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This is to certify that the dissertation entitled A UNIVERSAL ASYMMETRIC CATALYTIC AZIRIDINATION SYSTEM, AND OTHER FORAYS IN CHIRAL CATALYSIS presented by AMAN ASHVIN DESAI has been accepted towards fulfillment of the requirements for the Doctoral degree in Chemistry ajor Pro ssor’s Signature é[36//o Date MSU is an Affirmative Action/Equal Opportunity Employer LIBRARY Michigan State University 00-:---0-.-I-I-o-l-l-u-o-o-I_--o-o-o-I-I-I-o-I-I-l-I-o-I-o-u-I-I-O-O-I-u-I-I-v-I-O-c--v-I-I-----I-I-0---I-o-t-I-c------o. PLACE IN RETURN BOX to remove this checkout from your record. To AVOID FINES return on or before date due. MAY BE RECALLED with earlier due date if requested. DATE DUE DATE DUE DATE DUE 5/08 KzlProleccaPreleIRC/DateDue.indd A UNIVERSAL ASYMMETRIC CATALYTIC AZIRIDINATION SYSTEM, AND OTHER FORAYS IN CHIRAL CATALYSIS By Aman Ashvin Desai A DISSERTATION Submitted to Michigan State University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Chemistry 2010 ABSTRACT A UNIVERSAL ASYMMETRIC CATALYTIC AZIRIDINATION SYSTEM, AND OTHER FORAYS IN CHIRAL CATALYSIS By Aman Ashvin Desai A universal asymmetric catalytic aziridination system is described. Contributions were made to the development of a robust, efficient and scalable cis-selective aziridination of imines and diazoacetates. By simply switching to diazoacetamides, the diastereoselectivity could be cleanly reversed, and the corresponding trans-aziridines could be accessed efficiently. Thus, employing the same imine and the same chiral catalyst, we can now independently access both cis- and trans- aziridines with excellent yields, diastereoselectivities and asymmetric inductions. The substrate scope is broad for both the cis- and trans- selective aziridination protocols, and includes imines prepared from both electron rich and electron deficient aromatic aldehydes, and also from 1°, 2° and 3° aliphatic aldehydes. The face selectivity of the addition to the imine was found to be independent of the diazo compounds. The (S)-VANOL or (S)-VAPOL catalyst will cause both diazoesters and diazoacetamides to add to the Si-face of the imine when cis-aziridines are formed, and both to add to the Fla-face of the imine when trans-aziridines are formed. The stereochemistry determining step of the universal aziridination reactions was studied using ONIOM(B3LYP/6-31G*:AM1) calculations in collaboration with Dr. Mathew Vetticatt. The origin of cis-selectivity in reactions of ethyldiazoacetate, and trans-selectivity in reactions of N—phenyldiazoacetamide, was understood on the basis of the difference in specific non-covalent interactions at the stereochemistry determining transition state. An H-bonding interaction between the amidic hydrogen and an oxygen atom of the chiral counterion was identified as the key interaction responsible for this reversal in diastereoselectivity. KIE experiments subsequently provided evidence for a rate limiting ring closure for the step-wise mechanism in the universal aziridination reaction. Other forays in chiral catalysis were also made. New structurally distinct chiral Bronsted acids and ligands were prepared based on the framework of VAPOL and VANOL. Development of other catalytic asymmetric reactions was initiated, including the Darzens reaction, the transfer hydrogenation of quinolines, and the rhodium catalyzed aziridination of olefins, with varying degrees of success. To, Mom and Dad (words would never be enough) ACKNOWLEDGEMENTS It is difficult to put the last five years in perspective, life has changed so much. A PhD in the organic area at the Department of Chemistry, Michigan State University has certainly been a life changing experience, and there are numerous people to thank. Before getting to individuals, I must thank all the faculty, especially the organic ones, for making the department a wonderful, no- nonsense, and absolutely science driven institution. The friendly and completely informal atmosphere between the professors and students makes it an absolute pleasure and a lot of fun to work in this department. I must say I will be very sorry to go away from this place which has taught me and given me so much. The same feelings exist for my research group, that of Professor William Wulff. Not only have I learned a tremendous amount of science from being under his tutelage, but I have grown a lot in his group too. His completely hands-off approach towards running his research group has helped me develop as a researcher, and as a person. Right from the first year, he gave me a free hand to pursue my wild dreams in asymmetric catalysis. Looking back, some of these ideas of mine were pretty ludicrous, but he always encouraged me to pursue them. At the same time, his door was always open and he has always been available and ready to offer sound advice. Dr. Wulff has also infused in me an appreciation of the fine things in life; be it fine wine, good fresh coffee, or fine cheese. I have really enjoyed interacting with him, scientifically as well as socially; he has been a great boss. In what has been the most important stage of my education, I am sure I could not have learned more and grown more in any other place than the research group of Professor William Wulff, and I will always be extremely grateful. Babak. Professor Babak Borhan. l vividly remember him patiently talking to me for hours in his office in my first year in the program, and telling me that l was an idiot for not pursing a PhD. His advice and those conversations were instrumental in me deciding to stay for the PhD, and it has been the best decision that l have made for my career so far. Babak has always been ready to offer help, be it for chemistry or for anything else. His organic spectroscopy and bioorganic chemistry courses were two of the best courses I have ever taken; Babak is a great teacher and l have learned a lot from him. After a few glasses of wine or margaritas, that Babak was Professor Babak Borhan would usually be the farthest thought in my mind — it has truly been a pleasure interacting with, working with and learning from Babak. I thank him for everything. I also thank Professor Robert Maleczka was all the assorted help he has provided through the years. I have bugged him quite a bit with questions about the pharmaceutical / fine chemical industry, and other research related problems, and he has always been spontaneous and very generous with his advice, recommendations and suggestions. I also thank Dr. Borhan and Dr. Maleczka for organizing the Wednesday night mechanism clubs that I attended religiously until my fourth year. One of the fondest memories I will take from this department will be sitting in a room, drinking beer, joking with them, and proposing ridiculous structures and vii mechanisms, but learning an amazing amount of synthetic organic chemistry at the same time. I am guessing that I will never be able to live down my “SNZ’s on sp2 centers” reaction mechanisms. I thank Professor Aaron Odom for taking the time to be on my committee, and I also apologize for failing in our collaborative project. I assure him it was not due to a lack of effort on my part. I would like to thank Dr. Dan Holmes for being an amazingly considerate boss, when l was the NMR TA under him for a few years. I thank Ms. Lijun Chen in the Mass Spectrometry Facility at the Department of Biochemistry for her kind help whenever I needed to get some HFlMS samples. I must thank our collaborator, Dr. Mathew J. Vetticatt. Mathew is one of my best friends from college and also my roommate from college. To be able to collaborate with one of your best friends in science — I don’t think it can get better than that. I would also like to thank our other collaborators. Dr. Xiaoyong Li and Professor Babak Borhan, and Dr. Supriyo Majumder and Professor Aaron Odom - it was a lot of fun working with all of them. The Wulff group has been just an amazing and rocking place to pursue a PhD in, and there are quite a few Wulff group members to thank — past and present. I would like to thank Dr. Keith Korthals for being my lab neighbor in my early years, and patiently answering the million stupid questions that I used to ask him all the time. Keith truly went out of his way to help me and train me in the ways of organic synthesis; without his help I would have been a complete idiot in the lab. Dr. Zhenjie Lu also helped me tremendously in the early years. She was vii always ready to drop whatever she was doing, and answer my questions. Zhenjie was the perfect senior in the lab, always ready to help with a smile. I would also like to thank Dr. Zhensheng Ding for his friendship, and his absolutely hilarious jokes and drawings. Many a depressing day were lightened by Ding’s humor and laughter. I thank Dr. Yu Zhang for his help and advice in my first year; it was Yu’s project that I took up initially. Dr. Konstantinos Rampalakos (Kostas) and Dr. Cory Newman were good friends, and good lab mates. l have had quite a few wild memories in the company of Dr. Alex Predeus, we had fun hanging out together. From the present Wulff group, a big thank-you goes out to my two favorite Chinese girls in the world - Li Huang and Hong Ren. They have been wonderful companions in the group in the last few years. We have had great parties together, and we have had countless heated discussions, arguments and talks. Hong and Li have helped me a lot in my research, and they have helped me a lot in my personal life too. There have been quite a few times when l was about to do something very stupid that I would definitely regret later, and they have held me back, quite forcefully at times. They have been extremely good friends, and I do hope they will remain that way. Quanxuan Zhang has been a good friend also. Yong Guan has been a good lab mate in Room 529 all these years, and has always said yes whenever I wanted anything. Munmun Mukherjee has been very kind with help and suggestions whenever I have needed them. I would like to thank WenJun Zhao for very readily giving me her precious aziridine to play with. I had the good viii fortune to work with two post-doctoral research associates who had come to our group for short periods of time. Dr. Maria Pascual and Dr. Floberto Moran- Ramallal were fun to work with, and have become good friends. I thank all the group members, past and present, for making the group a rocking place to be in. l have been lucky to have numerous good friends through these years. Allison Brown was one of my first friends in the chemistry department, and has remained a close friend. We have had great times, partying, hanging out and going through the rigors of grad school together. At the mention of hanging out with friends, l have to mention our Cancun gang — Aman Kulshrestha, Luis Mori Quiroz and Luis Sanchez — for all those Friday nights arguing about everything under the moon over margaritas, chips and salsa, and Pollo Locos. They have been wonderful friends, for multiple reasons, and grad school would have been very boring without them. Hovig has been a good friend in the last few years, and has thrown some amazing parties. Maryam and Borzoo have been good friends too, and along with Monica, Alli, Hovig and Luis Mori formed our Crunchy’s gang. Buckets of beer, perfect company, wonderful songs and rock and roll on the karaoke will remain a hard combination to beat for a long time. Monica Norberg. One of the most courageous and stubborn girls I have ever met. It has been just wonderful having her by my side in the last few years. My fondest memories from these years will. be those shared with Monica. l have learned a lot from her; she has made me a better person, both personally and professionally. For all the love and support she has given me in these years, and for all the great times we have had, I will always be grateful. l have been very fortunate to have a wonderful family. My brother and my sister-in-law have been solid supporters for whatever I have done, and I am sure they will continue being so for all my life. Finally, all of this would be meaningless if not for my Mom and Dad. Words would never be enough for me to thank them, and I will not even try to do it. All those hour long conversations on Sundays have gone a long way in getting me to where I am today. Without Mom’s constant supply of wonderful food, I would have probably starved before I got anywhere close to my PhD. They have always believed in me, and have been absolutely selfless in their love, encouragement and support, to the point where I have taken it for granted at times. I only hope that I can give back to them a fraction of what they have given to me in my life. This thesis and my PhD are dedicated to my Mom and Dad. TABLE OF CONTENTS LIST OF TABLES ................................................................................................ xiv LIST OF FIGURES .............................................................................................. xvi LIST OF SCHEMES ........................................................................................... xvii CHAPTER ONE CHIRAL AZIRIDINES IN ORGANIC CHEMISTRY 1.1 . Chiral aziridines as invaluable motifs in organic chemistry ......................... 1 1.2. Major approaches towards chiral aziridines ................................................ 2 1.3. The Wulff catalytic asymmetric aziridination system ................................... 3 1.3.1. Proposed catalytic cycle in the Wulff aziridinations .......................... 4 1.4. Other chiral Brensted acid catalyzed imine aziridination systems .............. 8 1.4.1. Maruoka’s trans-aziridination system ............................................... 8 1.4.2. Zhong’s trans-aziridination system ................................................. 10 1.4.3. Akiyama’s cis-aziridination system ................................................. 11 1.5. Conclusions ............................................................................................... 12 CHAPTER TWO CATALYTIC ASYMMETRIC CIS-AZIRIDINATION: STRENGHENING OLD FRONTIERS, AND BUILDING NEW ONES 2.1 . Revisiting the aziridinations with benzhydryl imines ................................. 14 2.1.1. The reasons behind the revisit ....................................................... 14 2.1.2. A solvent study ............................................................................... 16 2.1.3. The substrate scope in dichloromethane and toluene ................... 17 2.1.4. Enhancement of asymmetric inductions at 0 °C ............................ 20 2.1.5. Optically pure benzhydryl aziridines via crystallization .................. 21 2.1.6. Recovery of the VAPOL ligand post-aziridination .......................... 22 2.2.Aziridinations with o-bromophenyl benzhydryl imine: First glimpses of trans-aziridines .......................................................................................... 26 2.3. Aziridinations with 5-nonylimine, dicyclohexylmethylimine and 5H— dibenzo[a,djcyclohepten-S-imine .............................................................. 28 2.4. cis-2,3-Dicarbonylaziridines from the Wulff aziridination .......................... 30 2.5.A gram scale catalytic asymmetric aziridination process ......................... 34 2.6. Failed attempts for the direct access to tri-substituted aziridines ............. 37 CHAPTER THREE CATALYTIC ASYMMETRIC TRANS-ARIDINATION: DEVELOPMENT OF A UNIVERSAL AZIRIDINA TION PROTOCOL 3.1 . Introduction ............................................................................................... 39 3.2. Initial attempts towards a catalytic asymmetric trans-aziridination ........... 40 3.3. Large scale preparation of the MEDAM amine ......................................... 43 xii 3.4. Catalytic asymmetric trans-aziridination: Development of a universal aziridination protocol ................................................................................. 44 3.4.1. The initial optimization of the trans-aziridination protocol .............. 45 3.4.2. The issue of trans-aziridine invertomers ........................................ 49 3.4.3. The diazoacetamide substrate scope ............................................ 51 3.4.4. The aryl imine substrate scope ...................................................... 54 3.4.5. The alkyl imine substrate scope ..................................................... 57 3.4.6. Puzzling aziridination reactions of two substrates ......................... 61 3.4.7. Temperature vs. diastereoselectivity in the trans-aziridinations....62 3.4.8. All four stereoisomers of 3-aziridine-2-carboxylates ...................... 64 3.4.9. TfOH catalyzed aziridination reactions .......................................... 65 3.4.10. General absolute configurations in the universal aziridination ..... 66 3.4.1 1 . Attempts at deprotection of the trans-aziridines ........................... 69 3.4.12. Puzzling origins of the stereoselections in our universal aziridination ................................................................................... 71 CHAPTER FOUR CATALYTIC ASYMMETRIC TRANSFER HYDROGENATION OF 2- QUINOLINES: AN EXPERIMENTAL AND COMPUTATIONAL STUDY 4.1 . Introduction ............................................................................................... 72 4.2.The different attempts in the optimization study ....................................... 73 4.3. Confirmation of the VAPOL-B3 spiro-boroxinate active catalyst ............... 78 4.4. Self-assembly of a family of 8;, catalysts for the quinoline reductions ...... 81 4.5. Asymmetric transfer hydrogenation of 2-phenquuinoline ......................... 84 4.6. Transition state analysis via computational chemistry .............................. 84 4.7. Future directions for the project ................................................................ 86 CHAPTER FIVE NEW DERIVATIVES OF VAPOL AND VANOL: STRUCTURALLY DISTINCT VAUL TED CHIRAL LIGANDS AND BRQNSTED ACID CATALYSTS 5.1. Introduction ............................................................................................... 89 5.2. New Bronsted acid derivatives of VANOL ................................................ 92 5.3. New Bronsted acid derivatives of VAPOL ................................................ 93 5.4. A new family of vaulted ligands — 8,8’-diaryl VANOL derivatives ............. 94 5.5. Conclusions .............................................................................................. 99 CHAPTER SIX OTHER FORAYS IN CHIRAL CATALYSIS 6.1 .Asymmetric catalysis via chiral dirhodium catalysts ................................ 101 6.2. Organocatalytic asymmetric aziridination mediated by chiral Bronsted acid catalysts .................................................................................................. 105 6.3.Asymmetric catalytic Darzens reaction ................................................... 107 CHAPTER SEVEN COMPUTATIONAL CHEMISTRY AND UNIVERSAL AZIRIDINATION 7.1 . Background and significance .................................................................. 111 xii 7.2. Spectral data in support of the VANOL-B3 boroxinate complex .............. 113 7.3. Exploring the geometry of the catalyst-imine complex ............................ 116 7.4.Transition state models ........................................................................... 119 7.5. Mechanistic probes for the proposed transition state models ................. 123 7.6. Conclusions and future direction ............................................................. 126 CHAPTER EIGHT KINETIC ISOTOPE EFFECTS AND MECHANISM OF THE AZIRIDINATION REACTION 8.1 .Transition state theory and kinetic isotope effects .................................. 128 8.2. Design of experiment .............................................................................. 130 8.3. Experimental KlEs .................................................................................. 132 8.4. Predicted KlEs and interpretation ........................................................... 133 8.5. Discussion and future experiments ......................................................... 135 CHAPTER NINE RAMBLING FANTASIES OF AN ASYMMETRIC CATALYSIS AFICIONADO .................................................................................................... 138 APPENDICES EXPERIMENTAL INFORMATION .................................................................... 144 REFERENCES .................................................................................................. 292 xiii LIST OF TABLES Table 2.1 Repeating the aziridinations under the exact original conditions ......... 15 Table 2.2 A solvent study for the basic aziridination system with imine 1b ......... 16 Table 2.3 The substrate scope in dichloromethane ............................................. 18 Table 2.4 The substrate scope in toluene ............................................................ 19 Table 2.5 Enhancement of asymmetric inductions at 0 °C .................................. 21 Table 2.6 Optically pure benzhydryl aziridines via crystallization ........................ 21 Table 2.7 Recovery of 4 and 27 based on the equivalents of EDA 2 used .......... 23 Table 2.8 Cis- and trans-aziridines from aziridination of imine 1e ....................... 26 Table 2.9 Contributions to the study to map the active site of our catalyst .......... 30 Table 2.10 cis-2,3-Dicarbonylaziridines from the Wulff aziridination protocol ...... 31 Table 3.1 Optimization study for the trans-aziridination protocol ......................... 46 Table 3.2 Solvent study for the trans-aziridination protocol ................................. 48 Table 3.3 Ratio of invertomers for 603 in deuterated NMR solvents ................... 50 Table 3.4 The diazoacetamide substrate scope .................................................. 