 min (major enantiomer, 461a), Rt = 14.73 min (minor enantiomer, ent-461a). 1 Spectral data for 461a: Rf = 0.36 (1:5 EtOAc/hexane); H NMR (CDCl3, 300 MHz) δ 1.22 (s, 3H), 1.24 (s, 3H), 3.69 (s, 3H), 4.55 (brs, 1H), 4.87 (brs, 1H), 5.31 (s, 1H), 6.39 (dd, J = 7.7, 1.3 Hz, 1H), 6.54 (td, J = 7.5, 1.4 Hz, 1H), 6.62 (td, J = 7.5, 1.3 Hz, 1H), 6.69 (dd, J = 7.5, 1.2 Hz, 1H), 7.32-7.19 (m, 5H); 13 C (CDCl3, 75 MHz) δ 19.93, 24.22, 47.27, 52.31, 64.27, 113.18, 114.10, 117.56, 120.79, 127.34, 127.93, 128.32, 135.60, 138.90, 144.03, 177.70. These spectral data match those previously reported for this compound. 5b (b) At –45 ºC (R)-methyl 3-((2-hydroxyphenyl)amino)-2,2-dimethyl-3-phenylpropanoate 461a: To a 10 mL flame-dried round bottom flask were added (S)-VAPOL (59.25 mg, 0.1100 mmol) and i i Zr(O Pr)4• PrOH (19.38 mg, 0.0500 mmol) in toluene (0.9 mL). To this solution was added 1methylimidazole (4.78 µL, 0.060 mmol) in toluene (0.1 mL) at room temperature. The mixture was stirred for 1 h at the same temperature. A solution of imine 457a (49.31 mg, 0.2500 mmol) in toluene (1 mL) was added to the flask containing the catalyst and the mixture was stirred for an additional 5 min. Then the mixture was cooled to –45°C followed by the addition of the silyl ketene acetal (62 µL, 0.3 mmol). The resulting reaction mixture was stirred for 24 h at – 45 ºC. 833 Aqueous NaHCO3 (2 mL) was added to quench the reaction. The mixture was extracted with CH2Cl2 (10 mL × 2). The combined organic layer was concentrated in vacuo to give the crude product. The crude product was then treated with a mixture of THF and aqueous 1N HCl (11 mL, 10:1, v/v) at 0 ºC for 30 min. The hydrolysis was quenched with aqueous NaHCO3 (2 mL) and then extracted with ethyl acetate (10 mL × 2). The combined organic layer was washed with brine and dried with anhydrous MgSO4 and concentrated in vacuo to give the crude product 461a. Purification of the crude product by silica gel column chromatography (20 × 280 mm, 5:1 hexanes/EtOAc as eluent) afforded pure ester 461a in 92% yield (69 mg, 0.23 mmol). The optical purity of 461a was determined to be 91% ee by HPLC analysis (Daicel Chiralpak AD, 90:10 Hexanes/i-PrOH at 222 nm, flow rate: 1.0 mL/min): retention times; Rt = 8.47 min (major enantiomer, 461a), Rt = 14.73 min (minor enantiomer, ent-461a). The ligands 59, 197 and 482 were also screened using the procedure described above and the results are presented in Table 9.2. 9.10.4 DFT Calculations 8 All quantum mechanical calculations were performed using the Gaussian '03. The B3LYP 11 and BHandHLYP 9,12 density functional were used along with 6-31G* basis sets. The coordinates of all transition states were provided to Prof. Wulff as a separate file. 834 REFERENCES 835 REFERENCES (1) Mannich, C.; Krösche, W. Archiv Der Pharmazie 1912, 250, 647-667. (2) (a) Kobayashi, S.; Mori, Y.; Fossey, J. S.; Salter, M. M. Chem. Rev. 2011, 111, 2626-2704. (b) Ting, A.; Schaus, S. E. Eur. J. Org. Chem. 2007, 