51 Table 3.5 The aryl imine substrate scope ............................................................ 55 Table 3.6 Trans-aziridination of the cyclohexyl (2° alkyl) imine substrate ........... 57 Table 3.7 Trans-aziridination of the t—butyl (3° alkyl) imine substrate .................. 59 Table 3.8 Trans-aziridination of other 1°, 2° and 3° alkyl BUDAM imines ........... 60 Table 3.9 Temperature vs. diastereoselectivity in the trans-aziridinations .......... 63 Table 3.10 Attempts at deprotection of the trans-aziridines ................................. 70 Table 4.1 The catalyst screen .............................................................................. 74 Table 4.2 Temperature/additives screen ............................................................. 75 xiv Table 4.3 The Hantzsch ester screen .................................................................. 76 Table 4.4 Solvent screen for VAPOL-33 catalyst 12 ............................................ 77 Table 4.5 Solvent screen for the VAPOL phosphoric acid catalyst 91 ................. 78 Table 4.6 Asymmetric transfer hydrogenation of 2-phenquuinoline 100 ............. 84 Table 6.1 Proof of principle for the asymmetric catalytic Darzens reaction ....... 108 XV LIST OF FIGURES Figure 1.1 (S)-VANOL-B3 catalyst - the active catalyst in Wulff aziridinations ...... 7 Figure 4.1 “B NMR and 1H NMR of complex 99 ................................................. 80 Figure 4.2 The enantioselectivity determining step, and the enantioselectivity determining transition state calculated via ONIOM(BSLYP/6-31G*:AM1) ........... 85 Figure 7.1 “B NMR spectrum of the VANOL-83 boroxinate complex ............... 114 Figure 7.2 1H NMR spectra of the VANOL-83 boroxinate complex .................... 115 Figure 7.3 NBO analysis of the (Fl)-VANOL-counterion performed at the BSLYP/6-31 G*//RHF/3-21 G level of theory ........................................................ 1 16 Figure 7.4 Division of ONIOM layers; Final geometries and relative energies of four possible catalyst-imine complexes ............................................................. 117 Figure 7.5 Transition structures T81, T82 and T81 (ent.) accounting for the diastereoselectivity and enantioselectivity in reactions of 9a and 2 ................... 121 Figure 7.6 Transition structures T83, T84 and T84 (ent.) accounting for the diastereoselectivity and enantioselectivity in reactions of 9a and 14a ............... 122 Figure 7.7 Transition structures T85 and T86 accounting for the diastereoselectivity in reaction of 9a and 67 ...................................................... 124 Figure 7.8 Transition structures T87 and T88 accounting for the diastereoselectivity in reaction of 1b and 14a .................................................... 125 Figure 8.1 Experimental ‘30 KIEs (k12C/k13C, 25 °C) for the reactions of 9a with 2 ......................................................................................................................... 132 Figure 8.2 Relevant transition structures for the theoretical interpretation of experimental KlEs .............................................................................................. 134 Figure 8.3 Comparison of experimental and predicted KIEs for the two key transition structures ............................................................................................ 134 xvi LIST OF SCHEMES Scheme 1.1 Chiral aziridines in natural products ................................................... 1 Scheme 1.2 Aziridine-2-carboxylates as versatile synthetic intermediates ........... 1 Scheme 1.3 Major approaches towards catalytic asymmetric aziridination ........... 2 Scheme 1.4 The seminal Wulff catalytic asymmetric aziridination system ............ 4 Scheme 1.5 Proposed catalytic cycle in the Wulff aziridinations ........................... 6 Scheme 1.6 Maruoka’s trans-aziridination system with N- phenyldiazoacetamide ........................................................................................... 9 Scheme 1.7 Use of diazoacetate 19 by Maruoka furnishes the alkylation product ................................................................................................................. 10 Scheme 1.8 Zhong’s trans-aziridination system with N-aryldiazoacetamides 14 ......................................................................................................................... 10 Scheme 1.9 Use of diazoacetate 19 by Terada furnishes the alkylation product ................................................................................................................. 11 Scheme 1.10 Akiyama’s cis-aziridination system with ethyldiazoacetate 2 ......... 12 Scheme 2.1 Independent synthesis of VAPOL-EDA adduct 27 .......................... 24 Scheme 2.2 The Curtius rearrangement for the recovery of VAPOL ................... 25 Scheme 2.3 The Smlz mediated reduction for the recovery of VAPOL ............... 25 Scheme 2.4 Absolute configuration determination and attempts at ozonalysis...27 Scheme 2.5 Proposals to further improve the asymmetric inductions in this study .................................................................................................................... 33 Scheme 2.6 A gram scale catalytic asymmetric aziridination process ................. 36 Scheme 2.7 Failed attempts for the direct access to tri-substituted aziridines....37 Scheme 2.8 Examples from Maruoka’s tri-substituted aziridination study ........... 38 Scheme 3.1 Proposed trans-aziridination with oc-halosilylketene acetals ............ 41 Scheme 3.2 Akiyama’s protocol for racemic trifluoromethyl aziridines ................ 43 Scheme 3.3 Large scale synthesis of the MEDAM amine ................................... 44 Scheme 3.4 Cis-aziridination with N-methyl-N-benzyldiazoacetamide 67 ........... 53 Scheme 3.5 Puzzling aziridination reactions of two substrates ........................... 62 Scheme 3.6 All four stereoisomers of 3-aziridine-2-carboxylates ........................ 64 Scheme 3.7 TfOH catalyzed aziridination reactions ............................................ 66 Scheme 3.8 Absolute configurations in the trans-selective aziridinations ........... 68 Scheme 3.9 General absolute configurations in the universal aziridination ......... 69 Scheme 4.1 A collaborative effort with the Odom group ...................................... 72 Scheme 4.2 The active catalyst-quinoline complex in quinoline reductions ........ 79 Scheme 4.3 Self-assembly of a family of 83 catalysts for the quinoline reductions ............................................................................................................ 82 Scheme 4.4 Future directions for the project ....................................................... 86 Scheme 5.1 Chiral Bronsted acid catalysts from the BINOL scaffold .................. 89 Scheme 5.2 Structurally distinct vaulted biaryl diol ligands ................................. 90 Scheme 5.3 Multi-gram scale synthesis of VANOL phosphoric acid 93 .............. 92 Scheme 5.4 Multi-gram scale synthesis of N-triflyl VANOL phosphoramide 94..92 Scheme 5.5 Multi-gram scale synthesis of VAPOL phosphoric acid 91 .............. 93 Scheme 5.6 Multi-gram scale synthesis of N-triflyl VAPOL phosphoramide 92.93 Scheme 5.7 N-benzene sulfonyl VAPOL phosphoramide Bronsted acid catalysts ............................................................................................................... 94 Scheme 5.8 A new family of structurally distinct vaulted ligands ......................... 95 Scheme 5.9 Multi-gram scale synthesis of (S)-8,8’-Ph2VANOL 121 .................... 97 Scheme 5.10 Preparation of Brcnsted acid derivatives of 8,8’-Ph2VANOL ......... 98 xviii Scheme 6.1 Proposed asymmetric aziridination with chiral dirhodium catalysts ............................................................................................................. 102 Scheme 6.2 Asymmetric aziridination with the ha(POzBINOI—)4 complex 133 ..................................................................................................................... 103 Scheme 6.3 Asymmetric aziridination with the Rh2(P02VANOL)4 complex 139 ..................................................................................................................... 104 Scheme 6.4 Asymmetric cyclopropenation with the Rh2(P028|NOL)4 complex 133 ..................................................................................................................... 105 Scheme 6.5 Asymmetric aziridination with VAPOL/VANOL chiral Bronsted acids ................................................................................................................... 106 Scheme 6.6 Attempted Darzens reaction with ethyldiazoacetate 2 ................... 108 Scheme 7.1 Universal catalytic asymmetric aziridination .................................. 111 Scheme 7.2 General mechanism of aziridination reaction of imines and diazo nucleophiles catalyzed by Lewis/Brcnsted acid ................................................. 112 Scheme 7.3 Generation of the VANOL-B3 boroxinate complex ......................... 113 Scheme 8.1 Design of intermolecular product KIE measurement ..................... 130 Scheme 9.1 lshikawa’s applications of non-activated trans-ester aziridines ..... 141 Scheme 9.2 Ackermann’s proof of principle for intramolecular hydroamination .................................................................................................. 141 Scheme 9.3 Lectka’s filactam and Akiyama’s Mannich-type systems .............. 142 Scheme 9.4 Potential substrates for tri-substituted aziridination ....................... 143 Images in this dissertation are presented in color. xix CHAPTER ONE CHIRAL AZIRIDINES IN ORGANIC CHEMISTRY 1.1 Chiral aziridines as invaluable motifs in organic chemistry Aziridines are important 3-membered heterocycles, found in numerous natural products with promising biological activities (Scheme 1.1).1 Aziridines are also invaluable building blocks in organic synthesis; by virtue of their inherent ring strain, they participate readily in a multitude of stereoselective ring opening and ring expansion reactions?"3 Scheme 1.2 provides a snapshot of the multi- dimensional reactivity of aziridine-2-carboxylates,2a which is the general motif that we have targeted in our research. Scheme 1.1 Chiral aziridines in natural products O O o o 0 II N OH O O O OH OMe AcO HO Madurastatin BI Azinomycin A Mitomycins anti-bacterial activity anti-tumor activity anti-tumor activity Scheme 1 .2 Aziridine-2-carboxylates as versatile synthetic intermediates reaction at N \ deprotonation and / electrophilic substitution f \ 1 R1 / I N H ring opening and VRZHCOR <— reaction at carboxylic ring expansion reactions I f gr 0UP azomethine ylide formation 1 1.2 Major approaches towards chiral aziridines Chiral aziridines could be conceptually obtained in one of two different ways. The first approach would be to start from optically pure starting material, i.e. utilize the chiral pool, and construct the aziridine motif thereon. The second and alternative approach would be the way of catalytic asymmetric synthesis, i.e. induce chirality with the help of chiral catalysts. There has been tremendous growth in both these fields over the last few decades, and this growth has been extensively detailed in several excellent reviews?4 Scheme 1.3 Major approaches towards catalytic asymmetric aziridination 3 R3 LG + R ‘ ’ . .. 3 RL/\R2 I fl N(RR )* Ln*M=N—R T N * A? R2 \ H R2 ‘R‘ R1 3 Rib/\Rz R. H ._ R ,H L,,*M=( \C; R1 LG Approaches towards catalytic asymmetric aziridination could be chiefly differentiated into four categories (Scheme 1.3). From left to right, the first approach involves the transfer of a nitrene from a chiral metal center to an alkene. The second approach involves the transfer of a carbene from a chiral metal center to an imine. Imine activation by a chiral Lewis or Bronsted acid catalyst and subsequent attack of a carbenoid species provides the third approach towards the catalytic asymmetric synthesis of aziridines. The final, and the most recently developed, approach entails the use of chiral enamine organocatalysis. The Wulff group has pioneered the third approach towards catalytic asymmetric aziridination viz. the chiral Bronsted acid catalyzed imine aziridination approach. A detailed discussion on the state-of-art in the literature for this approach will be included in subsequent sections of this chapter. Several efficient and successful systems exist in the literature which furnish chiral aziridines utilizing the other approaches depicted in Scheme 1.3. For details on these systems, reference is given to two comprehensive reviews. Muller has published an excellent compilation which reviews the entire field of catalytic asymmetric aziridination till 2003,4b and Pellissier has done the same for the time period between 2003 and 2009.“ 1.3 The Wulff catalytic asymmetric aziridination system Based on the pioneering studies of Brookhart and Templeton with achiral Lewis acids in 1996,“1 our group in 1999 developed an efficient aziridination protocol which was originally thought to involve a chiral Lewis acid catalyzed addition of ethyl diazoacetate 2 to imines 1 (Scheme 1.4).6 The catalyst was prepared in-situ from the reaction of the vaulted ligands VAPOL 4 or VANOL 5 and triphenyl borate 6. In the years since this aziridination protocol was discovered, an enormous amount of work has been carried out in our group towards further developing this methodology. Efforts towards fine-tuning numerous aspects of the reaction, increasing the scope, elucidating the mechanism and the active catalyst structure, and applying the reaction towards use in organic synthesis and towards total synthesis of natural products have been undertaken.”11 Contributions to these efforts made during the period of this dissertation will be discussed further in Chapter 2. A review of our early work in this field has been published.12 The Wulff catalytic asymmetric cis-aziridination system, as it stands today, is arguably the most studied and the most efficient and general catalytic asymmetric aziridination protocol in the literature. Scheme 1.4 The seminal Wulff catalytic asymmetric aziridination system 0 Ph Ph 15 examples with RvN Ph + (JL 10 mole/o prmtalyi \Nr VANOL & VAPOL OEt o 1 yield = 54-91% Ph INIIZ CHZCIZ' 25 C' 24 h RACO Et cisztrans = 238:1 2 ee = 90-98% 1 2 3 R = aryl, heteroaryl, 1°, 2°, 3° alkyl B(OPh)3 6 "I 3 ‘ 0.1 mm H OH ( equ) > 9 > pre_ OH CH2C|2, 55 °C,1h 55°C, 0.5h catalyst (S)-VAPOL ( S)-VANOL 1.3.1 Proposed catalytic cycle in the Wulff aziridinations A significant part of this dissertation has been devoted to the study of the mechanism of the Wulff aziridination. The origins of the enantio- and diastereo- selections in our cis-selective as well as the newly developed trans- selective aziridination systems have been studied in detail with the aid of computational chemistry. While these studies will be discussed in later chapters, they merit at this stage a brief discussion of the proposed catalytic cycle in our aziridination reactions. Two previous group members, Yu Zhang and Gang Hu, spent a considerable amount of time during their dissertations in attempting to solve the structure of the active catalyst in our aziridination reactions. Their findings were quite remarkable, and these are depicted in our proposed catalytic cycle, exemplified for the (S)-VAPOL ligand 4, the imine 9a and a general diazo compound in Scheme 1.5. Scheme 1.5 Proposed catalytic cycle in the Wulff aziridinations 1) B(OPh)3 6 (4 equiv) H20 (1 equiv) toluene, 80 °C, 1 h 2) 0.1 mm Hg 80 °c, 0.5 h _ 4 (SH/A POL O | R N2 N2 1 1 catalyst-aziridine complex catalyst-imine complex (crystal structure) PG N Ph' COR 9a The active catalyst is prepared in-situ in the reaction from VAPOL 4 and triDhenyl borate 6. In the initial years after the discovery of the aziridination reaction, it was believed in our group that the active catalyst in our reactions would resemble the meso-monoborate 7 (B1). However, we had no evidence to support this hypothesis. After an extensive study based on high resolution mass spectrum analysis, 1H NMR and 11B NMR,8 Yu Zhang was able to ascertain that the product of the initial reaction between VAPOL and triphenylborate was actually a mixture of two species, the monoborate 7 (B1) as well as a linear pyroborate 8 (32). The pyroborate 8 (B2) was formed as the major species in the reaction - Yu Zhang and Zhenjie Lu, another previous group member, were then able to obtain evidence that suggested that the pyroborate 8 (82) was actually the active catalytic species in our reaction.8 Subsequently, Gang Hu tried to gather solid state evidence for this proposal by attempting to grow crystals of the complex formed between the pyroborate 8 (82) and a substrate imine 9a.11b Much to our surprise, the crystals that he solved the structure for revealed an entirely different complex — the spiroboroxinate catalyst-imine complex 10.11b Figure 1.1 (S)-VAPOL-Ba catalyst - the active catalyst in Wulff aziridinations (8)-VAPOL-B3 catalyst This discovery, and subsequent studies,11 have since led us to believe that the active catalyst in the Wulff aziridination reactions is actually a spiro- bOroxinate Bronsted acid catalyst (Figure 1.1, (S)-VAPOL—B3 catalyst 12), and 7 not a Lewis acid catalyst as we had believed for several years. In our catalytic cycle then, the catalyst-imine complex 10 reacts with the diazo compound to give the catalyst-aziridine complex 11 (Scheme 1.5). It was not possible to detect species 11 and this was presumed to be due to a more favorable binding of the imine to the catalyst than the aziridine which leads to turnover.11b 1 .4 Othe It chiral Bransted acid catalyzed imine aziridination systems Til l 2008, the Wulff cis-aziridination system was the only example of a chiral B rensted acid catalyzed imine aziridination protocol. Since 2008, there has been a flurry of activity in this field, and three research groups have reported imine azi ridination systems catalyzed by different chiral Brensted acid catalysts. 1 .4.1 Maruoka’s trans-aziridination system In 2008, Maruoka reported the first trans-selective chiral Bronsted acid catalyzed aziridination of imines (Scheme 1.6).13 In their system, the reactions between aryl N-Boc imines 13 and N-phenyldiazoacetamide 14a mediated by the chiral BINOL dicarboxylic acid catalyst 15 furnished the corresponding trans- aziridines 16a with excellent control of enantio— and diastereo- selectivities. It was a beautiful system for the first example, but there were several significant Clri=1Wbacks. Only 8 examples were reported for the imine substrate scope, all of WhiCh were derived from aromatic aldehydes with a fixed substitution pattern and ele(:tronic allowance. The yields were strictly moderate, and significant amounts 0f the enamines 17 were formed as side products. They proposed that transition State 18 was favored due to hydrogen bonding between the Boc group of the imine and the diazoacetamide N-H bond, which provided the observed trans diastereoselectivity. In a separate study, Maruoka has reported that if they use diazoacetates instead of diazoacetamides, and use the same aryl N-Boc imines 13 and the same Bl NOL dicarboxylic acid catalyst 15 as in their trans-aziridination system, 14a they obtain the corresponding alkylation products (Scheme 1.7). Scheme 1.6 Maruoka’s trans-aziridination system with N-phenyldiazoacetamide N,Boc 0 Ph 5300 BOC‘NH o | + NI > N + \ ’P J l ,./_\ H N h Ar1 N2 H 00 Ar2 Ar“ CONHPh N1 H 13 14a COZH 168 17 upto 21% COZH 8 examples CO 31-66% yield Ar2 89-99% ee 15 trans:crs = >20:1 5 mol% Ar2 = 2,4,6-Me3-C5H2 i— - RCQz k 13 Ar1 H favored + H-bonding N2 Scheme 1.7 Use of diazoacetate 19 by Maruoka furnishes the alkylation product I + AOtBu 4' Ar1 2 u Ar". I Ar2 fir]; N2 0‘ 13 19 COZH 20 C COZH 3 Ar2 15 5 mol% Ar2 = 2,4,6-Me3-C6H2 1 .4.2 Zh ong’s trans-aziridination system P resumably taking the initiative from Maruoka’s seminal report,‘3Zhong in 2009 reported a similar trans-selective aziridination protocol catalyzed by the chiral BINOL phosphoric acid catalyst 21a (Scheme 1.8).15 Excellent control over the enantio- and diastereo- selectivities was demonstrated, but the significant improvements in Zhong’s system over that of Maruoka’s were the higher yields for the trans-aziridine products and the extremely short reaction times (10 min for most Substrates). Scheme 1.8 Zhong’s trans-aziridination system with N—aryldiazoacetamides 14 , Boc O Boc Hk R ,1; /” '1' N’ > | ,.L\ Ar1 N2 H 00 Ar2 Ar1‘ CONHR 13 14 0‘ 1,0 16 R=awl P 0’ \OH 14 examples 81-97% yield 88-98% ee Arz transzcis = >19:1 21a 5 mol% A? = 9—anthryl 10 Scheme 1.9 Use of diazoacetate 19 by Terada furnishes the alkylation product i o NHCOR t N O + t = 1 - COZ BU J' I 0 Eu Ar2 Ar /\n/ A" ”2 00 ”2 22 19 o , 23 R = p-MezN-c6H4 I ’ CO ° Ar2 21a 5 mol% Ar2 = 9-anthryl However, as with Maruoka’s trans-aziridination system, Zhong’s protocol was also limited to imines prepared from aromatic aldehydes with a fixed substitution pattern and electronic allowance. Furthermore, in analogy to Maruoka’s system again, Terada in a separate study has demonstrated that if they use diazoacetates instead of diazoacetamides, and use similar imines and the same chiral BINOL phosphoric acid catalyst 21a as in Zhong’s trans- aziridination study, they obtain the corresponding alkylation products (Scheme 1 .9).‘° 1 .4.3 Akiyama’s ole-aziridination system Akiyama in 2009 reported a cis-aziridination system between activated imines 24 and ethyldiazoacetate 2, mediated by the chiral BINOL phosphoric acid catalyst 21b (Scheme 1.10).17 The imines 24 were prepared in-situ in the reaction from the corresponding phenyl glyoxal derivatives and p-anisidine. Ex(tellent results were obtained for the cis-aziridine products (Scheme 1.10). However, it was a very specific system; the major drawback was the need for activated imines i.e. only imines prepared from phenyl glyoxal derivatives were 11 reported. They speculated that having an electron rich group on the imine nitrogen facilitates the nucleophilic aziridine formation, as against the alkylation pathway reported by Maruoka14a (Scheme 1.7) and Terada16 (Scheme 1.9) in their reactions between diazoacetates and imines with electron deficient groups on the n i irogen. Scheme 1.10 Akiyama’s cis-aziridination system with ethyldiazoacetate 2 OMe OMe O o 1 I . Hoe _ Ar\“/l N V 2 Ar2 N 0 AI'1 \\°Q'l’ _ 2 \n c0251 0 0‘ 40 24 0’ p\ prepared in-situ OH 25 CO Ar2 10 examples 84-100% yield 21 b 92-95% ee 2 5 mol°/ cis: trans = >50:1 . 0 Ar2 = Si(4-tBu-06H4)3 1 .5 Conclusions Aziridines are invaluable motifs in organic chemistry; by virtue of their widespread presence in natural products, and more importantly, by virtue of their incredible versatility as building blocks in organic synthesis. The oxygen analogs of aziridines are the epoxides, and numerous ex'(remely general and efficient systems for catalytic asymmetric epoxidation eXi'an in the literature.18 The corresponding progress in catalytic asymmetric aZiridination has lagged behind considerably, and although this field has seen SiQnificant growth in the last few decades, catalytic asymmetric aziridination to this day remains largely an unsolved problem. Several reasonably efficient 1‘2 catalytic systems exist for the asymmetric synthesis of cis—aziridines, as do those for trans-aziridines; but there is no example in the literature of a protocol that could provide efficient access to both cis- as well as trans- aziridines, utilizing the same starting material and the same chiral catalyst. The development of such a universal catalytic asymmetric aziridination protocol has remained an elusive, albeit an actively pursued goal in the field. 13 CHAPTER TWO CATALYTIC ASYMMETRIC CIS-AZIRIDINATION: STRENGTHENING OLD FRONTIERS, AND BUILDING NEW ONES 2.1 Revisiting the aziridinations with benzhydryl imines The seminal Wulff catalytic asymmetric cis-aziridination system involved imines prepared from the commercially available benzhydryl amine (Chapter 1, Scheme 1.4).6 Early on during this dissertation, it was decided to revisit this seminal system.8 2.1.1 The reasons behind the revisit Yu Zhang, a previous group member, discovered a serious problem with our basic aziridination system around 2003.19 He found that when he tried to repeat the aziridinations from our seminal report,6b the corresponding cis- aziridine products were obtained with asymmetric inductions which were consistently lower by 4-5% ee as compared to the originally reported values. This led Yu Zhang to launch a comprehensive study of all the possible parameters involved in the reaction to account for the lowering of the observed inductions and to regain the previously obtained inductions.19 However, to the disappointment of everybody involved, neither a reason to account for the low inductions evolved, nor a solution to get them back to the original values. To this day, this discrepancy remains a mystery. At the start of the work done for this project during this dissertation, it was desired to confirm these differences from our seminal report. Thus, several 14 reactions were repeated under the exact conditions as originally reported,6b and sure enough, consistently lower asymmetric inductions were obtained (Table 2.1). Table 2.1 Repeating the aziridinations under the exact original conditionsa o - _ WW“ + 80. T ph I OEt CH2Cl2, 25 °C, 24 h A N2 R COzEt 1 2 3 first) (£21,512,- 12:23:41 3:34:32: 1 Ph (D) (S)-VAPOL 83 89 77d 95 2° p-BrC5H4 (f) (S)-VAPOL 85 9o 91 98 3 p-BrCeH4 (r) (FD-VANOL 86 9o 85 98 4 o-MeCeH4 (c) (S)-VAPOL 68 88 69 94 5 o-MeC6H4 (c) (FD-VANOL 69 83 65 91 6 t-butyl (I) (S)-VAPOL 83 83 78 91 7f f-butyl (I) (FD-VANOL 93 83 77 97 8 o-C6H11 (k) (S)-VAPOL 74 78 74 94 8‘ Unless otherwise specified, all reactions were run with 1 mmol of imine 1 in dichloromethane (0.5 M in imine 1) with 1.2 equiv of 2. The catalyst was prepared by heating 1 equiv of ligand with 3 equiv of B(OPh)3 in dichloromethane 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. These reaction conditions were identical to those reported in ref. 6b. Reaction with (R)-VANOL gives ent. 3. b Isolated yield after chromatography on silica gel. ° Chiral HPLC. d Reaction with 2 mol% of catalyst and 1.0 M imine. 9 Reaction in toluenezdichloromethane (1:1). fToluene, 0 °C for 4 h, then 25 °C for 20 h. Thus, the primary reason behind revisiting our seminal aziridination system was to determine and report the actual values of the asymmetric inductions obtained for all reactions contained in the original reports", and thus 15 set the record straight. There were a few secondary reasons. It was desired to try toluene also as the solvent for the main substrate scope; dichloromethane had been used in the original reports. It was also desired to add a few more substrates to the original study. The catalyst loading would also be reduced to 5 mol% from 10 mol%. Furthermore, the work reported in Sections 2.1.2, 2.1.4, 2.1.5, and 2.1.6 was also new to this study. 2.1.2 A solvent study It was initially desired to carry out a thorough solvent study for our basic aziridination system (Table 2.2). Table 2.2 A solvent study for the basic aziridination system with imine 1ba . O 10 mol% Ph Ph Ph V N Ph + {li‘OEt (S)-VAPOL-B3 catalyst : 7: Ph [‘52 solvent, 25 °c, 24 h PhACOZEt 1 b 2 3!) Entry Solvent Yield 3b (%)b 99 3b (%)° Reference 1 THF 79 90 This work 2 820 83 95 This work 3d CHgCN 60 26 This work 4 CH2CI2 83 89 This work 5 CH306H5 83 91 This work 6 CCI4 84 93 This work 7 CF3C6H5 82 90 Ref. 19 8 CHCI3 81 90 Ref. 19 9 C32 73 91 Ref. 19 10 CSHS 83 92 Ref. 19 a Unless otherwise specified, all reactions were run in the mentioned solvent containing 0.5 M imine 1b with 1.2 equiv of ethyl diazoacetate with respect to imine 1b. The catalyst was prepared 16 (Table 2.2 continued...) by heating 1 equiv of ligand with 3 equiv of B(OPh)3 in dichloromethane 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. b Isolated yield after chromatography on silica gel. c Chiral HPLC. d 77% completion. 2.1.3 The substrate scope in dichloromethane and toluene The study of our basic aziridination with VAPOL and VANOL in dichloromethane (Table 2.3) and in toluene (Table 2.4) was carried out, and a few insights were obtained: (1) In dichloromethane, VANOL is superior to VAPOL for all substrates. (2) In toluene, the general trend is that VANOL is similar to or slightly better than VAPOL, with the exception of imine 1]. (3) In the original report,6b dichloromethane was the solvent used. However, this study proves that toluene is better for all substrates, with the exception of imine 1e, where dichloromethane offered the best asymmetric induction. (4) VANOL and toluene emerged as the best combination for our basic catalytic asymmetric aziridination system. Exceptions to this were the imine 1e and imine 1]. (5) Asymmetric inductions as high as those originally reported6b were never obtained. However, for all the aromatic substrates from the original report, similar albeit slightly‘ lower inductions were obtained (>90% ee in each case). (6) For all aliphatic substrates, >90% ee was observed in the original report.6b However, in this study, even the best inductions for these substrates were in the range of 80-90% ee. (7) For the new imines introduced in this study, the best asymmetric inductions were encouraging (85-94% ee, imines 1d, 1e, 19 and 1h). Interestingly, aziridinations with imines derived from n-propanal failed in this study while those with imines derived from n-butanal were successful, 17 although the yields obtained were low. Additionally, aziridinations with imines derived from 2-furaldehyde also failed in this study. Table 2.3 The substrate scope in dichloromethanea o . R \é NY Ph + (3‘08 ligang-Bm3oLfitalyst : Ph \Nr Ph Phi-mg, C 02 E Ph biz CH2C12, 25 °c, 24 h RACOZB IR)” R(F11) 1 2 3 26 Entry Imine R1 Ligand Yggldb3 ee 3 (°/o)c cisztrans “(3,2926 1 16 Ph (S)-VAPOL 67 91 233:1 2/<1 2 1b Ph (FD-VANOL 77 91 250:1 <1/5 3 1c o-MeCsH4 (S)-VAPOL 56 85 10:1 7/3 4 1c o-MeC6H4 (FD-VANOL 57 88 1 1 :1 4/10 5 1d p-MeCsH4 (S)-VAPOL 80 88 250:1 6/2 6 1d p-MeC6H4 (FD-VANOL 82 93 250:1 <1/2 7 1e o-BrCsH4 (S)-VAPOL 40f 75 2.0:1 6/7 8 1e o-BrCsH4 (FD-VANOL 41' 85 2.2:1 4/9 9 11 p-BrC5H4 (8)-VAPOL 71 84 20:1 2r<1 10 11 p-BrCeH4 (FD-VANOL 81 92 34:1 4/8 11 lg p-NOQC5H4 (S)-VAPOL 61° 61 13:1 9/2 12 1g p-N02C6H4 (FD-VANOL 76h 86 34:1 <1/4 13 1h p-OMeCeH4 (S)-VAPOL 42i 77 5:1 2/<1 14 1h p-OMeC5H4 (FD-VANOL 51j 88 6:1 2/3 15 1i ( o A3231. (S)-VAPOL 83 86 250:1 4/3 16 1| (OASI:05H3 (R)-VANOL 88 91 250:1 3/7 17 1a 1-naphthyl (S)-VAPOL 76 89 26:1 2/3 18 1a 1-naphthyl (R)-VANOL 73 93 21 :1 3/5 19 1k c-CeHn (S)-VAPOL 76 76 250:1 <1r<1 20 1k c-CsH11 (Fl)-VANOL 80 83 250:1 4/<1 18 (Table 2.3 continued...) 21 1| t—butyl (S)-VAPOL 66k 74 218:1 1/2 22 1| t-butyl (FD-VANOL 85 84 250:1 6/<1 23 1| n-propyl (S)-VAPOL 24 73 8:1 1 0/5 24 1i n-propyl (FD-VANOL 55 81 14:1 8/9 8 Unless otherwise specified, all reactions were run with 1 mmol of 1 at 0.5 M in 1 with 1.2 equiv of 2. The catalyst was prepared by heating 1 equiv of ligand, 4 equiv of B(OPh)3 and 1 equiv of water in toluene at 80 °C for 1 h, followed by removing all volatiles under high vacuum at 80 °C for 0.5 h. Reaction with (FD-VANOL gives ent. 3. b Isolated yield after chromatography on silica gel. ° Chiral HPLC. d'e Determined from 1H NMR spectrum of the crude reaction mixture. f Reaction time was 48 h. g 81% conversion. h 97% conversion. i 70% conversion. j 81% . k . conversron. 86% conversron. Table 2.4 The substrate scope in toluenea O 5 mol% Ph Ph thHC\ R v N Ph ligand-83 catalyst Y NH \l/ + OEt > + R H \ (3023 ph | toluene, 25 °C, 24 h A ( I N2 R COzEt R(H) 1 2 3 26 . . Y' Id 3 Y' Id 2 Entry Imine R Ligand (if 99 3 (%)c cisztransd I; )9 6 1 1b Ph (S)-VAPOL 82 94 250:1 <1/<1 2 1b Ph (FD-VANOL 87 93 250:1 <1/2 3 1c o-MeC5H4 (S)-VAPOL 63 91 10:1 9/5 4 1c o-MeCeH4 (FD-VANOL 67 90 12:1 2/9 5 1d p-MeCeH4 (S)-VAPOL 80 92 250:1 <1/<1 6 1d p-MeCsH4 (R)-VANOL 79‘ 94 250:1 <1/2 7 1e o-BrCeH4 (S)—VAPOL 37° 82 1.6:1 5/5 8 1e o-BrCeH4 (FD-VANOL 43° 82 1 .9:1 1 1/13 9 1r p-BrCeH4 (S)-VAPOL 78f 90 20:1 <1r<1 10 1f p-BrC5H4 (FD-VANOL 86 94 220:1 6/10 19 (Table 2.4 continued...) h 11 1g p-NOgCaH4 (S)-VAPOL 79 79 15:1 <1/<1 12 1g p-N02CeH4 (R)-VANOL 86 89 250:1 <1/<1 13 1h p-OMeC5H4 (S)-VAPOL 51 '1‘ 86 6:1 13/10 14 1 h p-OMeC6H4 (FD-VANOL 61 87 34:1 <1r<1 15 11 (OA:;:('36H3 (S)-VAPOL 87 89 250:1 3/3 16 11 (OASSCeHa (FD-VANOL 84 93 250:1 <1/<1 17 1a 1-naphthyl (S)-VAPOL 76 93 34:1 <1 /<1 18 1a 1-naphthyl (FD-VANOL 80 93 51 :1 <1 /2 19 1k c-Can (S)—VAPOL 73 81 250:1 <1 /<1 20 1k c-CsH11 (FD-VANOL 79 82 2 50:1 6/< 1 21 11 t-butyl (S)-VAPOL 72j 87 250:1 <1/<1 22 11 t-butyl (FD-VANOL 89 85 250:1 4/<1 23 1 j n-propyl (S)-VAPOL 40 81 14:1 4/3 24 1 j n—propyl (FD-VANOL 54 77 14:1 10/9 8 Unless otherwise specified, all reactions were run with 1 mmol of 1 at 0.5 M in 1 with 1.2 equiv of 2. The catalyst was prepared by heating 1 equiv of ligand, 4 equiv of B(OPh)3 and 1 equiv of water in toluene at 80 °C for 1 h, followed by removing all volatiles under high vacuum at 80 °C for 0.5 h. Reaction with (FD-VANOL gives ent. 3. b Isolated yield after chromatography on silica gel. ° Chiral HPLC. d'e Determined from 1H NMR of the crude mixture. f Reaction run in toluenezdichloromethane (4:1). 9 Reaction time was 48 h. h 95% conversion. i 73% conversion. ‘ 93% conversion. 2.1.4 Enhancement of asymmetric inductions at 0 °C For some imines, an attempt was made to enhance their asymmetric inductions by conducting the reactions at 0 °C in toluene (Table 2.5). Comparing with the corresponding entries in Table 2.4 for the reactions at room temperature, it can be seen that significantly better results were obtained at 0 °C. 20 Table 2.5 Enhancement of asymmetric inductions at O °Ca O 5 mol% PI'I thHC\ R vN Rh ligand-B3 catalyst Y NH Y + 0E1 t N 1' )Sfl-COzEI ph I toluene, 0 °C, 24 h A (R)H N2 cozEt R(H) 1 2 3 26 Y' I Y' I 2 Entry Imine R1 Ligand (£363 99 3 (%)° cisztransd £436 6 1 1g p-NOzCeH4 (S)-VAPOL 9o 95 33:1 <1/<1 2 1g p-N02C5H4 (R)-VANOL 93 93 25021 <1/<1 3 1k o-C6H11 (S)-VAPOL 70 85 33:1 9/4 4 1k C-C5H11 (R)-VANOL 81 82 25021 5/<1 5 1| t-butyl (S)-VAPOL 75f 93 33:1 <1/2 6 1l t-butyl (R)-VANOL 58f 83 250:1 <1/<1 7 1 j n-propyl (S)-VAPOL 54f 86 25:1 2/1 1 8 1 j n-propyl (R)-VANOL 60f 83 33:1 <1/4 a Unless otherwise specified, all reactions were run with 1 mmol of 1 at 0.5 M in 1 with 1.2 equiv of 2. The catalyst was prepared by heating 1 equiv of ligand, 4 equiv of B(OPh)3 and 1 equiv of water in toluene at 80 °C for 1 h, followed by removing all volatiles under high vacuum at 80 °C for 0.5 h. Reaction with (FD-VANOL gives ent. 3. b Isolated yield after chromatography. ° Chiral HPLC. °'° ‘H NMR of the crude reaction. ‘ Reaction time was 48 h with 10 mol% catalyst loading. 2.1.5 Optically pure benzhyde azirldlnes vla crystallization A pleasant discovery in this study was that all aziridines 3 could be crystallized to afford almost optically pure aziridines (299% ee) with excellent recoveries (Table 2.6). Table 2.6 Optically pure benzhydryl aziridines via crystallizationa 00 0 Recovery (o/o) Entry Aziridine R1 ee U) 3 before ee (“.3 Rfleii from crystallization crystallization crystallization 1 3b Ph 94 99.4 62 21 (Table 2.6 continued...) 2 3c o-MeCeH4 91 99.3 74 3 3d p-MeC5H4 94 99.2 80 4 3e o-BrCsH4 85 98.6 65 5 3f p-Br05H4 94 99.4 76 6 39 p-N0205H4 95 99.7 74 7 3h p-OM9C6H4 87 99.9 81 8 3i (OASI:06H3 93 99 67 9 3a 1-naphthyl 89 99.9 55 10 3k c-CGHH 83 99.1 80 1 1 3| t-butyl 87 99.7 76 12 3] n-propyl 86 96.6 40 a See experimental information for information on solvent mixtures used for crystallization. b Chiral HPLC. 2.1.6 Recovery of the VAPOL ligand post-aziridination The VAPOL 4 could be recovered from the aziridination reaction in high optical purity, however, usually part or all of the VAPOL is recovered as the ethyl diazoacetate (EDA) adduct 277° The ratio of VAPOL 4 to the VAPOL-EDA adduct 27 that is recovered at the end of the reaction depends on the amount of excess EDA 2 that is used in the reaction (Table 2.7). For example, with 1.1 equivalents of EDA, the reaction performed with the catalyst prepared by the procedure outlined in Table 2.4 gave, after purification by silica gel chromatography, a 46% recovery of (3)-VAPOL with >99°/o ee along with a 49% yield of the EDA adduct 27 (Entry 2). The same reaction with 1.2 equivalents of EDA gave only the EDA adduct 27 in 98% yield (Entry 3). The aziridination with 1.0 equivalent of EDA lead to an incomplete reaction (Entry 1), however this was 22 an expected result as the commercially available EDA (Aldrich) contains up to 15% dichloromethane. Table 2.7 Recovery of 4 and 27 based on the equivalents of EDA 2 useda N ACOzEf 2 Ph Ph Ph EDA Y 4 \ A = N + recovered PhA N Ph 5 mol% 4 3 (S)-V6Apoj_ (S)-VAPOL-B3 Ph c0251 >99 A: 99 1b catalyst 3b toluene, 24 h, 25 °C 27 VAPOL-EDA adduct ' conversion of 1b Entry EqurvugggDA 2 to 3b (ct/o)b yield 4 (°/<>)C yield 27 (%)° 1 1.0 31 ND ND 2 1.1 100 46 49 3 1.2 100 o 98 a Reaction conditions and catalyst preparation were exactly identical to those outlined in Table 2.4. ND = not determined. b Crude 1H NMR. c Isolated yield after chromatography. First, an independent route was sought to synthesize the adduct 27. Surprisingly, it was found there was no reaction to form the adduct 27 when the reagents, viz. (S)-VAPOL, 20-30 mol% triphenyl borate, toluene and 1.2 equivalents of EDA, were simply mixed. However, when a procedure similar to the aziridination protocol was followed, albeit without adding the imine, it was found that the reaction proceeded smoothly to give the VAPOL-EDA adduct in 93% isolated yield after flash column chromatography (Scheme 2.1). 23 Scheme 2.1 Independent synthesis of VAPOL-EDA adduct 27 1) B(OPh)3 (4 equiv) H20 (1 equiv) toluene, 80 °C, 1 h 2) 0.1 mm Hg 80 °C, 0.5 h 3) EDA 2 (2 equiv) toluene, 25 °C, 36 h; 4 27 93% yield One of the first routes tested to recycle the VAPOL-EDA adduct 27 back to VAPOL 4 was a zinc/glacial acetic acid reduction. However, even when the reaction was pushed (90 °C for 16 h), no progress for the reaction was observed by TLC. The EDA adduct 27 could be recycled to optically pure (S)-VAPOL 4 via a Curtius rearrangement (Scheme 2.2).20 Hydrolysis of 27 afforded the carboxylic acid 28, essentially as a single compound in the reaction, which could be used in the next step without purification. Acid 28 was then treated with diphenylphosphoryl azide (DPPA) and triethylamine and the resulting acyl azide was rearranged to an isocyanate. Trapping the isocyanate with H20 gave a carbamate that decarboxylated to give a hemiaminal that hydrolyzed to (S)- VAPOL. However, some of the acyl azide was trapped intramolecularly by the phenol to give the Iactone 29. The overall result was a mixture of free (8)- VAPOL (56%) and the Iactone 29 (34%). Although the Iactone 29 could be recycled to the ethyl ester 27 (see experimental information), a more efficient method for the liberation of VAPOL was found to be the direct reduction of 27 24 with samarium diiodide21 which gave (Sb-VAPOL in 91% yield and 99.8% ee (Scheme 2.3). Scheme 2.2 The Curtius rearrangement for the recovery of VAPOL ' A NaOH, EtOH pr, ”Q (3023 25 °C, 1h : Ph COZH Ph, OH Ph,,, 27 28 98% yield a) NEt3 (PhO)2PON3 b) H20, reflux 0) acid : 4 + (S)-VAPOL 56% yield 29 34% yield Scheme 2.3 The Smlg mediated reduction for the recovery of VAPOL Smlz-THF HMPA, EtOH THF, 25 °c, 1 h ' 27 4 91 % yield 99.8% ee A good outcome of the Curtius rearrangement study (Scheme 2.2) was the discovery that selective manipulation and functionalization of one of the 25 hydroxyl groups of VAPOL was indeed possible, and could be done with reasonably simple reactions and excellent yields. This chemistry could possibly be explored in the future for the development of new ligands based on VAPOUVANOL, perhaps in the domain of dual-functional catalysis. 2.2 Aziridinations with o-bromophenyl benzhydryl imine: First glimpses of trans-aziridines While screening different benzhydryl imines for the Wulff catalytic asymmetric cis-aziridination, it was found that the reaction with the o- bromophenyl benzhydryl imine 1e gave significant amounts of the trans-aziridine isomer (cisztrans = 2:1, Table 2.4, Entry 7 and 8). This was the first time that trans-aziridines, in isolable ratios, were observed in our aziridination reactions. While the reason for the low diastereoselectivity was not clear at the time, it was desired to isolate the trans-aziridine isomer, quantify its yield and asymmetric induction, and characterize it completely. This was done, and the results are presented in Table 2.8. Table 2.8 Cis- and trans-aziridines from aziridination of imine 1ea Bh Bh \ Bh EDA 2 (1.2 equiv) '1‘ '1‘ N’ 5 mol% ligand-B3 cat; + 1 E + Enamines Br toluene, 25 °C, 90 h (:(LA‘COzEt (:L“ COzEt 26° Br Br 19 (2R, 3R)-3e (2R,3S)-30 b Yield 99 (%) Yield 96 (%) Yield Entry Ligand olsztrans (%) 3ec 3ed (%) 30c 30d (%) 2666 1 (S)-VAPOL 1 .1 0:1 42 80 36 36 15 2 (Fl)-VANOL 1 .75: 1 47 82 24 35 22 26 (Table 2.8 continued...) 8 Unless otherwise specified, all reactions were run with 4 mmol of 1e at 0.5 M in 19 with 1.2 equiv of 2. The catalyst was prepared by heating 1 equiv of ligand, 4 equiv of B(OPh)3 and 1 equiv of water in toluene at 80 °C for 1 h, followed by removing all volatiles under high vacuum at 80 °C for 0.5 h. Reaction with (FD-VANOL gives ent. 3e and ent. 30. b Determined from 1H NMR of the crude reaction mixture. c Isolated yield after chromatography. d Chiral HPLC. Scheme 2.4 Absolute configuration determination and attempts at ozonalysis Ph Ph Y 20 mol% Pd(OH)2/C N MeOH, 25 °c, 7 h /\/<302Et .L\ = Ph 5 (eq 1) “ COzEt 1 atm H2 NH2 8 313 r 2 runs (16% and 34% yields) (2R'3SI'30 [21230 found: 415 (c = 1.2, EtOH) Literature values (ref. 6a, 28a): -23.0 (c = 3.2, EtOH) P" P" 25% Pd(OH)2/C Br N MeOH, (800)20 COZEt L3 = P“ w. .,I (eq 2) 00251 1 atm H2, 22 h, 25 °c NHBOC 31b (2838-30 29% yield [021230 found: .37 (c = 1, MeOH) Literature values (ref. 28b): -4.4 (c = 1, MeOH) PhYPh 1) Ozone, CH2Cl2 Br H B, N -78 °C, 5 h N = + 21 °/ recovered 39 e 3 c0213 2) NaBH4. MeOH @0028 o ( q ) -78 °C to 25 °C 39 32 48% yield “1th 1) Ozone, CH2CI2 Br H gr N -78 °C,8 h IN: A ; v" CO Et (eq 4) o‘ C023 2) NaBH4, MeOH 2 -78 °C to 25 °C 30 33 15% conversion 27 The absolute configurations of the cis-aziridine 3e and the trans-aziridine 30 were determined by chemical correlation, and subsequently comparing the optical rotation of the products to literature values (Scheme 2.4, eq 1 and 2). Interestingly, opposite facial selectivity was observed for the cis-aziridine 3e and the trans-aziridine 30 with the same enantiomer of the ligand. For example, in the reaction with the catalyst prepared from (S)-VAPOL (Scheme in Table 2.8), the cis-aziridine 3e was configured (2R,3H), which results from a Si face attack of the diazoacetate. The trans-aziridine 30 from the same reaction however was configured (2R,3S), which results from a Re face attack of the diazoacetate. Furthermore for this study, the cleavage of the benzhydryl group via ozonalysis was also attempted (Scheme 2.4, eq 3 and eq 4). 2.3 Aziridinations with 5-nonylimlne, dicyclohexylmethylimine and 5H- dibenzo[a,d]cyclohepten-5-imlne Yu Zhang and Zhenjie Lu from our group, around 2006, carried out an elegant study to map out the active site of the catalyst in our aziridination reactions.9 To do this, they synthesized numerous diarylmethylamines of varying electronic and steric properties, and prepared the corresponding imines with benzaldehyde. These imines were then subjected to our standard aziridination reactions, and the effects of the different N-protecting groups studied. It was in this study that Yu and Zhenjie discovered the tetra-tert-butyldianisylmethyl (BUDAM) and tetramethyldianisylmethyl (MEDAM) groups, which have since then been established as the protecting groups of choice in our catalytic asymmetric aziridination reactions. 