5797-5815. (c) Friestad, G. K.; Mathies, A. K. Tetrahedron 2007, 63, 2541-2569. (d) Kobayashi, S.; Ueno, M. In Comprehensive Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Supplement 1; Springer: Berlin, 2003; Chapter 29.5, p 143. (e) Kobayashi, S.; Ishitani, H. Chem. Rev. 1999, 99, 10691094. (f) Arend, M.; Westermann, B.; Risch, N. Angew. Chem., Int. Ed. 1998, 37, 1044-1070. (3) (a) KLeinman, E. F. In Comprehensive Organic Synthesis; Trost, B. M., Ed.; Pergamon Press: Oxford, 1991; Chapter 2.3, Vol. 2, p 893. (b) Arend, M. Angew. Chem., Int. Ed. 1999, 38, 2873-2874. (c) Enantioselective Synthesis of β-amino acids; 2nd ed.; Juaristi, E.; Soloshonok, V. A., Eds.; John Wiley & Sons: Hoboken, New Jersey, 2005. (4) (a) Ishihara, K.; Miyata, M.; Hattori, K.; Tada, T.; Yamamoto, H. J. Am. Chem. Soc. 1994, 116, 10520-10524. (b) Müller, R.; Goesmann, H.; Waldmann, H. Angew. Chem., Int. Ed. 1999, 38, 184-187. (5) (a) Benaglia, M.; Biaggi, C.; Annunziata, R.; Rossi, S. Chirality 2010, 22, 369-378. (b) Akiyama, T.; Katoh, T.; Mori, K.; Kanno, K. Synlett 2009, 1664-1666. (c) Marcel Sickert, C. S. Angew. Chem., Int. Ed. 2008, 47, 3631-3634. (d) Giera, D. S.; Sickert, M.; Schneider, C. Org. Lett. 2008, 10, 4259-4262. (e) Yamanaka, M.; Itoh, J.; Fuchibe, K.; Akiyama, T. J. Am. Chem. Soc. 2007, 129, 6756-6764. (6) Ishitani, H.; Ueno, M.; Kobayashi, S. J. Am. Chem. Soc. 1997, 119, 7153-7154. (7) Xue, S.; Yu, S.; Deng, Y.; Wulff, W. D. Angew. Chem., Int. Ed. 2001, 40, 2271-2274. (8) Gaussian 03, Revision D.01 M. J. Frisch, G. W. T., H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman, J. A. Montgomery, Jr., T. Vreven, K. N. Kudin, J. C. Burant, J. M. Millam, S. S. Iyengar, J. Tomasi, V. Barone, B. Mennucci, M. Cossi, G. Scalmani, N. Rega, G. A. Petersson, H. Nakatsuji, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, M. Klene, X. Li, J. E. Knox, H. P. Hratchian, J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R. E. Stratmann, O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli, J. W. Ochterski, P. Y. Ayala, K. Morokuma, G. A. Voth, P. Salvador, J. J. Dannenberg, V. G. Zakrzewski, S. Dapprich, A. D. Daniels, M. C. Strain, O. Farkas, D. K. Malick, A. D. Rabuck, K. Raghavachari, J. B. Foresman, J. V. Ortiz, Q. Cui, A. G. 836 Baboul, S. Clifford, J. Cioslowski, B. B. Stefanov, G. Liu, A. Liashenko, P. Piskorz, I. Komaromi, R. L. Martin, D. J. Fox, T. Keith, M. A. Al-Laham, C. Y. Peng, A. Nanayakkara, M. Challacombe, P. M. W. Gill, B. Johnson, W. Chen, M. W. Wong, C. Gonzalez, and J. A. Pople, Gaussian, Inc., Wallingford CT, 2004 (9) (a) Zhao, Y.; Truhlar, D. G. J. Chem. Theory Comput. 2005, 1, 415-432. (b) Yu, W.; Liang, L.; Lin, Z.; Ling, S.; Haranczyk, M.; Gutowski, M. J. Comput. Chem. 2009, 30, 589-600. (10) López, C.; Caubet, A.; Péreza, S.; Solans, X.; Font-Bardı́a, M. J. Organomet. Chem. 2003, 681, 82-90. (11) (a) Becke, A. D. Phys. Rev. A 1988, 38, 3098. (b) Lee, C. Y., W.; Parr, R. G. Phys. Rev. B 1988, 37, 785. (12) Becke, A. D. J. Chem. Phys. 1993, 98, 1372-1377. 837