28 A small contribution to this study was made during the period of this dissertation. To confirm the importance of the diaryl groups on the N-protecting group for our aziridination reactions, it was desired to test the di-n—butylmethyl and the dicyclohexylmethyl N—protecting groups. To test the importance of relative orientation of the diaryl groups, it was desired to test the imine prepared from 5H—dibenzo[a,dchclohepten-S-amine. The amines for this study were prepared according to, or in an analagous manner to, literature procedures, and the corresponding imines were subsequently made with benzaldehyde (see experimental information). These were then subjected to our standard aziridination reaction conditions, and the results are presented in Table 2.9. The aziridination reactions of the imine 1b with the benzhydryl protecting group are shown for comparison (Entries 1-2). The reactivity, yields and asymmetric inductions with imines 34 and 35 dropped significantly (Entries 3-6), thus confirming our belief that diaryl groups are indeed important in the N-protecting group for our aziridination protocol. However, the results improved slightly with the imine 36 (Entries 7-8). The exact reasons behind this are unclear at this time, but these results suggest that the relative orientation of these diaryl groups is important in our aziridination protocol. 29 Table 2.9 Contributions to the study to map the active site of our catalysta imine PG aziridine 34 n-BuYn-Bu 37 1.10equiv EDA 2 PG ' phAN G 10 mol /0 ligand-B3 cat: A 35 38 CH2CI2, 25 °C, 24 h Ph C023 “’1’" 36 0‘0 39 ".35- Entry imine ligand azir. conversion yield c Iee d rel. rate a (%) az1r. (%) ale'.(°/o) (1 b.imlne) 1 1b (S)-VAPOL 3b 100 83 89 1:1 2 1b (FD-VANOL 3b 100 81 88 1 :1 3 34 (S)-VAPOL 37 29 27 84 1 :0.23 4 34 (FD-VANOL 37 45 40 79 ND 5 35 (S)-VAPOL 38 23 18 74 1 :0.04 6 35 (FD-VANOL 38 42 35 70 ND 7 36 (S)-VAPOL 39 100 65 96 1 :2.2 8 36 (FD-VANOL 39 1 00 66 94 ND 8 Reactions were run with 1 mmol of imine at 0.5 M in imine. The catalyst was prepared by heating 1 equiv ligand and 3 equiv BIOPh)3 at 80 °C in toluene for 1 h, then all volatiles were removed under high vacuum for 0.5 h at 80 °C. (FD-VANOL gives ent. aziridine shown. b Crude 1H NMR. ° Isolated yield. d Chiral HPLC. 9 Relative rate studies were carried out in pairwise competitions in CCl4 with 1 equiv of 1b, 1 equiv of competitor imine, 0.2 equiv of 2, and 5 mol% catalyst at 25 °C for 24 h. 2.4 cIs-2,3-Dicarbonylazlridines from the Wulff aziridination cis-2,3-Dicarbonylaziridines would be attractive targets for a catalytic asymmetric aziridination protocol. A Bronsted acid catalyzed reaction providing racemic cis-aziridine-2,3-dicarboxylate derivatives has been previously reported '30 by Johnston.22 Shortly after the promising attempts reported in this section were carried out, a chiral Bronsted acid catalyzed aziridination protocol affording cis- 2,3-dicarbonylaziridines was reported by Akiyama (Chapter 1, Scheme 1.10).17 Table 2.10 cis-2,3-Dicarbonylaziridines from the Wulff aziridination protocola 10 mol% ligand-B3 A ,PG + l/COZ B” toluene _ N EtOzC N i ' ”2 Etozc’ ‘cozteu 403, PG = Bh 19 41a, PG = Bh 40b, PG = MEDAM 1.3 equiv 41b, PG = MEDAM 40¢, PG = BUDAM 41c, PG = BUDAM Me Me tBu tBu o 0 o 0 wrv Me Me tBU tBU Bh MEDAM BUDAM (8)-Ph2VANOL 43 (S)-ISOVAPOL # PG ligand TerZLpC(‘II'1i;ne) cisztransb Jig/(eff 416(2))d 1 Bh no catalyst 25 (24) 5% conversion 2 Bh VAPOL -40 (24) to 25 (24) >50:1 65 4 3 Bh VANOL ~40 (24) to 25 (24) >50:1 75 34 4 Bh VANOL -40 (24) >50:1 ND ND 5 Bh VANOL 0 (24) >50:1 55 42 ‘31 (Table 2.10 continued...) 6 Bh VANOL 25 (24) >50:1 64 31 7 Bh Ph2VANOL° -20 (48) to 25 (12) >50:1 57 8 8 MEDAM VAPOL o (24) 20:1 80 14 9 MEDAM VANOL o (24) 20:1 77 46 1o MEDAM VANOL -20 (24) 25:1 74 45 11 MEDAM VANOL -4o (24) 25:1 77 42 12 MEDAM ISO-VAPOL' -20 (24) 33:1 80 46 13 MEDAM Ph2VANOL° -20 (64) to 25 (24) >50:1 42 5 14 BUDAM VAPOL-B3 o (24) 15:1 58 15 15 BUDAM VANOL-83 o (24) 15:1 <76 1 1 a All reactions were run with 0.25 mmol of imine 40 at 0.125 M in imine 40. The catalyst was prepared by heating 1 equiv of ligand, 4 equiv of B(OPh)3 and 1 equiv of water at 80 °C in toluene for 1 h, followed by removing all volatiles at high vacuum (0.1 mm Hg) for 0.5 h at 80 °C. ND = not determined. b Crude 1H NMR analysis. c Isolated yield after chromatography. d Chiral HPLC. a See chapter 6 for ligand preparation. f Provided by Anil Gupta. A significant amount of time was devoted during this dissertation in trying to access cis-2,3-dicarbonyl aziridines via the Wulff catalytic asymmetric aziridination. A systematic optimization was undertaken, and although excellent diastereo-control and reactivity was observed, the best asymmetric induction obtained was only 46% ee. These results are summarized in Table 2.10. cis-2,3-Dicarbonylaziridines have never been accessed before from the Wulff catalytic asymmetric aziridination. lf successfully obtained, they would be a nice addition to the already wide repertoire of the cis-aziridines available from our protocol. It is proposed that the asymmetric inductions obtained during this dissertation could be further improved in the future in one of three ways (Scheme 2.5). 32 Scheme 2.5 Proposals to further improve the asymmetric inductions in this study 1) 3 equiv BH3-SM92 3 equiv H20 2 equiv ROH toluene, 100 °C, 1 h 2) 0.1 mm Hg, 0.5 h (eq 2) New members of the VANOL ligand family MEDAM AHVNMEDAM EDA 2 N "'_ """"""" ’ Ar' (eq 3) O ligand-B3 catalyst CO2Et O The BHaoSMezlphenol route could be utilized for preparing the 83 catalyst, which provides an additional handle with which the active site of catalysis could be tweaked i.e. electronically and sterically different phenols/alcohols could be used to generate a large number of 83 catalysts from VANOL (eq 1), since VANOL offered the best inductions during this study. Alternately, the 83 catalyst for this reaction could be prepared from the new members of the VANOL ligand family, which are being actively pursued in our laboratory (eq 2). Finally, a last avenue for improving the asymmetric inductions in this system could be switching 33 from MEDAM imines prepared from ethyl gloxylate to MEDAM imines prepared from phenyl glyoxal derivatives (eq 3), similar to those used in Akiyama’s protocol (Chapter 1, Scheme 1.10).17 Having an aromatic group on the imine might help in establishing better non-covalent interactions in the catalyst-imine complex and thus further fine-tune the active site of catalysis to engender higher asymmetric inductions. 2.5 A gram scale catalytic asymmetric aziridination process To make our cis-aziridination protocol easily accessible to the scientific community at large, it was desired to scale up one example and convert the reaction into an easy and practical process. Thus, it was decided to develop a procedure with one example from our catalytic asymmetric cis-aziridination protocol for submission to the journal Organic Synthesis. Procedures submitted to Organic Synthesis (usually on a larger scale than the discovery chemistry scale) are independently verified in the laboratories of the board of editors before publication, and thus are widely accepted as robust and reliable procedures. This study was carried out with Dr. Roberto Moran-Ramallal, a post- doctoral research associate in our group for a short period in 2009. It was decidedto scale up an example from our full report in 2008 (Section 2.1);8 the aziridination reaction of p-bromophenyl benzhydryl imine 1f and ethyldiazoacetate 2 mediated by the (S)-VANOL-B3 catalyst was chosen (Table 2.4, Entry 10). VANOL was chosen since it afforded better results with imine 1f as compared to VAPOL (86% yield and 94% ee with VANOL for aziridine St). The imine prepared from p-bromobenzaldehyde was chosen as the substrate 34 since the presence of bromine would offer a convenient handle in the product cis- aziridine for further synthetic transformations viz. cross-coupling reactions. The benzhydryl group was chosen as the N-protecting group since it is commercially available, and since the benzhydryl aziridines are solids and can be readily crystallized up to almost optical purity with excellent recovery (Table 2.6). Initially a catalyst loading study was pursued with both VAPOL and VANOL ligands. At 1% catalyst loading, the above mentioned reaction with the catalyst prepared from VAPOL gave incomplete completion, whereas that with the catalyst prepared from VANOL went to full completion. Thus VAPOL was dropped from the study at that point. The catalyst loading with VANOL could be further reduced to 0.5 mol% without affecting the reaction outcome. The reaction time at this catalyst loading was optimized to 8 h. Scheme 2.6 depicts the optimized large scale procedure that evolved from this study. The imine II was prepared under extremely mild conditions at a 58.14 mmol scale from commercially available starting materials. After just one crop of crystallization, 17.04-17.36 g of imine 1f was obtained as white crystals (84-85% yield). The subsequent aziridination reaction was carried out at a 20 mmol scale in the imine. 0.5 mol% of the B3 catalyst prepared from (S)-VANOL was used, which corresponds to only 44 mg of (S)-VANOL being used. The reaction was complete at room temperature in 8 h, and the first crop of crystallization afforded the aziridine product 3f as a white solid in 62-64% yield (5.41-5.59 9). Almost optically pure aziridine 3f (99% ee) was obtained in the first crop. A second crop could be taken, and this afforded the aziridine 3f, again as a white solid, in 25- 35 27% yield (2.20-2.35 g) and 75-78% ee. Thus, the overall yield for the reaction was 89% (7.76-7.79 g) and the overall asymmetric induction was 92-93% ee. Scheme 2.6 A gram scale catalytic asymmetric aziridination process CH2CI2, M9304 O O©O 22 °C rt(), 20 h T \ fih‘ I Br 58.14 mmol scale 1.1 equiv 1t (1064 9) 84-85% yield (17.04-17.36 9, single crop) 0.5 mol% (S)-VANOL-B3 catalyst OEt 44 mg of (S)-VANOL used = N [SD/NO toluene, 22 o (rt), 8 h M00251 122 equiv Br 20 mmol scale (7 g) 31‘ 1st crop: 62-64% yield (5.41-5.59 g) 99% ee 2n d:crop 25-27% yield (2.20-2.35 9) 75-78% ee overall: 89% yield (7.76-7.79 9) 92-93% ee Worthy of note is that no column chromatography is used in this entire process, which makes it attractive from a process chemistry point of view. The entire process involves commercially available starting materials; even the ligand VANOL is now commercially available from Aldrich as well as Strem Chemicals, Inc. The reactions proceed under mild conditions, and essentially optically pure aziridine product is obtained in good yield in just one crop. That such an operationally simple and highly efficient catalytic asymmetric aziridination process could be evolved from this study was very gratifying. 36 2.6 Failed attempts for the direct access to tri-substltuted aziridines A few attempts were made to directly access tri-substituted aziridines via the Wulff catalytic asymmetric aziridination, either by using di-substituted imines or di-substituted diazo compounds. All these reactions failed, and are summarized in Scheme 2.7. Scheme 2.7 Failed attempts for the direct access to tri-substituted aziridines J, MEDAM _ 10 mol% MEDAM N ligand-B3 cat. ' /II\ + EDA t I +- Ph N o uene P" 0025‘ 48 h (25 °C), EtO2C 0023 45 2 24 h (50 °C), 46 12 e uiv 24 h (80 0C), q 22 h (25 °C) entry catalyst result 1 VAPOL-33 only s.m. recovered 2 VANOL-B3 only s.m. recovered N2 VANOL-B3 cat. Bh \ (10 mol%) _ ' Ph/\N’Bh t Ph/lkffo\ - N Ph CHZCIZ, 36 h A 0 temperature Ph COZMe 1b 47 48 1.2 equiv entry temperature result 1 25 °C only s.m. + junk + diazo 2 80 °C dimer - no aziridine A gigantic amount of work has been devoted to the catalytic asymmetric synthesis of aziridines by numerous research groups all over the world since the last two decades. In spite of this, there are no reports in the literature to access tri-substituted aziridines in a catalytic asymmetric fashion. If such a system could be developed using our VAPOL/VANOL-Ba catalysts, it would undoubtedly be a 37 big addition to the utility of our catalytic asymmetric aziridination system. It would also be a standalone high impact research project. Very recently in 2010, Maruoka has reported a diastereoselective synthesis of tri-substituted aziridines from imines and disubstituted diazo compounds, catalyzed by triflic acid (Scheme 2.8).14b This constitutes the first stereoselective synthesis of tri-substituted aziridines in the literature. Scheme 2.8 Examples from Maruoka’s tri-substituted aziridination study 20 mol% BF3-Et20 CH Cl -78 °C, 10 pnA NB°° + Mei/[LL J20 2 2 mm: 4”, OCJOL N40 (e41) Me ‘\\/O 52% yield 20 mol% TfOH Boc NBoc + CH2CI2, -78 °C, 5—20 min 0 (eq 2) Ph/\ MeWV/lLN (N E \\U\ 2028 Ph MeOZS 74% yield The reaction shown in eq 1 of Scheme 2.8 is catalyzed by BF3-Et20. They mention in a footnote that the same reaction could be catalyzed smoothly by camphorsulfonic acid; however the product was obtained in racemic form. Our trans-selective aziridination protocol (described in Chapter 3) was inspired from Maruoka’s trans-aziridination13 between N-Boc imines and N- phenyldiazoacetamide catalyzed by chiral Bronsted acids. Compiling the above three sentences makes a very sound argument to attempt the aziridination reaction shown in eq 1 of Scheme 2.8, mediated by our VAPOL/VANOL-83 catalysts and with the diarylmethyl imines used in our protocol. 38 CHAPTER THREE CATALYTIC ASYMMETRIC TRANS-AZIRIDINATION: DEVELOPMENT OF A UNIVERSAL AZIRIDINA TION PROTOCOL 3.1 Introduction The Wulff catalytic asymmetric cis-aziridination was discovered around 2000, and all through the long years of developing that system, a constant effort had been made in our laboratories to access the corresponding trans—aziridines. As mentioned in Chapter 1, there is no example in the literature of a protocol that could provide efficient access to both cis- as well as trans— aziridines, utilizing the same starting imine and the same chiral catalyst. The development of such a universal catalytic asymmetric aziridination protocol has remained an elusive, albeit an actively pursued goal in the field. One of the early hopes in our laboratories towards realizing this goal was to do this by epimerization of the ester group on the cis-aziridine, but it was found that the enolate was configurationally stable. This proved to be synthetically quite valuable since the cis-aziridine-2-carboxylate ester could be alkylated with complete retention of configuration at the 2-position.70 After the work towards developing the cis-aziridination protocol described in this dissertation ended, attention was turned to the tantalizing goal of expanding this protocol to include trans-aziridines, thereby creating the first universal catalytic asymmetric aziridination protocol in literature. Quite a few of 39 what started out as very promising avenues were initially explored in this regard; however all these efforts were in vain. 3.2 Initial attempts towards a catalytic asymmetric trans-aziridination Eq 1 in Scheme 3.1 depicts the proposed stereochemistry determining transition state in the Wulff catalytic asymmetric cis-aziridination reaction. The high cis diastereoselectivity has been presumed to be due to the stabilization of the developing charges in the zwitterionic intermediate at the transition state. It was hypothesized that if ethyldiazoacetate 2 was then switched with a different aziridinating nucleophile, such as the a-halogenated silylketene acetals 49 depicted in eq 2, an analogous Newman projection of the zwitterionic transition state would predict the opposite trans diastereoselectivity. The trans selectivity would be favored not only due to a similar charge stabilization at the transition state, but also due to the additional opposing dipoles indicated. Thus, it was thought to be very interesting to prepare and test various a- halogenated trimethylsilylketene acetals as aziridinating agents in a catalytic asymmetric aziridination protocol of the same diarylmethylimines as in our original aziridination, catalyzed by the same VANOUVAPOL-83 catalysts (Scheme 3.1). For this purpose, the trimethylsilylketene acetals of oc- bromoethylacetate (49a)35 and a-chloromethylacetate (49b)36 were chosen to be prepared and tested. However, although literature procedures existed for making these compounds, attempts at repeating these procedures resulted in polymerized crude products. Numerous permutations and combinations of the '40 reaction parameters were subsequently tried, but all failed miserably, giving only polymerized crude products or polymerized products after distillation. Scheme 3.1 Proposed trans-aziridination with a—halosilylketene acetals Ar 0 Ar\rAr *Ar + (K N (901) J l OEt 5 r R N2 R COzEt 2 1 OTMS (S)-VAPOUVANOL-B3 NY Ar 4. catalyst ; j' A’ Xe/kOR. , ,N, (eq 2) R u \ R u’COzR' 49a,x=Br,R =Et 49b, x = Cl, R' = Me TMS-X — — — 3: mi 1' H‘N’8?G él/TMS H “ ow R O H ‘1' Br5_ OTlPS OTMS OTBDPS X / OR. X / Ph 8" / 50 51 52 41 Thus, the a—halogenated trimethylsilylketene acetals 49 for this project could never be prepared during this dissertation, and the essence of the project i.e. the actual catalytic asymmetric aziridination could not be attempted. If successfully realized, this method would represent an unprecedented protocol for preparing chiral aziridines. Since the high reactivity, and thus the instability, of 49 is probably the cause of the failure behind its preparation, this might be attenuated by either increasing the bulk of the silyl protecting group (50) or by switching to the a-halogenated silyl enol ethers (51 or 52) (Scheme 3.1). Silyl enol ether 52 has actually been previously prepared in our laboratories by Nilanjana Majumdar, for research related to carbene complexes. A separate attempt at developing a trans-selective aziridination protocol was inspired by a report by Akiyama and co—workers‘”, who found that they could stereoselectively obtain trans-aziridines if they used an extremely bulky . diazoacetate compound viz. 4-methyl-2,6-di-tert-butylphenyldiazoacetate (Scheme 3.2). Thus, this particular diazoacetate was prepared according to a literature procedure.38 Disappointingly however, when this diazoacetate was evaluated under our standard aziridination conditions (imine 1b, 10 mol% of 8;, catalyst prepared from either VAPOL or VANOL, 25 °C or 50 °C), there was no reaction at all, presumably due to the extreme steric bulk of the diazoacetate. No further work was done for this trans-aziridination approach. 42 Scheme 3.2 Akiyama’s protocol for racemic trifluoromethyl aziridines 0 PMP Owe (12 BF3-0Et2 or SnCl4 I“ + ‘ OR ' A l o A F30 N N2 CH2CI2, -40 C. 2-7 h F3C COZR generated insitu good yields e -§<:> 4+ 443 4Q 3%} cisztrans 93:7 92:8 85:15 79:21 77:23 10:90 3.3 Large scale preparation of the MEDAM amine The N-protecting group of choice in our cis-selective aziridinations is the tetramethyldianisylmethyl (MEDAM) group.10 In the trans-selective aziridinations that will be discussed in the subsequent sections of this chapter, the MEDAM group also proved to be the protecting group of choice for the aryl imines. The small scale synthesis of the MEDAM amine 57 was developed by Yu Zhang from our group.9'19 This synthesis was scaled up for the first time early on during this dissertation (Scheme 3.3), and was accomplished in three overall steps starting from the commercially available phenol 53. Thus, 100+ g of the MEDAM amine 57 was prepared with excellent yields at each step. Each reaction was carried out at least 4 times at different scales; the average yields are reported in Scheme 3.3. '43 Scheme 3.3 Large scale synthesis of the MEDAM amine OMe OMe NaH (2.5 equiv) Mel (4 equiv) CuCN, DMF 2 DMSO, 25 °C, 3 h' 180 °C, 8 h o 91 °/ Br 89 A Br ° CN 53 upto 100 g 54 upto 75 g 55 scale scale r _ OMe OMe Meo OMe Mg, THF, 2h_ 1)55, THF,6h 2 O O V 2) LiAIH4 (1.3 equiv) 3, mm THF, 12 h NH2 54 upto 32 g 56 57 scale 71% (from 54) 3.4 Catalytic asymmetric trans-aziridination: Development of a universal aziridination protocol During the period in this dissertation when the futile attempts (Section 3.2) towards developing a trans-selective aziridination protocol were being carried out, Maruoka reported the first chiral Bronsted acid catalyzed trans-selective aziridination of imines (Scheme 1.6, Chapter 1). In their system, the reaction of aryl N-Boc imines and N-phenyldiazoacetamide mediated by a chiral BINOL dicarboxylic acid catalyst furnished the corresponding trans-aziridines. They proposed that H-bonding between the Boc group of the imines and the NH of the diazoacetamide at the carbon-carbon bond forming transition state was responsible for the observed trans diastereoselectivity (18, Scheme 1.6, Chapter 1). If this proposal were true, having an electron rich protecting group on the imine nitrogen such as the diarylmethyl groups we have in our cis-aziridination '44 reactions, instead of the electron deficient Boc group, would not offer such an H- bonding opportunity, and thus would not us provide any trans selectivity. 3.4.1 The initial optimization of the trans-aziridination protocol R. B. Woodward had once said “...faced with a decision based solely upon hypothetical arguments, consider all reasons not to perform an experiment, and disregard them.”39 Keeping in spirit with these words, around November 2008, the reactions between imine 1b and N-phenyldiazoacetamide 14a mediated by 20 mol% of the 83 catalyst prepared from VAPOL and VANOL were set up (Table 3.1, Entry 2 and 5). Much to our pleasure, both reactions furnished trans- aziridines with very encouraging results. Borrowing from the abundance of experience gleaned from fine-tuning our cis-selective aziridinations, we were able to optimize the trans-selective aziridination protocol. These optimization details are presented in Table 3.1. In the final optimized system, MEDAM was the protecting group of choice, VANOL was the ligand of choice, and the reaction temperature was either 0 ° or -20 °C. This optimized system is represented by Entries 8 and 17 in Table 3.1. An intriguing outcome of these reactions was that the catalyst prepared from VAPOL was consistently, and significantly, inferior to that prepared from VANOL. This is quite contrary to our cis-selective aziridinationsf"12 where both VAPOL and VANOL have always afforded very similar results. The minor diastereomer, the cis aziridine, was isolated from the reaction in Entry 19 in 14% yield and with 77% ee (see Section 3.4.10). '45 Furthermore in this study, an extensive solvent screen convinced us that toluene was indeed our solvent of choice (Table 3.2). Table 3.1 Optimization study for the trans-aziridination protocola 5 mol% 0 ligand-B3 catalyst E’G PG~ NH toluene N ,Ph 4 PhAN’PG * {LN , Ph\‘,.L\‘/NHPh + (H)Ph \ HtPh) N2 H time, temperature 0 O NHPh 11'), PG = Bh 143 593, PG = Bh 623, PG = Bh 93, PG = MEDAM 1.3 equiv 603, PG = MEDAM 633, PG = MEDAM 583, PG = BUDAM 613, PG = BUDAM 643, PG = BUDAM Me Me tBu tBu Meo O O OMe MeO I ] OMe -;~ Me Me tBU tBU I ”1‘” Bh MEDAM BUDAM yield of ee yield of # PG ligand tel“ p. time cgmjl; transzcisb trans- o d enamines ( C) (h) ( 4’) azi (0/°)° ( /°) (%)b 1 Bh (R)-VAPOL o 19 91 12:1 65 69 17 e,f - O 12 , 2 Bh (n) VAPOL 25 24 100 13.1 72 7o 19 39'f Bh (S)-VAPOL 25 6 100 4:1 49 71 28 4 8h (S)-VANOL o 19 65 9:1 47 77 12 e,f _ 0 12 . 5 Bh (S) VANOL 25 24 100 6.1 59 80 22 6° MEDAM (S)-VANOL o 23 100 7:1 69 91 10 7g MEDAM (S)-VANOL o 23 100 7:1 73 87 <1 8h MEDAM (S)-VANOL o 24 100 12:1 84 90 1o 9 MEDAM (FD-VANOL o 19 100 11:1 81 89 9 1o MEDAM (S)-VANOL o 4 83 ND ND ND ND 11 MEDAM (S)-VANOL o 9 100 13:1 83 89 9 12' MEDAM (R)-VANOL o 24 100 12:1 81 92 10 46 (Table 3.1 continued...) 13' MEDAM (S)—VANOL o 18 100 10:1 84 90 7 14i MEDAM (S)-VANOL o 16 100 14:1 87 92 7 15j MEDAM (S)-VANOL o 18 100 8:1 75 84 2 16 MEDAM (S)-VANOL -4o 24 100 18:1 90 94 6 17 MEDAM (S)-VANOL -2o 24 100 21 :1 90 96 5 18 MEDAM (S)-VANOL 22 (rt) 18 100 5:1 69 67 16 19":I MEDAM (S)-VANOL 22 (rt) 16 100 5:1 71 88 8 20 MEDAM (S)-VAPOL o 20 100 4:1 63 7o 20 21 BUDAM (FD-VAPOL o 19 100 5:1 35 51 21 22 BUDAM (S)-VANOL 0 20 100 16:1 75 91 10 23h BUDAM (S)-VANOL -2o 24 100 27:1 74 89 13 24 BUDAM (S)-VANOL -4o 24 100 19:1 73 92 11 a Unless otherwise specified, all reactions were carried out with 0.1-0.3 mmol of imine at 0.1-0.2 M in imine. The catalyst was prepared by heating 1 equiv of ligand, 3 equiv of BH30$M62 (2 M in toluene), 2 equiv PhOH and 3 equiv of water at 100 °C for 1 h in toluene, followed by removing all volatiles at high vacuum (0.1 mm Hg) for 0.5 h at 100 °C. Stock solution of catalyst used. Reaction with (R)-ligand gives ent. trans-aziridine shown. ND = not determined. Reaction times have not been optimized. Crystallized imines used. b 1H NMR analysis of crude reaction mixture. ° Isolated yield after chromatography. d Chiral HPLC. e 20 mol% catalyst loading. f Catalyst prepared by heating 1 equiv of ligand, 4 equiv of B(OPh)3 and 1 equiv of water at 80 °C in toluene, followed by removing all volatiles at high vacuum (0.1 mm Hg) for 0.5 h at 80 °C. 9 10 mol% catalyst. h Average of two runs. i 1 day old stock solution of catalyst used. j 10 day old stock solution of catalyst used. k The cis aziridine was isolated in 14% yield and 77% 66 (see Section 3.4.10). ' Reaction run with 1 mmol of imine at 0.2 M in imine. 47 Table 3.2 Solvent study for the trans-aziridination protocola 5 mol% 0 (S)-VANOL-B3 catalyst MEDAM MEDAM~NH solvent N PhANMEDAM + (lLNmn e Ph\\,.L\fNHpn + (H)Ph \ ”(PM N2 H 24h, 0°C 0 o NHPh 9a 14a _ 60a 63a 1.3 equv lt'ilED AM + N PhArNHPh 0 65a yield 99 yield yield 89 # solvent conv. (%)b transzcisb 50% 50% 538D 5580 558d (%) (%) (%) (%) (%) 1° toluene 100 12:1 84 90 7 ND ND 2 xylenes 100 1 1 :1 83 90 8 ND ND 3 CeHsCFa 100 5:1 74 91 10 ND ND 4 CeHsCl 100 4:1 75 91 6 16 85 5 CH20I2 100 7:1 69 86 2 ND ND 6 CHCI3 100 6:1 77 89 7 ND ND 7 CCI4 100 5:1 78 88 6 ND ND 8 THF 80 2:1 28 -25 - 12 14 1o 9 Eth 100 4:1 60 41 26 ND ND 10 CHgCN 98 1:1 22 39 24 31 21 1 1 EtOAc 100 1 :1 37 39 25 32 13 12f cyclopentane 18 ND 15 90 ND ND ND 13"9 n-hexane 0 ND ND ND ND ND ND 14'4"h n-hexane 5 ND ND ND ND ND ND 8 Unless otherwise specified, all reactions were carried out with 0.1-0.2 mmol of imine at 0.1-0.2 M in imine. The catalyst was prepared by heating 1 equiv of ligand, 3 equiv of BH30$M92 (2 M in toluene), 2 equiv PhOH and 3 equiv of water at 100 °C for 1 h in toluene, followed by removing all volatiles at high vacuum (0.1 mm Hg) for 0.5 h at 100 °C. Stock solution of catalyst used. ND = 48 (Table 3.2 continued...) not determined. Reaction times have not been optimized. Crystallized 9a used. b 1H NMR analysis of crude reaction mixture. c Isolated yield after chromatography. d Chiral HPLC. 9 Average of two runs, reaction complete in 9 h. f Very poor solubility of catalyst-imine complex in solvent. 9 Reaction time was 48 h. h Reaction was carried out at room temperature. 3.4.2 The issue of trans-aziridine invertomers 1H NMR analysis of almost all isolated pure trans-aziridines reveals the presence of aziridine invertomers (two species). The ratio of these invertomers depends on the deuterated NMR solvent used, and also on the aziridine substrate itself. The ratio of invertomers for the trans-aziridine 60a in various deuterated NMR solvents is presented in Table 3.3. The ratio of invertomers for aziridine 60a in CDCI3 is usually 120.31, while the same ratio in DMSO-d6 is 120.06. DMSO-d6 gives predominantly one invertomer for almost all trans- aziridines, and is the solvent of choice for characterization of the trans-aziridines by NMR analysis. However, there have been certain trans-aziridines in this study for which even DMSO-d6 indicates a significant presence of both invertomers in the NMR analysis. NMR temperature experiments were carried out to check whether the signals from the invertomers for aziridine 60a would coalesce at high temperatures. Thus, solutions of 60a were made in 0606 and toluene-d3, and heated from 15 °C —> 25 °C —9 50 °C —> 70 °C and from 21 °C —> 40 °C —> 50 °C -> 60 °C —> 80 °C respectively, and 1H NMR analysis was carried out at each stage. While the respective peaks for the two aziridine invertomers were sharp at lower temperatures, the same peaks broadened at higher temperatures and ‘49 gradually disappeared into the baseline. These peaks did not coalesce at higher temperatures as expected. Table 3.3 Ratio of invertomers for 60a in deuterated NMR solvents Entry Solvent Ratio of invertomers for 60a‘al Polarity of solventb 1 DMSO-dg 120.06 A 2 CD3CN 1:0.4 3 CD30H 1:0.22 4 acetone-d5 1 20.25 5 THF-d3 1:0.32 6 C02CI2 120.35 7 CDCI3 120.31 8 EtZO-dto 1:0.08 9 C506 120.65 10 toluene-d3 120.63 a lnvertomers have not been assigned. b Taken from “Solvent selection guide”, Pirrung, M. C. The Synthetic Organic Chemist’s Companion, John Wiley 8 Sons, lnc., Hoboken, New Jersey, 2007. The conversions, transzcis ratios and yields of enamines for the trans- selective aziridinations are usually calculated on the basis of the 1H NMR analysis of the crude reaction mixture in CDCI3. For the relative integrations, the trans-aziridine ring methine proton signals are taken into consideration. For the major invertomer, these methines usually exhibit sharp doublets (J = 2-3 Hz) in the region of 2-4 ppm. For the minor invertomer, these are small broad singlets in the same region. The minor diastereomers, the cis aziridines, are single species and do not show invertomers as do the trans-aziridines. Thus, for the relative integrations, the cis-aziridine ring methine proton signals (sharp doublets, J = 68 Hz, 2-4 ppm) are taken into consideration. For the enamines, the signals from the '50 N-H proton (doublets or doublet of doublets, 8-10 ppm) are considered. Before the practitioners get comfortable with the trans-aziridination protocol, they are advised to isolate the trans-aziridine, confirm the location of the signals from the two invertomers, and then revert to the crude 1H NMR analysis to calculate the necessary ratios of products. 3.4.3 The diazoacetamide substrate scope After the completion of the initial optimization, we set out to explore the generality of our new trans-aziridination protocol. In the secondary diazoacetamide screen (Table 3.4), both aryl and alkyl groups performed well. Both electron rich and electron deficient phenyl rings gave excellent results (Entries 9, 10, 12). Alkyl diazoacetamides were outstanding substrates, and gave near perfect asymmetric inductions under their optimized conditions (Entries 19, 22). These are the first examples for alkyl groups on the diazoacetamide component in the asymmetric trans-selective imine aziridination literature‘3'15. Table 3.4 The diazoacetamide substrate scopea 5mol% o ligand-B3 catalyst MEDAM MEDAM‘NH toluene N PhAN'MEDAM + HN’R : '3th R + (H)ph/L\:H(Ph) H “ ‘ N2 24 h, temperature 0 O u,R 9a 14 1.3 equiv , yield ee yield R . temp conv. trans. . . . . # ligand b .b aznr. am. am. enamines diazo °C % CIS o O d o b l l ( l ( l (/..)c (/o) (4.) 1° Ph (S)-VANOL o 100 12:1 84 90 10 60a 2 (14°) (S)-VANOL -20 100 21:1 90 96 5 51 (Table 3.4 continued...) 3"9 (S)-VANOL o 7 ND ND ND ND 4’ ””8336” (S)-VANOL 22 23 4:1 66b ND ND ND 5' (R)-VAPOL o 0 ND ND ND ND 6 (S)-VANOL o 53 9:1 40 80 6 7":i ”11:3?“ (FD-VANOL o 54 821 66c 30 78 6 Bj'k (S)-VANOL o 77 8:1 58 78 13 9 (S)-VANOL o 100 13:1 75 91 11 10 ”0336*“ (Ft)-VANOL o 100 13:1 66d 84 93 1o 11 (FD-VANOL -2o 74 19:1 ND ND ND 12 S-VANOL 100 13:1 82 92 8 p-CIC6H4 ( ) 0 668 13 (14°) (R)-VANOL -2o 53 18:1 ND ND ND 14 (S)-VANOL o 100 3:1 62 94 8 15 (FD-VANOL o 100 3:1 60 94 9 16 En (S)-VANOL -20 100 5:1 78 97 5 66f 17 (14') (R)-VANOL -4o 76 10:1 ND ND ND 18j (S)-VANOL -4o 81 10:1 73 98 1 19' (S)-VANOL -40 100 10:1 88 98 3 20 (S)-VANOL o 100 3:1 62 95 10 21 ”Bu (FD-VANOL o 100 4:1 669 66 96 13 22 (‘49) (FD-VANOL -20 100 8:1 84 98 6 23 (S)-VANOL -4o 68 1 1 :1 ND ND ND a Unless otherwise specified, all reactions were carried out with 0.2 mmol of imine at 0.2 M in imine. The catalyst was prepared by heating 1 equiv of ligand, 3 equiv of BHaoSMez (2 M in toluene), 2 equiv PhOH and 3 equiv of water at 100 °C for 1 h in toluene, followed by removing all volatiles at high vacuum (0.1 mm Hg) for 0.5 h at 100 oC. Stock solution of catalyst used. ND = not determined. Reaction times have not been optimized. Reaction with (R)-ligand gives ent. 52 (Table 3.4 continued...) trans-aziridine shown. Crystallized 9a used. b 1H NMR analysis of crude reaction mixture. ° Isolated yield after chromatography. d Chiral HPLC. 9 Average of two runs, reaction complete in 9 h. f Low conversion probably due to very poor solubility of diazo in toluene. g Average of two runs. h Reaction time 66 h. i Some compound spilled during work-up leading to low yield. 1 Reaction time 48 h. k 10 mol% catalyst. I 0.1 mmol imine scale, 0.1 M in imine, 10 mol% catalyst. Scheme 3.4 Cis-aziridination with N-methyl-N-benzyldiazoacetamide 67 20 mol% 0 (S)-VANOL-B3 MEDAM B catalyst N Me N M e toluene (0.2 M) n 2 rt, 24 n 0 9a 67 68 0.2 mmol 1.3 equiv 39% conversion no trans-aziridine seen (cisztrans = >50:1) no enamines seen 32% yield 93% ee 5 mol% 0 (S)-VANOL-B3 MEDAM MEDAM catalyst N H N H A ,MEDAM + 'JL .Bn 2 , + P“ N '1‘ u toluene (0.2 M) Ph‘“ WN‘Bn Ph/LWN‘Bn (eq 2) 2 rt, 10 min 0 0 9a 14f 66f 69 0.1 mmol 1.3 equiv 36% yield (isolated) 21% yield (isolated) 86% ee 70% ee 70% conversion 1.621 transzcis 13% yield (enamines, crude 1H NMR) In our original aziridination protocol, the reactions between various diarylmethylimines and ethyldiazoacetate provided the corresponding cis- aziridines (Chapter 2). In the work discussed in this chapter, simply switching to diazoacetamides affords the opposite diastereomers, the trans-aziridines. The N- H bond of the diazoacetamide has been found to play a pivotal role in this reversal of diastereoselectivity (further discussion in Chapter 7). Indeed, if the N- '53 H bond is removed from the diazoacetamide, and replaced with a group not capable of H-bonding, the diastereoselectivity of the reaction reverts again to afford the corresponding cis-aziridines. This is exemplified in Scheme 3.4, where the reaction of N-methyl-N-benzyldiazoacetamide‘0'31 67 and imine 9a gives exclusively the corresponding cis-aziridine 68 with excellent asymmetric induction (eq 1). This reaction is quite sluggish, and is compared to the corresponding reaction of diazoacetamide 14f (eq 2). 3.4.4 The aryl imine substrate scope For the imine substrate scope, those prepared from aryl aldehydes were explored first (Table 3.5). A wide range of aromatic imines with varying electronic and steric demands gave excellent diastereoselectivities, yields and asymmetric inductions for the corresponding trans-aziridines. Both electron rich and electron deficient aryl imines were well tolerated. The imine 9e bearing the 4- methoxyphenyl moiety had completely failed for the other trans-selective imine 13215, giving messy mixtures and low aziridination systems in the literature conversions. In our protocol however, this substrate performed very well, giving the corresponding trans-aziridine 60e in 66% yield and 94% ee (average from Entries 14, 15). Sterically demanding substrates have also not been reported in these other trans-selective aziridination systems in the literature‘3'15. We took up this challenge and designed a substrate possessing a 2-chlorophenyl moiety (99) and an ortho-di-substituted substrate with a 4-bromo-2-fluorophenyl moiety (9j). Both these imines performed exceedingly well, the former providing 84% yield 54 and 98% ee (Entry 25) and the latter providing 74% yield and 95% ee (Entry 37) for their corresponding trans-aziridine products. Table 3.5 The aryl imine substrate scopea x mol% \ M E DAM Ph toluene '1' NH RAN’ + (“\u’ 24 h tem erature 7 \" ‘ (HR \ HR) N2 . p R CONHPh CONHPh 9 14a so 63 1.3 equiv , yield 99 yield R . x temp. b trans. # . llgand o o conv. (%) , b 60 60 63 (serles) (/o) ( C) CIS (%)c (%)d (%)b 1° Ph (5)-VANOL 5 o 100 12:1 84 90 1o 2 (a) (S)-VANOL 5 -20 100 21 :1 90 96 5 3 pCH3C6H4 (S)-VANOL 5 o 100 14:1 84 95 6 4 (b) (S)-VANOL 5 -2o 19 ND ND ND ND 5 (S)-VANOL 5 o 100 18:1 87 97 5 6 8336”“ (R)-VANOL 5 o 100 16:1 85 94 7 7 (S)-VANOL 5 -2o 82 36:1 74 99 3 8 (S)-VANOL 5 o 100 1 1 :1 80 92 1 1 9 p-N02C5H4 (S)-VANOL 5 -2o 96 18:1 85 93 7 10 (d) (FD-VANOL 5 -2o 92 19:1 81 93 6 1 1 (S)-VANOL 5 -4o 22 ND ND ND ND ' 12 (FD-VANOL 5 o 37 9:1 ND ND ND 13 (S)-VANOL 10 o 100 6:1 61 89 9 149 ”O“:396H4 (S)-VANOL 15 o 100 8:1 69 96 8 15“:i (S)-VANOL 15 o 100 6:1 62 91 7 16h'i (S)-VANOL 20 -2o 70 16:1 ND ND ND '55 (Table 3.5 continued...) 179'j (S)-VANOL 5 o 100 1 1 :1 82 87 8 139-1 (R)-VANOL 5 o 100 9:1 79 81 1o 199'j ”0730*“ (FD-VANOL 5 -2o 12 ND ND ND ND 2092‘ (S)-VANOL 10 -2o 55 9:1 ND ND ND 21Mk (S)-VANOL 20 -20 100 12:1 87 9o 4 229'j (S)-VANOL 5 o 100 14:1 78 90 16 23 oCICth (FD-VANOL 5 o 100 11:1 75 89 17 24 (9) (R)-VANOL 5 -2o 82 30:1 ND ND ND 25 (R)-VANOL 10 -20 100 26:1 84 98 13 26j (S)-VANOL 5 o 100 1 1 :1 76 92 1o 27j ”’OmC‘SH‘i (FD-VANOL 5 o 100 9:1 75 93 9 28j (S)-VANOL 10 -20 100 9:1 74 97 6 29j (FD-VANOL 5 o 62 1 1 :1 ND ND ND 3oj (R)-VANOL 5 -2o 26 ND ND ND ND 31j 2'”ag)mhy' (FD-VANOL 10 -2o 33 ND ND ND ND 32j (R)-VANOL 10 o 100 7:1 81 81 8 33j (S)-VANOL 10 o 100 7:1 79 81 9 34 (S)-VANOL 5 o 84 5:1 62 92 10 35 4_Br-2_F-C6H3 (Fi)-VANOL 5 o 91 5:1 66 90 10 36 (I) (S)-VANOL 5 -2o 82 821 ND ND ND 37 (S)-VANOL 10 -20 100 7:1 74 95 1 1 8 Unless otherwise specified, all reactions were carried out with 0.2 mmol of imine at 0.2 M in imine. The catalyst was prepared by heating 1 equiv of ligand, 3 equiv of BHaoSMeg (2 M in toluene), 2 equiv PhOH and 3 equiv of water at 100 °C for 1 h in toluene, followed by removing all volatiles at high vacuum (0.1 mm Hg) for 0.5 h at 100 °C. Stock solution of catalyst used. ND = not determined. Reaction times have not been optimized. Reaction with (FD-VANOL gives ent. 60. Crystallized imines used. b 1H NMR analysis of crude reaction mixture. ° Isolated yield after ‘56 (Table 3.5 continued...) chromatography. d Chiral HPLC. 6 Average of two runs, reaction complete in 9 h. ' The chiral HPLC conditions were verified by running two additional experiments (not shown), with (S)- and (FD-VANOL, which ave unreliable transzcis ratios, but identical ee’s. g 0.133 M in imine. h 0.1 9 mmol scale in imine. I0.1 M in imine.J Crude imine used. k 0.07 M in imine. 3.4.5 The alkyl imine substrate scope We knew that the real test of our trans-selective aziridination would be the imines prepared from alkyl aldehydes; such examples are unprecedented in this field”:15 . lmines prepared from 1°, 2° as well as 3° alkyl aldehydes provide excellent results in our cis-selective aziridinations;6‘12 we strongly felt that these should be successful in our trans-selective aziridinations too, for us to be able to develop a universal catalytic asymmetric aziridination protocol. Table 3.6 Trans-aziridination of the cyclohexyl (2° alkyl) imine substratea x mol% 0 ligand-B3 catalyst 'IDG \N’PG R toluene N O/\ + ll/‘LN’ ; ‘CONHR N2 H 24 h, temperature _ 1.3 equiv 9k, PG — MEDAM 14a, R = Ph 1": PG'B“ 14f R=Bn 58k, PG - BUDAM 14g,'R = n-Bu . x temp. . conv. yield of trans-azi ee # PG R It and o ,, az r. o o o 9 Va) ( C) ' (4)b we)" <4)d 1 MEDAM Ph (S)-VANOL 5 0 60k 0 - - 2 MEDAM Bn (S)-VANOL 5 0 70f low conversion 3 MEDAM Ph (FD-VAPOL 10 22 60k 100 73 59 4 MEDAM Ph (S)-VAPOL 10 22 60k 100 70 52 57 (Table 3.6 continued...) 5° MEDAM Ph (Fi)-VANOL 10 22 60k 100 57 25 6 MEDAM Bn (FD-VANOL 10 22 701 100 34 22 7 MEDAM n-Bu (FD-VANOL 10 22 709 100 28 8 8 MEDAM Ph (3)-VAPOL 10 0 60k 35 19 68 9 MEDAM Ph (FD-VANOL 10 0 60k 69 43 32 10 MEDAM Ph (S)-VANOL 10 0 60k 82 50 30 1 1 Bh Ph (R)-VAPOL 20 0 59k 100 61 43 12 Bh Ph (S)-VANOL 20 0 59k 100 57 47 13 BUDAM Ph (S)-VANOL 20 0 61k 100 62 26 14 BUDAM Ph (FD-VAPOL 20 0 61k 100 61 70 15 BUDAM Ph (FD-VAPOL 20 0 61k 100 66 70 16 BUDAM Ph (FD-VAPOL 10 0 61k 100 66 73 17 BUDAM Ph (S)-VAPOL 20 -20 61k 100 67 50 18 BUDAM Ph (FD-VAPOL 20 -20 61k 100 72 49 19f BUDAM Ph (S)-VAPOL 20 -40 61k 69 55 53 20 BUDAM Ph (FD-VAPOL 20 rt (22) 61k 100 62 69 a Unless otherwise specified, all reactions were carried out with 0.2 mmol of imine at 0.2 M in imine. The catalyst was prepared by heating 1 equiv of ligand, 3 equiv of BHaoSMez (2 M in toluene), 2 equiv PhOH and 3 equiv of water at 100 °C for 1 h in toluene, followed by removing all volatiles at high vacuum (0.1 mm Hg) for 0.5 h at 100 °C. Stock solution of catalyst used. Trans:cis ratios and yields of enamines = not determined, due to overlapping/unidentified signals in crude 1H NMR. Reaction times have not been optimized. Reaction with (FD-ligand gives ent. trans-aziridine shown. Crystallized imines used. b 1H NMR analysis of crude reaction mixture. ° Isolated yield after chromatography. d Chiral HPLC. ° Trans:cis = 1121, determined from isolated yields of the cis- and trans-aziridines. f48 h reaction time. Initial results in this regard were disappointing. Under our optimized conditions (MEDAM protecting group, 5 mol% VANOL catalyst, 0 °C), the imine '58 with a cyclohexyl group (2° alkyl) gave no reaction at all (Table 3.6, Entry 1)! This made us launch an extensive optimization for this substrate, and the results are presented in Table 3.6. The best result that could be obtained for this substrate was only 66% yield and 73% ee (Entry 16). The optimized conditions for this alkyl imine substrate were surprisingly different as compared to those for the aryl imine model substrate 9a (Table 3.1). BUDAM gave better results for the reaction rates as compared to MEDAM (compare Entries 16 vs. 8), and VAPOL was superior to VANOL for the asymmetric inductions (compare Entries 14 vs. 13). The first 3° alkyl substrate (t-butyl) examined was outstanding in its performance, and afforded exclusively the trans-aziridine product in 90% yield and 90% ee (Table 3.7, Entry 3). The BUDAMNAPOL combination again was better for this substrate, albeit by a much smaller margin as compared to the cyclohexyl imine substrate. Table 3.7 Trans-aziridination of the t—butyl (3° alkyl) imine substratea x mol% 0 ligand-B3 catalyst PG PG. NH \ toluene N ,PG Ph t X“ + N’ = ,.L\ + H tl3 JEN Bu) “'1 H 24 h, temperature a“ CONHPh ( ) u 2 CONHPh 9|, PG = MEDAM 1.3 equiv 60I, PG = MEDAM 58l, PG = BUDAM 14a 61I, PG = BUDAM # 'm'n l' nd x temp. conv. trans: yield 99 yield ' ' 9 19a (%) (°C) (%)b cisb trans-azi (%)° (%)d enamines (%)b 1 58I (S)-VANOL 20 0 81 1721 65 80 <1 2 58I (FD-VAPOL 20 0 1 00 26:1 85 83 2 3 58I (S)-VAPOL 20 -20 1 00 >50:1 90 90 <1 4 58I (R)-VAPOL 1 0 -20 1 00 >50:1 88 89 2 59 (Table 3.7 continued...) 5 9| (R)-VAPOL 20 0 66 8:1 49 75 <1 6 9| (S)-VANOL 20 0 95 1 7:1 68 88 3 8 Unless othentvise specified, all reactions were carried out with 0.2 mmol of imine at 0.2 M in imine. The catalyst was prepared by heating 1 equiv of ligand, 3 equiv of BH30SM92 (2 M in toluene), 2 equiv PhOH and 3 equiv of water at 100 °C for 1 h in toluene, followed by removing all volatiles at high vacuum (0.1 mm Hg) for 0.5 h at 100 °C. Stock solution of catalyst used. Reaction times have not been optimized. Reaction with (R)-ligand gives ent. trans-aziridine shown. Crystallized imines used. b 1H NMR analysis of crude reaction mixture. ° Isolated yield after chromatography. d Chiral HPLC. Other 1°, 2° and 3° alkyl imines were subsequently evaluated with the BUDAM protecting group, and all could be optimized to provide good to excellent results for their corresponding trans-aziridine products (Table 3.8). Table 3.8 Trans-aziridination of other 1°, 2° and 3° alkyl BUDAM iminesa xmol% A BUDAM + Ph to'uene — N + H R R N, I n a ,.L\ (H)R \ ( ) N2 24 h, temperature R‘ CONHPh C ONHPh 58m, R = Et 1.3 equiv 61 64 58n, R=i-Pr 14a WWBUDAM 580 . . . x temp. b trans: yield 69 61 yield # °o . lmine llgand (%) (°C) conv. U) Cle 61 (%)c (%)d 64 (%)b 1 58m (S)-VANOL 20 0 100 ND° 66 88 27 2 58m (FD-VANOL 20 0 100 310° 68 87 27 3 58m (FD-VANOL 10 0 100 No° 67 82 17 4 58m (FD-VANOL 20 -20 100 ND° 63 80 21 5 58m (FD-VAPOL 20 0 100 No° 51 2 27 6 58m (S)-VAPOL 20 0 100 310° 57 54 27 '60 (Table 3.8 continued...) 7f 58o (FD-VAPOL 20 0 55 ND ND ND ND 8f 58o (S)-VANOL 20 0 28 ND ND ND ND 9f 58c (FD-VAPOL 20 rt 25 ND ND ND ND 10"9 58o (FD-VAPOL 20 0 70 5:1 53 81 6 1 1 58h (S)-VANOL 20 0 100 190° 60 58 310° 12 58h (FD-VAPOL 20 0 100 ND° 73 81 No° 13 58h (S)-VAPOL 20 0 100 No° 68 83 No° 14 58h (S)-VAPOL 10 0 100 No° 67 83 No° 15 58h (3)-VAPOL 20 -20 100 ND° 69 74 No° 16 58h (S)-VAPOL 10 -20 100 No° 70 75 ND° 3 Unless otherwise specified, all reactions were carried out with 0.2 mmol of imine at 0.2 M in imine. The catalyst was prepared by heating 1 equiv of ligand, 3 equiv of BH30SM62 (2 M in toluene), 2 equiv PhOH and 3 equiv of water at 100 °C for 1 h in toluene, followed by removing all volatiles at high vacuum (0.1 mm Hg) for 0.5 h at 100 °C. Stock solution of catalyst used. Reaction times have not been optimized. Reaction with (FD-ligand gives ent. trans-aziridine shown. Crystallized imines used. ND = not determined. b 1H NMR analysis of crude reaction mixture. c Isolated yield after chromatography. d Chiral HPLC. 9 Not determined, due to overlapping/unidentified signals in crude 1H NMR. t Crude imine used, 0.08 M in imine. 9 67 h reaction time. 3.4.6 Puzzling aziridination reactions of two substrates When the aziridination reactions of imines 9p40 and 40b were attempted, the 1H NMR analysis of the crude reaction mixture revealed the presence of the corresponding cis-aziridines as the major diastereomers (Scheme 3.5). The reaction with imine 9p was especially very clean, and a 90% NMR yield was observed for the cis-aziridine product. The reasons behind the reversal of diastereoselection for these imines are not understood at the moment; these reactions were not pursued any further. 61 Scheme 3.5 Puzzling aziridination reactions of two substrates O 10 mol% MEDAM \N’MEDAM (S)-VANOL-B3 catalyst N H / + ")LNHPh #7 N. P“ N toluene (0.2 M) é P“ 2 0 °C, 24 h Ph 0 9p 14a 100% conversion 71 0.2 mmol 1.3 equiv 1:9 trans:cis 90% NMR yield 0 10 mol% MEDAM S -VANOL-B catal st A ,MEDAM , ( ) 3 Y _ N H EtO2C N | NHPh ' N. N toluene (0.2 M) EtO2C Ph 2 0 °C, 24 h 0 40b 14a 100% conversion 72 0.2 mmol 1.3 equiv 1:2 trans:cis 3.4.7 Temperature vs. diastereoselectivity in the trans-aziridinations A study to monitor the diastereoselectivities in the trans-aziridination reactions as a function of the reaction temperature was carried out, and the results for the aziridines 60a and 66f are presented in Table 3.9. The trans:cis diastereoselectivity gradually decreased with increasing temperature, and eventually switched over to marginally favor the cis aziridines under refluxing conditions. However, this was accompanied by concomitant erosion in the quality of the reactions; the reaction conversions to the aziridine products decreased significantly and the imine was recovered unreacted, presumably due to the decomposition of the diazoacetamide at high temperatures. Decomposition of related trans-aziridine carboxylate esters has been previously noted by HossainSID and Mayer“, which might be a factor affecting the observed diastereoselectivies in the present study. However, this idea was not investigated any further. ‘62 Table 3.9 Temperature vs. diastereoselectivity in the trans-aziridinations 5 mol% (S)-VANOL-B3 catalyst MEDAM \ MEDAM R solvent N PhAN' + “/‘LN’ = Ph““ NHR H 10 min - 24 h N2 temperature 0 14a, R = Ph 60a, R = Ph 14f, R = Bn 66f, R = Bn 1.3 equiv Entry R solvent temp. (°C) trans:cisal 1b Ph toluene -40 18:1 2b Ph toluene -20 21 :1 3° Ph toluene 0 12:1 4c Ph xylenes 0 1 121 5b Ph toluene 22 (rt) 5:1 6 Ph xylenes 60 3:1 7d Ph xylenes 100 121.5 8° Ph CHgCN 0 1:1 9° Ph CH3CN 22 (rt) 1 :1 .3 10° F“ CHaCN 60 1:2 1 1f Bn toluene -40 10:1 12f Bn toluene -20 5:1 13f Bn toluene 0 3:1 149 En toluene 22 (rt) 1.621 1 5d Bn xylenes 100 1 :2 3 Crude 1H NMR analysis. b Table 3.1. c Table 3.2. d Mostly diazoacetamide decomposition, traces of aziridines. e Enamines were the major products. f Table 3.4. 9 Scheme 3.4. 63 3.4.8 All four stereoisomers of 3-aziridine-2-carboxylates After confirming the generality of our substrate scope, we sought to demonstrate the universality of our aziridination protocol. The amide group in trans-aziridine 60a was smoothly converted to the corresponding ethyl ester (Scheme 3.6).41 Thus, the trans-aziridine 73 could be obtained with an overall yield of 86% and 96% ee from imine 9a via our trans-aziridination protocol. Of course, switching the enantiomer of the VANOL ligand in the trans-aziridination would give us access to the enantiomer of 73. Scheme 3.6 All four stereoisomers of 3-aziridine-2-carboxylates 1) (Boc)2O, DMAP MEDAM DCM/ACN, 22 °C, 1 h MEDAM MEDAM N 2) NaOEt, EtOH, 0 °C, 1 h N N ,. t (,c OEt fir, OEt Ph“ WNW 96% P“ W P“ ll’ 0 (2 runs) 0 0 60a 73 ent. 73 (86% yield, 96% ee (from imine 9a from imine 9a using R-VANOL) using S-VANOL) MEDAM MEDAM N A Ph/Lfi/OEt PW... ..,,n,0Et O O 74 ent. 74 (94% yield, 97% ee (from imine 93 from imine 9a using R-VANOL) using S-VANOL, and ethyldiazoacetate) Through our previous work, we have shown that we can access the diastereomers of 73, the cis-aziridine 74 and its enantiomer, in 94% yield and 97% 96 starting from the same imine 9a and using 5 mol% of the same catalyst prepared from the VANOL ligand, by simply switching to ethyldiazoacetate instead of phenyldiazoacetamide.1O 64 Thus, we can now access, in an efficient and straightfonlvard manner,42 all four possible stereoisomers of these 3-aziridine-2-carboxylates — synthetic intermediates of seminal importance in organic synthesis“3 — via our universal catalytic asymmetric aziridination protocol (Scheme 3.6). 3.4.9 TfOH catalyzed aziridination reactions Switching from a diazoacetate to a diazoacetamide completely reversed the diastereoselectivity of our aziridination reactions. We were interested to check if this reversal was specific to our 3;; catalysts. Thus, the imine 1b was reacted with ethyldiazoacetate 2 and N-phenyldiazoacetamide 14a in the presence of catalytic amounts of TfOH (Scheme 3.7).22-The reaction with 2 furnished the corresponding cis-aziridine as the major diastereomer, while the trans-aziridine was formed as the major diastereomer in the reaction of 14a. Thus, the reversal of diastereoselectivity in our catalytic asymmetric aziridinations was not specific to our 83 catalysts only; rather it seemed to be solely due to the diazo component. Removal of the N-H from the Nphenyldiazoacetamide 14a, via the use of N-methyl-N-benzyldiazoacetamide 67, had resulted in the re-reversal of the diastereoselectivity for the reaction of imine 9a catalyzed by the VANOL-B3 catalyst, furnishing the cis-aziridine 68 exclusively as the major diastereomer (Scheme 3.4). The same re-reversal was seen with diazoacetamide 67 for the triflic acid catalyzed reactions also, where again the cis-aziridine was observed as the major diastereomer (Scheme 3.7). '65 Scheme 3.7 TfOH catalyzed aziridination reactions o OEt N2 1.3 equiv 6h 6h Bh‘NH 2 A ,Bh e N + N + \ H(Ph) + 1b Ph N H Ph 25 mol% TfOH A A, ( ) 1b toluene (0.2 M) P“ C02‘Et P“ C02Et 0023 0.2 mmol rt, 22 h 6 : 1 : 3 : 0 (crude 1H NMR ratios) cis : trans : enamines : s. m. imine o “/‘LNHPh Bh. N2 1.3 equiv 6h Rh NH A ,Bh “3 s N + + + 1b Ph N 10 mol% TfOH / "I A (H)Ph \ ”(PM to uene( . ) 0.2 mmol _20 8C 23 h 1 rt 2’ h 2 : 1 : 2 : 1 (crude H NMR ratios) trans : cis : enamines 2 s. m. imine O ,Bn Ht N2 Me 1'3 equiv Eh Me Eh Me decomposition 67 2 Ph/PN’Bh ' N. + #' k + 1b + products 20 mol% TfOH Ph Bn Ph "n’ Bn (significant) 0 2") I toluene (0.2 M) O O . mm° -10°C, 20h rt, 1 h 3 : 1 : 11 (crude 1H NMR ratios) cis : trans : s. m. imine 12% cis : 4% trans : 38% imine (NMR yields, with internal standard Ph3CH) 3.4.10 General absolute configurations in the universal aziridination The absolute configuration of the major diastereomer, the cis aziridine, in our cis-selective aziridinations with ethyldiazoacetate has been previously determined by chemical derivatization.6 The cis aziridine in these reactions results from a Si face attack of the diazoacetate on the (S)-catalyst-imine complex; the same facial selectivity was also determined for the cis-aziridine 3e formed from the reaction of the o-bromophenyl benzhydryl imine 1e (see Section 66 2.2, Chapter 2). The reaction with the o-bromophenyl benzhydryl imine 1e has been the only reaction in our cis-selective aziridinations with ethyldiazoacetate that has given us isolable quantities of the minor diastereomer, the trans-aziridine 30 (see Section 2.2, Chapter 2). Determination of the absolute configuration then surprisingly led to the discovery that the trans-aziridines in this protocol result from a Fie face attack of the diazoacetate on the (S)-catalyst-imine complex. Thus, the facial selectivity of the aziridinations with ethyldiazoacetate is opposite for the cis- and trans-aziridine diastereomers with the same enantiomer of the catalyst-imine complex. In the present study of the trans-selective aziridinations with diazoacetamides, the absolute configurations of both the major and minor diastereomers, the trans- and cis-aziridines respectively, have been determined by chemical derivatization (Scheme 3.8). The aziridines were converted to the corresponding Boc protected a—aminoamides, and their optical rotations were compared to literature values. Surprisingly again, opposite facial selectivity was observed for the trans- and cis-aziridine diastereomers with the same enantiomer of the catalyst-imine complex. The trans-aziridines in this protocol result from a He face attack of the diazoacetamide on the (3)-catalyst imine complex, whilst the cis-aziridines result from a Si face attack of the diazoacetamide on the same catalyst-imine complex. Thus, the absolute configurations in our universal aziridination protocol can be generalized as follows. Irrespective of the diazo compound (ethyldiazoacetate or diazoacetamides) and irrespective of the 67 diastereoselectivity of the aziridination reaction (cis- or trans-selective), all cis aziridines in our protocol result from a Si face attack of the diazo compound on the (5)-catalyst-imine complex, whilst all trans aziridines result from a Fie face attack of the diazo compound on the same catalyst-imine complex. This generalization is exemplified for the aziridination reactions with the (S)- VAPOL/VANOL-83 catalyst in Scheme 3.9. Scheme 3.8 Absolute configurations in the trans-selective aziridinations \ Ph/\N,MEDAM 9a 5 mol% 1 "WC” (S)-VANOL-B3 cat. EEDAM EEDAM + > + o toluc-Etne1 53052 M) Pn\“‘3 2‘CONHPh Ph’ 3 2‘CONHPh l N'P“ (2R,38)'60a (2R,3R)-653 N H 100% conversion 71% yield 14% yield 2 14a 5:1 trans:cis 38% ee 77% ee 1'2 “U” 26 h 25% Pd(OH)2/C 40 h ( , rt, MeOH, (Boc)20 1 atm H2 S NH h Ph CO P NHBOC Ph/\|R’/CONHPh Ph/\R/CONHPh Literature values for optical rotation: i i c = 1, MeOH, +229 (ref. 43) NHBOC NHBoc c = 2, CHZCIZ, —37 (ref. 44) 75 75 L J 76% yield 66% yield Optical rotations obtained: Optical rotations obtained: C = 1, CH2C|2, +165 C = 1, CH2C|2, +17.9 c = 1, MeOH, -29.8 c = 0.5, MeOH, -14.7 10 mol% Pd(OH) IC MEDAM 2 I 1 atm H2, 22 °C, 6 h s CONHPh CONHPh N e Ph/Y + Ph Ph/agz'EONHPh MeOH. (Boc)2O NHBoc NHMEDAM (28,3R)-60a ent. 75 76 91 % ee 13% yield 62% yield Optical rotations obtained: 0 = 0.4, CH2C|2, -25.6 c = 0.4, MeOH, +261 68 Scheme 3.9 General absolute configurations in the universal aziridination Ar (S)-VANOL/VAPOL “\r A' NY A' B3 catalyst N N N Ar = R' R' 9' 0 RW WW (“\RI 0 0 N2 (25’. 3B) (2R, :8) , ,, crs-aZIrdlnes trans-aZIrdlnes R = NHR or OEt from Si face from Re face addition addition 3.4.11 Attempts at deprotection of the trans-aziridines The cis-aziridines from our aziridination reactions with ethyldiazoacetate and imines derived from the MEDAM/BUDAM amine have been previously shown by others in our group to undergo smooth and efficient deprotection with TfOH, revealing the corresponding N-H aziridines.9'1o All attempts at deprotecting the trans-aziridines obtained in the study described in this chapter under similar conditions did not give clean reactions or the same high yields. Quite a few other variations were attempted for the deprotection, however none were found to work satisfactorily; these attempts are summarized in Table 3.10. 69 Table 3.10 Attempts at deprotection of the trans-aziridines"l # Substrate Conditions Results H N Ph‘“. CONHPh 77 22% yield OMe 1 5 equiv TfOH anisole, rt, 30 min Ph CONHPh NH2 MEDAM 78 N 49% yield 2 Ph“" \CONHPh 10 GQUi‘0("8C/::r2tsgh in TFA) mostly ring-opened prod1ucts _ 60a 60 °C, 45 min, anisole no deSlred product in crude H NMR 5 equiv TfOH, CH3CN 3 0 °C, 15 h 77 (35% yield) + 60a (50% yield) rt, 1 h 4 5 equiv TfOH, CH30N 77 (21 % yield) + mostly ring opened __ rt, 20 h products 5 equiv TfOH, CH3CN . 77 44% I i 43 h, 0 °C ( y'e d) Ph \ CONHPh 77 6 D00 (1.2 equiv) NHMEDAM . DCM2H20 (5:1), rt, 20 h 79 5% VIEW 27% yield (tentative assignment) MEDAM fl 7 (N3 5 equiv TfOH, 0 °C to rt, pw‘“ ‘COzEt ph\“' COZEt 3 h, anisole 80 73 ~14% yield (isolated with impurities) H MEDAM AN 8 iii 8 equiv TfOH, CH3CN Ar‘” CONHPh (WA 0 °C, 24 h 81 Ar CONHPh 67% conversion 60f Ar = 4-Br-2-FC6H3 9 Ar ‘ 4’B"2'FC6H3 3 equiv TfOH, CH3CN 81 (53% yield) 0 °C to rt, 3 h 8' Isolated yields reported after chromatography on silica gel. 70 3.4.12 Puzzling origins of the stereoselections in our universal aziridination Thus, switching from a diazoacetate to a diazoacetamide completely and cleanly reversed the diastereoselectivity as well as the face selectivity of imine addition in our aziridination reactions. While this result was very welcome, and helped us develop the first universal aziridination protocol in the literature, the mechanistic origins of these opposite diastereo- and facial- selections fascinated us, and intrigued us to great ends. We decided to seek answers with the aid of computational chemistry, and thus initiated a collaborative project with Dr. Mathew Vetticatt (Albert Einstein College of Medicine, New York). The results from this separate study have been remarkably satisfying, and will be reported in Chapter 7. 71 CHAPTER FOUR CATALYTIC ASYMMETRIC TRANSFER HYDROGENATION OF 2- QUINOLINES: AN EXPERIMENTAL AND COMPUTATIONAL STUDY 4.1 Introduction A considerable amount of time during this dissertation was spent trying to develop a catalytic asymmetric transfer hydrogenation of quinolines, mediated by the VAPOL/VANOL Spiro-boroxinate Bronsted acid catalysts. The products of such a protocol would be 1,2,3,4-tetrahydroquinolines, structural motifs of significant importance in the pharmaceutical and fine chemical industry, as well as in the material sciences.47 This core is also common in numerous alkaloid natural products.48 Several successful systems exist for the asymmetric reduction of quinolines using organometallic catalysts.49 Successful organocatalytic systems for the asymmetric transfer hydrogenation of quinolines using the Hantzsch ester as the hydrogen source have been recently reported, mediated by phosphoric acid catalysts derived from the BINOL ligand.50 Scheme 4.1 A collaborative effort with the Odom group 1)Ti catalyst NH2 2) AcOH C H one-pot \ (:l + ¢/ 5 11 + CNBut Odom group: W 87 "’ W ""’ W N 'i H Me 88 89 (—)-Angustureine 72 This project initially started out as a collaborative effort between our group and that of Professor Aaron Odom at Michigan State University (Scheme 4.1). The Odom group had developed an elegant titanium catalyzed multicomponent coupling sequence to directly access substituted quinolines.51 Our group took up the task of developing a catalytic asymmetric transfer hydrogenation protocol, to transform the quinolines obtained from the Odom protocol into the corresponding 1,2,3,4-tetrahydroquinolines. The 2-pentquuinoline substrate 87 was initially chosen, since the corresponding reduced tetrahydroquinoline 88 was a simple N- methylation step away from a natural product 89, (—)-Angustureine.“8c'50a 4.2 The different attempts in the optimization study Numerous Bronsted acid and H-bonding catalysts, based on the parent ligands VAPOL and VANOL, were initially evaluated for the catalytic asymmetric transfer hydrogenation of 2-pentquuinoline 87 (Table 4.1). The preparation of these new derivatives of VAPOL and VANOL will be discussed in Chapter 5. Promising leads obtained from this catalyst screen were the VAPOL phosphoric acid catalyst 91 (Entry 2) and the VAPOL-Ba catalyst 12 (Entries 7, 8). These provided the product 88 in 63% ee and 72-79% ee respectively, and were chosen for further optimization. Quite a few parameters in the reaction conditions were then systematically varied with these two catalysts, in an attempt to increase the asymmetric inductions. All efforts were in vain; the asymmetric inductions could not be increased above the initial 72-79% ee value. These efforts are summarized herein: temperature/additives/other variations screen (Table 4.2), the Hantzsch 73 ester screen (Table 4.3), the solvent screen for the VAPOL-Ba catalyst 12 (Table 4.4), and the solvent screen for the VAPOL phosphoric acid catalyst 91 (Table 4.5). Table 4.1 The catalyst screena OPh o 0 OH PhO‘P’p \ ,0 \nO‘B: + , * ’ PhO \OH /P\X * /B\O_B/O H * O O bph OH 90 91 : VAPOL, x = OH 12 : VAPOL-B3 4 : VAPOL 92 : VAPOL, x = NHSOZCF3 95 : VANOL-B3 5 : VANOL 93 ; VANOL, x = OH 97 : 8,8'-Ph2VANOL-B3 94: VANOL, x = NHSOZCF3 95 : 8,8'-Ph2VANOL, x = OH W x mop/O cataIYSt 7 W / ' .7 N Hantzsch s ester 98a u (2.4 equiv) benzene, time, temperature 33 0.05 mmol ’ ‘ EtOZC 002Et n N H Hantzsch's ester 98a J Time Temperature Conversion Yield 88 ee 88 Entr Catal st x V y (h) (°C) (%)" (%)" (%)“ 1 90 20 10 60 100 >99 - 2 (FD-91 5 1 0 60 100 >99 63 3 (3)-92 1 0 1 2 60 100 >99 37 4 (S)-93 1 0 1 2 60 1 00 >99 50 5 (8)94 10 12 60 100 >99 31 31 60 6 (S)-95 10 6 70 ~90 88 17 (FD-12 7 (3 runs) 10 12 60 100 >99 72 8 (8)42 10 12 60 100 ND 79 9 (S)-96 10 1 2 60 100 88 20 74 (Table 4.1 continued...) 10 (S)-97 10 12 60 100 ND 9 39 60 . 11 (FD-4 20 14 70 incomplete ~80 0 39 60 . 12 (8)5 20 14 70 incomplete 78 0 3 ND = not determined. b 1H NMR analysis of crude reaction mixture. c Isolated yield after chromatography. d Chiral HPLC. Table 4.2 Temperature/additives screena W 10 mol% catalyst, additive ‘ W N/ Hantzsch's ester 98a N H (2.4 equiv) 87 benzene, time, temperature 88 0.05 mmol Ent Catal st Additive Time Temperature Conversion ee 88 “y V th) (°C) (%)" (%)" 1 none 12 60 100 73 2 none 24 35 100 72 3 d none 76 rt incomplete ND 12 4 activated 4A MS 12 50 100 48 5 1.2 equiv BnOH 12 60 100 3 6 1.2 equiv gla. AcOH 12 60 100 ~15 7 none 18 60 100 61 8 none is 3r; incomplete 58 9 91 activated 4A MS 68 60 incomplete ND 10 1.2 equiv gla. AcOH 18 60 100 56 11 1.2 equiv BnOH 18 60 100 56 a Product 88 was isolated by pipette column chromatography, usually in >99% isolated yield. ND = not determined. b Determined by TLC. c Chiral HPLC on isolated 88. d Catalyst prepared by heating 1 equiv of VAPOL, 4 equiv of B(OPh)3 and 1 equiv of water at 80 °C for 1 h in toluene (2 mL), followed by removing all volatiles under high vacuum (0.1 mm Hg) at 80 °C for 0.5 h. Stock solution of catalyst used. 75 Table 4.3 The Hantzsch ester screena W / N 87 0.05 mmol 10 mol% catalyst Hantzsch's ester 98 (2.4 equiv) benzene, 60 °C, 12-36 h H Hantzsch's ester 98 iROZC cozRi II N W H Entry Catalyst Hantzsch’s ester (R) ee 88 (%)b 1 Et (98a) 73 2 tBu (935) 43d 12C 3 Me (98c) 76 4 En (98d) 75 5 Et (98a) 53 6 tBu (98b) 53 91 7 Me (98c) 60 8° Bn (98d) <50 a Product 88 was isolated by pipette column chromatography, usually in >99% isolated yield. Conversion usually 100%, determined by TLC. b Chiral HPLC on isolated 88. C Catalyst prepared by heating 1 equiv of VAPOL, 4 equiv of B(OPh)3 and 1 equiv of water at 80 °C for 1 h in toluene (2 mL), followed by removing all volatiles under high vacuum (0.1 mm Hg) at 80 °C for 0.5 h. Stock solution of catalyst used. d Average of 4 runs. 9 Incomplete conversion, by TLC. 76 Table 4.4 Solvent screen for VAPOL-B3 catalyst 1261 \ W 10 mol% VAPOL-B3 catalyst Hantzsch's ester 98a W H (2.4 equiv) 87 solvent, time, temperature 0.05 mmol Entry Solvent Time (h) Temperature (°C) 99 88 (%)b 1 benzene 12 60 73 2 toluene 15 60 65 3 CeHsCI 1 3 60 64 4 CHCI3 15 60 46 5 CICH2CH20I 15 60 16 6 CCl4 13 60 3 23 60 7 EtOAc 12 70 3 8 CH30N 13 60 0 9 THF 15 60 12 c . 23 60 1o 1.4-dioxane 12 70 ND 11d 3:30 100 35 ND 41 60 12 n-Bu20 15 70 5 41 60 13 DMSO 15 70 0 a Product 88 was isolated by pipette column chromatography, usually in >99% isolated yield. Conversion usually 100%, determined by TLC. Catalyst prepared by heating 1 equiv of VAPOL, 4 equiv of B(OPh)3 and 1 equiv of water at 80 °C for 1 h in toluene (2 mL), followed by removing all volatiles under high vacuum (0.1 mm Hg) at 80 °C for 0.5 h. Stock solution of catalyst used. ND = not determined. b Chiral HPLC on isolated 88. c No reaction. d Incomplete reaction, by TLC. 77 Table 4.5 Solvent screen for the VAPOL phosphoric acid catalyst 91 a W / N 10 mol% VAPOL phosphoric acid catalyst Hantzsch's ester 98:! (ll/m H (2.4 equiv) 87 solvent, time, temperature 88 0.05 mmol Entry Solvent Time (h) Temperature (°C) 99 88 (%)b 1 benzene 10 60 63 2 toluene 12 60 64 3 C5H5Cl 12 60 63 4 CICHzCHzCi 12 60 48 5 CHCI3 12 60 51 6 CCl4 12 60 19 7 1 ,4-dioxane 18 60 37 8 n-Bu20 18 60 48 9° Eth 45 35 57 32 60 10 THF 23 70 42 32 60 1 1 CH3CN 44 70 19 32 60 12 EtOAc 23 70 41 32 60 13° DMSO 44 70 ND 24 90 a Product 88 was isolated by pipette column chromatography, usually in >99% isolated yield. Conversion usually 100%, determined by TLC. ND = not determined. b Chiral HPLC on isolated 88. ° Incomplete conversion. 4.3 Confirmation of the VAPOL-Ba spiro-boroxinate active catalyst Since so far the best result was with the VAPOL-B3 catalyst 12 (73% ee vs. 63% ee for VAPOL phosphoric acid catalyst 91), we decided to remove the VAPOL phosphoric acid catalyst from subsequent screens. We had initially 78 assumed the VAPOL-83 Spiro-boroxinate active catalyst structure for our quinoline reduction studies (Scheme 4.2), in analogy with the active catalyst/catalytic cycle in our aziridination studies11 (Section 1.3.1, Chapter 1). We next decided to seek evidence for this assumption. Scheme 4.2 The active catalyst-quinoline complex in quinoline reductions 1) 3 equiv BH3'SM82 3 equiv H20 2 equiv PhOH toluene, 100 °C, 1 h 2) 0.1 mm Hg, 0.5 h, 100 °C 3) 1-3 equiv 87, CDC|3 (3)-VAPOL (S)-VAPOL-B3 - quinoline complex For our aziridination studies, the method of choice for confirming the spiro- boroxinate 33 motif in the active catalyst is by way of 11B and 1H NMR analyses,11 which were carried out for our quinoline reduction studies too. The catalyst was prepared as indicated in Scheme 4.2. The 11B and 1H NMR spectra of the boroxinate-quinoline complex 99 are quite distinctive (Figure 4.1). Three-coordinate borate esters typically have broad absorptions for the boron between 16-20 ppm in CDCI3.”° Since 11B is a quadrapole, the sharpness of the absorption is related to the spherical symmetry around the boron, and this is reflected in the appearance of the 11B NMR spectrum of the boroxinate- quinoline complex 99 (Figure 4.1, top). The two three-coordinate borons in 99 appear as a very broad absorption at 15.97 ppm, and the four-coordinate boron as a very sharp peak at 5.76 ppm, with an integration of 2:1 respectively (not shown). This is in perfect accord with the 11B NMR spectrums obtained in our 79 aziridination studies.11 The most distinctive absorption for the complex 99 in the 1H NMR spectrum is the bay-region doublet (Hb in 4, Scheme 4.2) at 10.49 ppm (Figure 4.1, bottom), again in good agreement with that observed in our aziridination studies“. These NMR studies thus confirmed the presence of the Spiro-boroxinate 83 active catalyst in our quinoline reduction studies. Figure 4.1 Top: “3 NMR of complex 99 (CDCI3, 150 MHz); bottom: 1H NMR of complex 99 (CDCI3, 500 MHz) A—A—A AAA-h _# “J“ AAA—l A. A A - u u A_-‘ .4 ‘ .v. r. vfifirw TTTIUTIIIYUTIIIVIIIIIIIITIITITFTTIYFUIIII'rrrrTTIIIIIIUIII] 4O 30 20 1 0 0 ‘7 ———- -——. h A. A A L #A. A ._. #4.; A ‘ ' ' ' 11.0 10.0 9.0 Furthermore, the absolute configuration of the tetrahydroquinoline product 88 from the reaction of the VAPOL-83 catalyst was determined by comparison of the optical rotations to literature values, and is shown in Scheme 4.3 (see Experimental Information for details). 80 4.4 Self-assembly of a family of B3 catalysts for the quinoline reductions The spiro-boroxinate catalysts from VAPOLNANOL can be generated via two different methods, either using B(OPh)3 (Table 4.4) or using BH303m92 (Scheme 4.2). The catalyst prepared from either method affords identical results in both our aziridination studies as well as in the quinoline reduction studies. However, that the catalyst can be prepared using the BHgoSMeg route lends us the distinct opportunity to generate a large family of 8;, catalysts by simply incorporating different phenols and alcohols during the catalyst self-assembly. This was the approach taken to further enhance the asymmetric inductions in the reduction of quinolines study discussed in this chapter. A broad range of sterically and electronically different phenols and alcohols were screened, and the resulting asymmetric inductions and trends obtained are presented in Scheme 4.3. Unfortunately, in spite of all our efforts, we were never able to increase the asymmetric inductions beyond the initially obtained 72-79°/o ee range. 81 Scheme 4.3 Self-assembly of a family of 83 catalysts for the quinoline reductions BH3'SM62 (3 equiv) H20 (3 equiv) 0.1 mm Hg _ ph\“' ROH , o 7 (2 equiv) toluene, 80 °C, 1 h 80 C, 0.5 h Ph .\ O-B’ + 12 (R)-VAPOL (R)-VAPOL-B3 catalyst 10 mol% (R)-VAPOL-B3 W cataIYSt . W N/ N benzene, 60-70 °C, 12-18 h H 37 Hantzsch ester 98a 88 0.05 mmol (2.4 equiv) isolated ee values: OH 71 % Standard OH OH OH OH OH N02 OMe 72% 74% 51% 73% 72% Ph 4-sterics are similar or slightly better ...... except 4-tbutyl, too bulky 4-electronics don't make a difference OH OH OH OH 75% 75% 63% 43% 2-sterics are better... ...exoept 2-isopropyl, an oddity... ...exoept 2-phenyl, adverse CH-1t interactions? 82 (Scheme 4.3 continued...) OH OH OH OH U )\©/k HUM. 78% 71 % 8% (slow reaction) 41% 2,6-sterics are better or similar... ...exoept 2,6-di-‘butyl, too bulky... ...exoept 2,6-di-phenyl, adverse CH-1t interactions? 0H OH OH OH OH OH F3C CF3 F F Br F 40% 51% 67% 58% 61% 33% 3,5-sterics or 3,5-electronics are worse Halogens are consistently deleterious, adverse halogen-bonding? OH to” at, u, ”o 78% 73% 74% 76% 19% Bicyclic and tricyclic aromatics (up to "tri-substituted" phenols) are better... ...exoept "tetra-substituted" phenols, too bulky C” GM" M... 5 i ,3, g}... 19% 19% 2% (slow reaction) 25% 22% 15% 35% 70% (slow reaction) Several diverse aliphatic/benzyl alcohols tried, all are consistently worse... ...exoept one oddity OH OH OH l ‘ N l \ | \ / / N N/ -12°/o 2% 5% Pyridyl hydroxides are slow and disastrous VAPOL-B3 catalyst probably does not form, maybe due to the extra coordination site 83 4.5 Asymmetric transfer hydrogenation of 2-phenquuinoline The catalytic asymmetric transfer hydrogenation of a different substrate, 2- phenquuinoline, was also attempted (Table 4.6). The best asymmetric induction obtained with this substrate was also 67% ee, with the VAPOL-83 catalyst. Table 4.6 Asymmetric transfer hydrogenation of 2-phenquuinoline 1008 m 10 mol% catalyst m N/ ph Hantzsch's ester 98a 7 N Ph H (2.4 equiv) benzene, time, 60 °C 100 101 0.1 mmol Entry Catalyst Time (h) Yield 101 (%)b ee101 (%)° 1 (Fi)-VAPOL-B3 58 >99 67 2 (S)-VANOL-83 14 >99 36 a Catalyst prepared by heating 1 equiv of ligand, 4 equiv of B(OPh)3 and 1 equiv of water at 80 °C for 1 h in toluene (2 mL), followed by removing all volatiles under high vacuum (0.1 mm Hg) at 80 °C for 0.5 h. Stock solution of catalyst used. (S)-ligand gives ent. 101 shown. b Isolated yield after column chromatography. c Chiral HPLC. 4.6 Transition state analysis via computational chemistry As with our aziridination studies (Chapter 7), we entered into a collaboration with Dr. Mathew Vetticatt to study the origins of the stereoselections in the asymmetric reduction of quinolines also, using computational chemistry. Numerous transition states were located, and a detailed study based on theoretical calculations was conducted. Shown in Figure 4.2 is the preferred enantioselectivity determining transition state, corresponding to the final transfer hydrogenation step. As seen in the transition states for our aziridination studies (Chapter 7), multiple non- 84 covalent interactions are seen in this transition state also. The protonated quinoline H-bonds to oxygen O-3 of the boroxinate catalyst, whilst the Hantzsch ester H-bonds to oxygen O-1 of the catalyst. The additive effect of these interactions leads to a tight organization at the transition state, consequently lowering the energy of the transition state. The full details of the computational studies in the collaborative effort with Dr. Vetticatt, along with the experimental details for this project, will be published shortly. Figure 4.2 The enantioselectivity determining step, and the enantioselectivity determining transition state calculated via ONIOM(B3LYP/6-31G*:AM1) W "H-" W N/ N/ 87 7 N H enantioselectivity determining step 85 4.7 Future directions for the project While a reasonable level of asymmetric induction was achieved for the catalytic asymmetric transfer hydrogenation of quinolines during this dissertation (up to 78% ee), and a satisfying collaborative computational study carried out for the same, this cannot be billed as a successful protocol for the asymmetric reduction of quinolines. In our opinion, any catalytic asymmetric system to be called successful should provide >90% ee for at least two substrates. All efforts to reach this level during this dissertation have ended in frustration; however, for the future generations of the boroxinate-catalyst users, a few suggestions are made to convert this protocol into a successful system (Scheme 4.4). Scheme 4.4 Future directions for the project EtOZC COZEt ewe ewe OH R N R N H H 104 105 (EWG = COPh, N02) There was a distinct difference between the boroxinate catalysts prepared from VAPOL and VANOL in the initial catalyst screen (Table 4.1). Thus, since the system seems to respond to changes in the ligand structure (unlike our cis- aziridination studies, Chapter 2), it might be interesting to screen the newer 86 derivatives of both VAPOL (102) and VANOL (103) being actively developed in our laboratories (Scheme 4.4). There is a tight H-bond between the Hantzsch ester and the catalyst core at the enantioselectivity determining transition state (Figure 4.2). Numerous transition states without this H-bond were located, but they were all significantly higher in energy (15-20 kcanol). Thus, the hydrogen transfer reagent is intimately involved in the enantioselectivity determining step; varying its steric and electronic environment should definitely produce a variation in the asymmetric inductions. In this regard, it might be interesting to try Hantzsch ester derivatives of type 104 (R > Me),52 which would be sterically different. The H-bonding capability of the Hantzsch ester could be tuned by using derivatives of type 105.53 Alternately, the hydrogen transfer reagent could be completely switched. Akiyama has recently introduced benzothiazolines 106 as effective reducing agents for the asymmetric organocatalytic transfer hydrogenation of ketimines;54 it would be. very interesting to try these for our system. There seems to be a stabilizing CH-rr interaction between the hydrogen at the C-7 position of the partially reduced quinoline and the catalyst at the transition state (Figure 4.2). It might be worthwhile to examine substituted quinolines of type 107 and 108 (Scheme 4.4), in an attempt to exploit this interaction. Furthermore, catalytic asymmetric transfer hydrogenation is a vast and practically useful field, one which is untapped as of yet by our spiro-boroxinate 33 Bronsted acid catalysts. The quinoline reduction study could serve as a proof of principle; efforts towards the asymmetric transfer hydrogenation of other 87 substrates, especially those not successfully realized yet, could be initiated. One such example is that of pyridines, pioneered by Rueping in 2007.55a The Flueping protocol is the first organocatalytic example, one though with definite limitations and considerable room for improvement. For leads into the literature for the asymmetric hydrogenation of aromatic/heteroaromatic compounds, a few references are provided."’5"“’d 88 CHAPTER FIVE NEW DERIVATIVES OF VAPOL AND VANOL: STRUCTURALLY DISTINCT VAUL TED CHIRAL LIGANDS AND BRGNS TED ACID CATALYSTS 5.1 Introduction The field of chiral Bronsted acid catalysis has witnessed an exponential growth in the last decade.57 Countless efficient asymmetric reaction systems mediated by these organocatalysts have been developed by numerous research groups around the world, and this growth continues unabated till date. The BINOL ligand scaffold has been ubiquitous in the realm of organocatalysis, and is entitled to the label of a “privileged” ligand.58 Scheme 5.1 Chiral Bronsted acid catalysts from the BINOL scaffold 33%: C30H.30,p,,00. o.P,,0 i S OH .EX OH I ix 0 P/OH l00"NHsozc1=3 "privileged" BINOL Chiral BINOL Bronsted acid catalysts1 scaffold Shown in Scheme 5.1 are the three most extensively utilized groups of chiral Bronsted acids derived from the BINOL scaffold. As weakly acidic Bronsted acids, a variety of BINOL derivatives 109 have been developed and utilized in asymmetric organocatalysis.59 In 2004, the research groups of Akiyama60a and Terada6°° independently introduced the 3,3’-disubstituted BINOL phosphoric acids 110 for asymmetric Mannich-type reactions. These phosphoric acids have since then proven to be extremely versatile chiral Bronsted acid 89 catalysts, and a multitude of successful catalytic asymmetric systems have been developed under their aegis.61 Chiral BINOL N-triflyl phosphoramide catalysts 111 were subsequently introduced by Yamamoto in 2006 for an asymmetric Diels-Alder reaction.62 These are stronger Bronsted acids (pKa of -3 in water)570 as compared to the corresponding BINOL phosphoric acids (pKa of 1 in water)57°; these N-triflyl phosphoramides have also found considerable success in asymmetric organocatalysis in recent years.63 Scheme 5.2 Structurally distinct vaulted biaryl diol ligands (S)-VAPOL (S)-VANOL The vaulted biaryl diol ligands VAPOL (4) and VANOL (5) were introduced by our group in 1993 (Scheme 52).“65 These ligands possess a unique vaulted structure, and are thus structurally distinct from the BINOL ligands. Since their discovery, VAPOL and VANOL have served as the basis for a number of successful catalytic asymmetric systems by several research groups. Catalysts prepared from VAPOL/VANOL and various boron compounds have been shown to mediate extremely efficient and general asymmetric aziridinationsf"12 as well as asymmetric hetero-Diels-Alder cycloadditions.66 VAPOL/VANOL catalysts containing aluminum or zirconium have successfully catalyzed asymmetric Diels- 67 Alder reactions,“ imino-aldol reactions,"38 and Baeyer—Villiger reactions69. 90 Phosphoramidite derivatives of VAPOL and VANOL have been shown to be effective ligands in rhodium catalyzed enantioselective intramolecular hydroarylation of alkenes.70 VAPOL as a standalone species can mediate asymmetric Petasis reactions, affording chiral a-amino acid esters with high asymmetric inductions.71 An increasing number of systems in recent years have showcased the use of the chiral phosphoric acid catalysts prepared from VAPOL and VANOL. lmine amidations,72 imino ester reductions,73 imine imidations,74 as well as desymmetrization of mesa-aziridines to afford vicinal diamines75 and vicinal amidophenylthioethers76 have been all shown to proceed with excellent levels of asymmetric inductions under their catalysis. The utility of VAPOL and VANOL is poised to increase as both antipodes of these ligands are now commercially available.“""65 Despite the significant use of catalysts derived from VAPOL and VANOL in asymmetric catalysis, a dearth of information exists in the literature for the preparation of derivatives of these ligands. In the present study, we thus wish to report efficient, reproducible and multi-gram scale syntheses of several new derivatives of VAPOL and VANOL. These are structurally novel chiral ligands and Bronsted acid catalysts; the asymmetric active sites created by these derivatives will be electronically and sterically very different from those created from the corresponding BINOL derivatives, thus resulting in a profile for reactivity and asymmetric inductions that could be quite singular. We believe that the uniqueness of their structure, and the subsequent promise of radically different reactivity profiles, warrants the inclusion of these derivatives in any screen comprised of chiral Bronsted acids. 91 5.2 New Bransted acid derivatives of VANOL VANOL phosphoric acid 93 was prepared at a multi-gram scale from VANOL 5, in an excellent yield and under mild conditions (Scheme 5.3). Thus, VANOL was reacted with POCI3 at room temperature, followed by the addition of water, which upon work-up and purification afforded pure VANOL phosphoric acid 93 in 92% isolated yield (2.1 9 product). The stronger Bronsted acid, N-triflyl VANOL phosphoramide 94, was prepared in 76% isolated yield (2.2 9 product) in a one-pot two-step sequence62 starting from VANOL 5 (Scheme 5.4). Scheme 5.3 Multi-gram scale synthesis of VANOL phosphoric acid 93 a) POCI3, pyridine, 6 h, 25 °C Ph "'0H b) H20. 2 h. 25 °C _ Ph ”mp/,0 Ph/,. Ph/,' 0’ \OH 92% (2.1 9 product) 5 93 (S)-VANOL (S)-VANOL phosphoric acid Scheme 5.4 Multi-gram scale synthesis of N-triflyl VANOL phosphoramide 94 CHzclz, NEt3 ' POC|3 TfNHz, EtCN ”0H 0 to 25 °C, 2 n_ 100 °C, 12 ll Pb,“ OH 0 76% (2.2 9 product) (S)-VANOL (S)-N-trif|yl VANOL phosphoramide 92 5.3 New Bronsted acid derivatives of VAPOL As with VANOL, the phosphoric acid 9177 (Scheme 5.5) and the N-triflyl phosphoramide 92 (Scheme 5.6) Bronsted acid derivatives of VAPOL were also prepared at multi-gram scales, and with excellent yields. Scheme 5.5 Multi-gram scale synthesis of VAPOL phosphoric acid 91 a) POCI3, pyridine 0 °c - 25 °c, 6 h b) H20, 0 °C - 25 °C, 2 h phv“ 64-90% yield P“ .,.o’ 0“ (~ 6 9 product) (R)-VAPOL (R)-VAPOL phosphoric acid Scheme 5.6 Multi-gram scale synthesis of N-triflyl VAPOL phosphoramide 92 CH2C|2, NEt3 POCI3, DMAP TfNHZ, EtCN 0 to 25 °C, 2 h_ 100 °c, 12 h_ 70% (1.9 9 product) (R)-VAPOL (R)-N-triflyl VAPOL phosphoramide It was realized that the N-triflyl phosphoramide derivatives offered yet another handle with which to tune the asymmetric active sites of these catalysts — the triflate side chain. If the trifluoromethyl group in these derivatives was to be replaced with a bulky aromatic group, it would add yet another element of steric bulk into the system. Thus, the N-TRIP-benzene sulfonyl VAPOL phosphoramide 112 and the N-nitrobenzene sulfonyl VAPOL phosphoramide 113 Bronsted acids 93 were also prepared in an efficient manner using similar procedures (Scheme 5.7). Scheme 5.7 N-benzene sulfonyl VAPOL phosphoramide Bronsted acid catalysts iPr H2NOZS iPr CHzClz, NEt3 ipr POCI3, DMAP EtCN 0to25°C,2h> 100°C,12h : 73% 1 12 N-TRIP-benzene sulfonyl VAPOL phosphoramide H2NOZS‘Q‘NOZ CH2C|2, NEt3 POCI3, DMAP EtCN 0to 25 °c, 2 n: 100 °c, 12 h : 37% 4 1 13 (S)—VAPOL N-nitrobenzene sulfonyl VAPOL phosphoramide 5.4 A new family of vaulted ligands - 8,8’-diaryl VANOL derivatives Gaining inspiration from the enormous success of various 3,3’-diaryl BINOL derivatives in asymmetric catalysis, we were drawn towards the prospect of creating a new family of structurally distinct vaulted ligands, the 8,8’-diaryl VANOL derivatives (Scheme 5.8). These would be unique ligands, and could again be completely orthogonal in their reaction profiles as compared to the 3,3’- diaryl BINOL ligands. Not only would they be interesting chiral scaffolds for 94 standalone weak Bronsted acid catalysis, but their phosphoric acid and phosphoramide derivatives would be attractive in the realm of strong Bronsted acid catalysis too. Scheme 5.8 A new family of structurally distinct vaulted ligands CO Ar OH :9 00 0” Ar widely used a new family of 3,3'—diaryl BINOL ligands 8,8'-diaryl VANOL ligands transition metal dimerization and Ar OH catalyzed coupling 0H deracemization with ArX 00 P, “CC ,, 115 116 VANOL monomer ref. 65 ll 5 VANOL At the outset, it was desired to have a general route towards these new derivatives, which should make it possible to generate a large number of family members using similar reaction conditions. The ideal retrosynthetic analysis for 95 the preparation of a large family of these ligands is presented in Scheme 5.8. The syntheses would start from compound 116, which is the monomer used for the synthesis of the VANOL ligand. We have already reported an efficient multi- gram scale synthesis for this compound,65 and this was thus thought to be an attractive starting point for the present work. A transition metal catalyzed coupling reaction should then be able to install sterically and electronically different aromatic substituents on the 8-position of the VANOL monomer, thereby providing the requisite monomers 115 for the new ligands. Subsequent dimerization and deracemization, in a similar fashion as done during our previous syntheses of VAPOL and VANOL,65 should then afford the new family of 8,8’- diaryl VANOL ligands 114. The expectations from this retrosynthetic analysis were borne out quite satisfyingly when the multi-gram synthesis of (S)-8,8’-Ph2VANOL 121 was carried out as a proof of principle (Scheme 5.9). All reactions were optimized on a small scale first, and then demonstrated on larger scales for multiple times. The yields reported are the average of all runs on larger scales. The initial transition metal catalyzed coupling step was the key for the synthesis; it was our synthetic handle to be able to rapidly prepare the entire family of these new ligands. To our pleasure, a Pd-catalyzed a-arylation protocol developed by Miura and co- workers78 worked smoothly from the VANOL monomer 116 to afford the corresponding new acetylated monomer 118, in 75% isolated yield over 2 steps at a multi-gram scale. Attempts to purify the monomer after the initial Pd-coupling reaction by silica gel chromatography failed,78 thus requiring the subsequent 96 acetylation of the crude material to afford the acetylated monomer 118. This could then be isolated as a pure compound after silica gel column chromatography, and a simple de-acetylation was then optimized to afford the pure new monomer 119 in excellent yield, again at a multi-gram scale. The monomer was dimerized in air with acceptable yields; the dimer was then subjected to a deracemization protocol with CuCI and (-)-sparteine to afford the optically pure (S)-8,8’-Ph2VANOL ligand 121 in good yields in multi-gram quanfifies. Scheme 5.9 Multi-gram scale synthesis of (S)-8,8’-Ph2VANOL 121 l a) Pd( OAc) )2 (2. 5 mol%) Ph OAc 052003, DMF, 110 °C, 24 h> b)A020 pyridine 0C Ph 25 °C, overnight Ph 117 118 1. 2 equiv 75% (over 2 steps, 6 9 product) average of 3 runs K2CC§ CH2C|22H202M€OH Ph OH 25°C, overnight_ “ll Ph 119 92% (5 9 product) average of 3 runs CuCI (1.7 equiv) (—)-sparteine (3.5 equiv) MeOH, CHzclz, 25 °C 7 neat, air 200 °C, 60 h 120 121 53% (2.5 9 product) (S)-8,8'-Ph2VANOL average 0f 3 runs 62% (3 9 product), >99.9% ee average of 2 runs 97 Thus, a lean, efficient and multi-gram scale synthesis of 121 could be devised, and a proof of principle demonstrated for the synthesis of a new family of biaryl diol ligands in the future; this should in principle be easily achieved by simply substituting iodobenzene in the initial Pd-coupling reaction in the above synthetic route with a variety of electronically and sterically distinct aryliodides, and the rest of the synthesis should be identical as for 121. Scheme 5.10 Preparation of Bronsted acid derivatives of 8,8’-Ph2VANOL POCI3, pyridine a) Pools. pyridine 8’ 3,5960% 25 °c, 24 n 25 °C. 24 h 2 3' 3 b) H20, 25°C, 24h 0'25 0.111 b) TfNHz, EtCN V reflux, 24 h 123 69% We were subsequently interested in demonstrating the preparation of the phosphoric acid (123) and the N-triflyl phosphoramide (124) derivatives of the 98 new 8,8’-Ph2VANOL ligand. This was done using our standard procedures in acceptable yields, and is presented in Scheme 5.10. An interesting outcome during the optimization of these syntheses was that the phosphorous chloride intermediate 122 could also be isolated by silica gel chromatography in good yields (Scheme 5.10). Displacement of chloride from this intermediate should be facile, to introduce other functionality such as urea/thiourea groups, thus paving the way towards other novel Bronsted acid catalysts or H-bonding ligands for use in asymmetric catalysis. 5.5 Conclusions By the virtue of their unique vaulted structure, the biaryl diol ligands VAPOL and VANOL have carved a special niche for themselves in asymmetric catalysis. A multitude of different catalytic asymmetric reactions have been mediated by the catalysts prepared from these ligands, affording excellent selectivities, yields and asymmetric inductions.“2'64'6‘5'76 The use of these ligands in the future will be further facilitated by that they are now commercially available.“65 Anticipating an increased use of these ligands in asymmetric catalysis in the near future, we have initiated a program to prepare novel derivatives of these ligands. Herein, we have reported our preliminary results from this study; efficient, reproducible and multi-gram scale syntheses of several new chiral ligands and Bronsted acid catalysts based on the framework of VAPOL and VANOL have been presented. These are structurally distinct as compared to the traditional BINOL scaffolds, and should generate singular profiles for reactivity 99 and asymmetric inductions. We hope that this expectation gets borne out in our laboratories in the near future, and in those of others actively engaged in the science of asymmetric catalysis. 100 CHAPTER SIX OTHER FORAYS IN CHIRAL CATALYSIS During the first year of this dissertation, Professor Wulff had commented that nine out of ten projects that a synthetic organic chemist evaluates during a PhD will fail. Those words were certainly borne out during this dissertation; behind each working project mentioned in this dissertation, there were quite a few dead ends. Two of these projects will be detailed briefly in this chapter, and so will be another exciting project which was initiated towards the end of this dissertation. 6.1 Asymmetric catalysis vla chiral dirhodium catalysts One of the most widely studied approaches towards catalytic asymmetric aziridination has been the one in which a chiral metal nitrene intermediate is utilized to transfer a nitrene to an olefin. The best system till date in this approach has been reported by Katsuki, who utilized a highly modified salen ligand to provide high chiral inductions with aryl olefins (BS-99% ee).79 Aliphatic substrates gave good inductions but low yields (20-30%). Enormous success has been achieved in the development of chiral dirhodium catalysts for the asymmetric carbene transfer to olefins to give cyclopropanes.80 In contrast, the only known example for the use of chiral dirhodium catalysts for the asymmetric nitrene transfer to olefins to give aziridines is by Muller.81 The highest induction he reported involves a dirhodium catalyst Rh2L4 where L is the phosphoric acid ester 128 prepared from the BINOL 101 ligand (Scheme 6.1). The aziridination of cis-fi-methylstyrene can be achieved with 2 mol% of this catalyst and nosyliminoiodinane (NsN=lPh) to give the corresponding aziridine in 73% ee. This is to be compared with his second best catalyst, which is derived from the pyrolidinone 127, which gave an asymmetric induction of 35% ee for the same reaction. That the best chiral dirhodium catalyst developed so far involves a BINOL ligand thus gives encouragement for the evaluation of the corresponding dirhodium compounds derived from the VANOL and VAPOL phosphoric acid esters, 129 and 130 respectively (Scheme 6.1). Scheme 6.1 Proposed asymmetric aziridination with chiral dirhodium catalysts R2 RSOZN=lPh catalytic SOzR Rh2L4 ' 2 1/=:< 3 + or > N .‘R R R RSOZNHZ + Phl(OAc)2 R1 'R3 125 126 L = 0 N 127 128 129 130 POZBI NOL POZVANOL P02VAPOL To initiate the investigation, it was desired to reproduce Muller’s results81 with the Rh2(PO,o_BINOL)4 complex 133. Thus, the requisite catalyst 133 and the starting materials were prepared as indicated in Scheme 6.2, and Muller's results could subsequently be reproduced up to a satisfying degree (Scheme 6.2). It was then desired to explore the corresponding dirhodium catalyst 139 prepared from the VANOL ligand. Disappointingly, the dirhodium VANOL catalyst 139 102 performed inferior to the corresponding BINOL catalyst 133, providing the aziridine 138 in only 20% ee (Scheme 6.3 vs. Scheme 6.2). Scheme 6.2 Asymmetric aziridination with the ha4 complex 133 1) POCI3 00 pyridine, 100 °C 0O 0 ”0H 2) H20 > "04.5: CH 3) 6 N HCI, reflux / 0’ OH CO 4) recrystallization CO from EtOH 60% 131 132 (S)-BINOL RhZOAc4 CC "’0 ”0 ‘P C5H5CI, reflux, 48 h_ / \ o 52% CO 0 RhZ 4 133 802”“? AcO\I,OAc KOH, MeOH + : NsN=lPh g°cé035hh 5° . 136 N02 77% (crude) 134 135 2 mol% Ns Rh2(POZBINOL)4 133 l NsN=lPh + ph/\ : N CH2CI2, 4 A MS PIT/Q 136 137 25 °c, 6 h 138 54%, 46% ee Muller's results (ref. 81): 74%, 55% ee 103 Scheme 6.3 Asymmetric aziridination with the Flh2(P02VANOL)4 complex 139 haOAC4 CSH5CI, reflux, 36 h Ph > Ph,“ 81% 93 139 (S)-VANOL phosphoric acid 2 mol% Ns Rh2(POZVANOL)4 139 I NsN=lPh 1' ph/\ = N CH2Cl2, 4 A MS Ph/Q 136 137 25 °C, 6 h 138 40%, 20% ee The next steps in this project could have been a temperature study with the dirhodium VANOL catalyst 139, or trying a substrate other than styrene, such as cis-B-methylstyrene, which in fact performed better in Muller’s system81 than styrene. Alternately, the same asymmetric aziridination could have been attempted with the corresponding dirhodium catalyst prepared from the VAPOL ligand. Unfortunately at this stage in this dissertation, other projects were deemed to be of higher priority, and the asymmetric aziridination project mediated by chiral dirhodium catalysts was relegated to the back burner, where it has remained since then. The Rh2(POZBINOL)4 complex 133 was also evaluated briefly for an asymmetric cyclopropenation reaction.82 A few variations were attempted (Scheme 6.4), however no encouraging results were obtained. 104 Scheme 6.4 Asymmetric cyclopropenation with Rh2(P023INOL)4 complex 133 10 mol% 0 /// (1k Rh2(POzBINOL)4 133 P—COZB f OEt 5 Ph 1 CH2CI2, 25 °C, 14 h Ph N2 N0 reaction 140 2 141 o 10 mol% Ph / + Phfit/KOM Rh2(POZBINOL)4133> .= COzMe Ph 9 P J: solvent, 25 C, 14 h N2 Ph 140 47 142 Entry Solvent Yield (%) ee(%) ‘I CH2CI2 < 7 nd 2 hexanes 12 15 6.2 Organocatalytic asymmetric aziridination mediated by chiral Bronsted acid catalysts The field of chiral phosphoric acid catalysis has grown exponentially since the pioneering reports by Akiyama60a and Terada60b in 2004. Chiral phosphoric 60"” and their N-triflyl phosphoramide derivatives”63 have successfully acids catalyzed a plethora of nucleophilic additions to imines and carbonyl compounds. Surprisingly, at the stage of this dissertation when attention was focused towards this area, no report of an asymmetric aziridination protocol mediated by these versatile organocatalysts existed. Thus, a considerable amount of time during this dissertation was spent trying to develop an aziridination protocol catalyzed by the chiral phosphoric acid and phosphoramide derivatives of VAPOL and VANOL, the preparation of which has been discussed in Chapter 5. These efforts largely ended in vain, and subsequent to the end of work for this project during this dissertation, Akiyama and co-workers reported a successful asymmetric 105 aziridination protocol mediated by a chiral phosphoric acid catalyst derived from a 3.3-disubstituted BINOL ligand (Scheme 1.10, Chapter 1).17 Scheme 6.5 Asymmetric aziridination with VAPOL/VANOL chiral Bronsted acids OMe O 20 mol% catalyst pMp toluene I \ O + (“\OtBu F N /\ o A 3 143 19 0 °C (24 h) to rt (24 h) 144 1.3 equiv 6:1 cis:trans, 48% yield 15:1 cis:trans, 65% yield 5:1 cis:trans, 36% yield 11:1 cis:trans, 73% yield 24% ee 8% ee 5% ee <10% ee 112 113 4:1 cis:trans, 41% yield 12:1 cis:trans, 60% yield 5% ee 15% ee During the initial part of this investigation, the VAPOL/VANOL derived chiral Bronsted acid catalysts 91-94 and 112-113 (Chapter 5) were evaluated for the aziridination reaction between various imines and ethyldiazoacetate. lmines derived from various benzaldehydes, and with numerous electron 106 rich/neutral/deficient protecting groups were evaluated. However, all reactions resulted mostly in low conversion to the desired aziridine products. It was only when we switched to activated imines that we started getting good reactivity in our system, and good conversions to the desired aziridine products were observed. The important results from this investigation are summarized in Scheme 6.5, and as can be seen, although excellent reactivity and diastereoselectivity was observed, the asymmetric induction for this project could never be increased beyond 24% ee. 6.3 Asymmetric catalytic Darzens reaction Gong and co-workers have recently reported an efficient asymmetric catalytic Darzens reaction between aldehydes and N-phenyldiazoacetamide 14a, mediated by Lewis acid catalysts prepared from BINOL ligands and either Ti(O’Pr).,“1 or Zr(O"Bu)483. All successful systems till date for the asymmetric catalytic Darzens reaction are mediated by chiral Lewis acids involving metals.41 There are no examples with a chiral Bronsted acid. After successfully utilizing N- phenyldiazoacetamide 14a in our trans-selective aziridination protocol (Chapter 3), we became interested in evaluating the same for the Darzens reaction under catalysis of our VAPOLNANOL-B3 boroxinate catalysts. If successfully established, this would represent the first protocol for an asymmetric catalytic Darzens reaction mediated by a chiral Bronsted acid. It would also be exciting from that this would be the first time that our B3 catalysts were successfully able to activate carbonyl compounds, which is an entire realm of chiral acid catalysis that has been untapped as of yet by our research group. 107 Table 6.1 Proof of principle for the asymmetric catalytic Darzens reactiona O /\ (IL 10 mol% catalyst 0 Ph \0 + NHPh *7 A | toluene (0.1 M) Ph CONHPh N2 time, temperature 145 14a 146 1.2 equiv 0.2 mmol (1 equiv) Entry Ligand Temperature (°C) Time (h) cis:transb Yield (%)c 66 (%)d 1 (F?)-VAPOL-B3° 202 118 17:1 44 4 2 (S-VANOL-Bge 202 129 20:1 60 -32 e 0 24 . 3 (m-VANOL-Ba 22 2 13.1 47 40 4 no catalyst 22 19 no reaction 5 only VANOL 22 19 no reaction 6 only B(OPh)3 22 19 no reaction 3 Reaction with (S)-VANOL-B3 catalyst gives ent. 146 shown. b Determined from 1H NMR analysis of crude reaction mixture. ° Isolated yield after column chromatography, of approximately 97% pure product. d Chiral HPLC. 9 Catalyst prepared by heating 1 equiv of ligand, 3 equiv BH3-SM62, 2 equiv phenol and 3 equiv water at 100 °C in toluene for 1 h, following by removing all volatiles at 100 °C under high vacuum (0.1 mm Hg) for 0.5 h. Scheme 6.6 Attempted Darzens reaction with ethyldiazoacetate 2 O 10 mol% 1 (R)-VANOL-B3 catalyst No reaction (TLC 8r crude H NMR) Ph/‘\‘O + | O/\ -------------------------- e Only an EDA decomposition product N2 toluene (01 M) observed in the crude 1H NMR - possibly 145 2 0 C ' 24 h' 22 C ' 2 h the dimerization product. 1.2 equiv 0.2 mmol (1 equiv) A proof of principle for the asymmetric catalytic Darzens reaction was established during this dissertation (Table 6.1), when the reaction of benzaldehyde 145 and N-phenyldiazoacetamide 14a mediated by the VANOL-B3 108 catalyst was shown to afford the corresponding cis-epoxide 146 with a cis:trans ratio of 17:1, 54% yield and 36% 69 (average from Entries 2 and 3). The corresponding reaction mediated by the VAPOL-83 catalyst afforded the cis- epoxide 146 with only 4% ee (Entry 1). Interestingly, no reaction was observed when the same reaction was conducted with ethyldiazoacetate 2 instead of N- phenyldiazoacetamide 14a (Scheme 6.6). The reactions in Table 6.1 were the first few reactions conducted for the Darzens reaction project. Work was stopped due to a lack of time in this dissertation. This is an exciting project, the reasons for which have been mentioned above. There are quite a few parameters that could be easily tweaked in an attempt to convert this proof of principle into a successful system. A few suggestions that come to the mind instantly are as follows: (1) The results in Table 6.1 should be reproduced once, especially the reaction with the VAPOL-B3 catalyst (Entry 1). (2) A systematic solvent screen should be conducted, particularly with halogenated hydrocarbons and ethereal solvents. (3) An entire family of N-substituted diazoacetamides has been prepared and screened for the trans-selective aziridination protocol (Chapter 3, Table 3.4), the procedures for which have also been detailed in this dissertation (experimental information for Chapter 3). These should be screened for the Darzens system; it is thought that especially the N-alkyl substituted diazoacetamides (14f and 149) should produce a marked difference in the Darzens reaction results. (4) Different phenols could be used to generate a varied family of the VANOL-83 boroxinate catalysts, which could be tested (see Section 4.4, Chapter 4). (5) Finally, the new derivatives of 109 VAPOL and VANOL being developed in our laboratory could be evaluated, especially since there is a distinct difference between the results obtained from the VAPOL and VANOL boroxinate catalysts (Table 6.1, Entry 1 vs. Entries 2 and 3). Several research groups (Maruoka,13 Zhong,15 Gong“) are familiar with the chemistry of N-substituted diazoacetamides. All these groups also practice chiral Bronsted acid catalysis extensively. The asymmetric catalytic Darzens reaction is an attractive project since there is no example of a chiral Bronsted acid catalyzed system, yet. 110 CHAPTER SEVEN COMPUTATIONAL CHEMISTRY AND UNIVERSAL AZIRIDINATION 7.1 Background and significance Chapter 3 describes the extension of our catalytic asymmetric cis- aziridination methodology?"12 to now selectively form trans-aziridines. This reversal of diastereoselectivity, accomplished by a simple change in one of the substrates used, was accompanied by the observation of the opposite facial selectivity to the imine (Scheme 7.1). This chapter describes a combined experimental and computational study that examines the mode of catalysis of this unique catalyst and the origins of the enantio- and diastereo- selection in this unprecedented universal catalytic asymmetric aziridination methodology. This work was carried out in collaboration with Dr. Mathew Vetticatt. Scheme 7.1 Universal catalytic asymmetric aziridination MEDAM N 74 Ph‘ 'COZEt " ph >50:1 cis:trans, 99% y, 98% ee Ph 0 PhD MEDAM PhA .MEDAM Hn/ILR N 503 + N2 Ph‘“. ‘CONHPh _ . > 1:21 cis:trans, 90% y, -96% ee 9a 2, 14a, 67 ln-SItu generated (S)-VANOL-B3 catalyst MEDAM MEDAM = 3,5-tetramethyldianisylmethyl N 68 2; R = -OEt A 67; R = -N(CH3)Bn >50:1 cis:trans, 32% y, 93% ee The universal catalytic asymmetric aziridination is a computationally challenging system to explore. Each of the reactions studied computationally had 111 over 150 atoms. Exploring the conformational space and transition state geometries is a tedious task, if performed at a high level of theory. So we opted for the hybrid DFT:semi-emperical ONIOM method to obtain quality results in a reasonable time. Our primary goal was to gain a qualitative idea of the interactions between the catalyst and substrates at the transition states. Scheme 7.2 General mechanism of aziridination reaction of imines and diazo nucleophiles catalyzed by Lewis/Bronsted acid ,PG 0 (”G NI + H R' Lewis/Bronsted acid N + N2 /I\ catalyst A A R H N2 ' R COR' cis t trans 1 trans t cis 1 _ _ _ j _ 2 _ _ + H‘ + ,PG H‘ + ,PG l: t RJ‘TH RJEH R \H R \I‘f ‘. 1N2 ~, ,' ”2 H \ COR' R'OC \ H H COR' R'OCi \II/ T L d L H _ _ N2 _ L ”2 _ cisoid transition structures transoid transition structures — 1-1 H, ,PG bond rotation N z .3 - i H/R'OC H/COR' ‘ r 'P’G R' = -OEt, -NHPh + N2 —_> N PG = Protectin Grou L J A , g p ring closing transitlon structure R COR The mechanism of Lewis/Bronsted acid catalyzed aziridination reaction of imines and diazo compounds has received little experimental and no calculational scrutiny.86 The widely accepted mechanism invokes initial nucleophilic attack of the diazo compound at the iminium carbon to form a diazonium intermediate. There are four limiting orientations for this attack - two 112 cisoid approaches (quasi 3+2) and two anti-periplanar transoid approaches as shown in Scheme 7.2. This carbon-carbon bond forming step is the enantioselectivity and diastereoselectivity determining step of the reaction. Diastereoselection can be achieved if one of these approaches is preferred. This step is rendered enantioselective if the nucleophile can effectively discriminate between the Si and Re faces of the activated imine. Having formed the carbon-carbon bond, N2 is eliminated in an 8N2 fashion from the diazonium intermediate (directly from the transoid intermediates and after bond rotation from the cisoid intermediates) to form the three-membered aziridine ring. 7.2 Spectral data in support of the VANOL-Ba boroxinate complex The VANOL-83 boroxinate complex was generated according to Scheme 7.3, and was analyzed by "B NMR and 1H NMR. Scheme 7.3 Generation of the VANOL-83 boroxinate complex 1) 3 equiv BH3-SMe2 3 equiv H20 2 equiv PhOH toluene, 100 °C, 1 h 2) 0.1 mm Hg, 0.5 h, 100 °C 3) 1 equiv 9a, CDCI3 (S)-VANOL (S)-VANOL—B3 boroxinate (catalyst-imine complex) The 11B NMR spectrum of the VANOL-83 boroxinate complex is quite distinctive (Figure 7.1). Three-coordinate borate esters typically have broad absorptions for the boron between 16-20 ppm in CDCI3. Since 11B is a quadrapole, the sharpness of the absorption is related to the spherical symmetry 113 around the boron, and this is reflected in the appearance of the 11B NMR spectrum of the VANOL-Ba boroxinate complex (Figure 7.1). The two three- coordinate borons in the complex appear as a very broad absorption at 16.16 ppm, and the four-coordinate boron as a very sharp peak at 6.10 ppm, with an integration of 2:1 respectively (not shown). This is in perfect accord with the 11B NMR spectrums obtained previously for the VAPOL-Ba boroxinate complexes.11 Figure 7.1 11B NMR spectrum of the VANOL-83 boroxinate complex (CDCI3, 160 MHz) (top: complete spectrum, bottom: expanded view) 114 Figure 7.2 1H NMR spectrum of the VANOL-Ba boroxinate complex (CDCI3, 500 MHz) (top: complete spectrum, bottom: expanded view) 'le'IYYITIIV'IIYYIIIIIIV'IIYY'IYYI'IIII'jYTIIIYITl'WrYIT'TIIUUTIIVUIIIUVUTIjUYIl I I I I I T [I U I I l Tirr I I 1 I I 1' 65 55 The 1H NMR spectrum of the VANOL-Ba boroxinate complex is presented ' I 1 fi F I ‘T I T T I I ‘l' I 8.5 7.5 in Figure 7.2. The 1H NMR spectrum of the VANOL-83 boroxinate complex shows the absence of the signature doublet for VANOL at 8.34 ppm (J = 9.5 Hz), 115 and the presence of a new doublet at 8.55 ppm (J = 8.8 Hz). The singlet signals from the methines of the iminium were found at 5.38 and 8.37 ppm. The proton on the protonated iminium was located at 13.74 ppm. The complexity of the aromatic region suggests that the iminium is complexed to one face of the ligand and exchange with the other face is slow on the NMR time scale. While temperature studies were not performed to probe this, this was found to be the case for a related VAPOL complex at ~40 °C.11b 7.3 Exploring the geometry of the catalyst-imine complex The active catalyst in our universal aziridination protocol is a self assembled chiral polyborate Bronsted acid of unique structure.11 The iminium ion can potentially be bound to one of the four oxygen atoms 01, 02, 03 or 04 of the chiral counterion. NBO (Natural Bond Order) analysis performed on the (F?)- VANOL counterion (B3LYP/6-31G*//RHF/3-21G) revealed that electron densities on these oxygen atoms follow the order 02>O4>O1 >03 (Figure 7.3). Figure 7.3 NBO analysis of the (H)-VANOL-counterion -(‘).7 l 5 OPh —B 4 0 41950 Figure 7.4 Division of ONIOM layers; Final geometries and relative energies of four possible catalyst-imine complexes ONIOM Scheme Red - B31.YP/6-3l(i* Blue - AM] 04 bound imine O3 bound imine* EM = 8.9 kcals’inol l-ZRCI : 10.4 kcal/mol pno 0., PhD 0., l 75 1"” Ph I’ll/Ph Ar H _____ /B_O\g’ol 4O/B O\E_3’O )1“ > \8—0/ "”’//0 3\B—-O/ "”"Io Ar N PhO/ 2 P“ Phq/ 2 P“ \ \Ph 3 .‘2.07 ‘ Ar: + .\\H H Ar N \ ,ph H Ol bound imine* EM : 2.6 kcul/mol O2 bound imine [{Rcl : 0.0 kcul/mol PhO PhO 4 \B O 4 B 0 o/ 7 o/ \ B \ _- O \ B—O/ I!” Phg/ \Hl. Ph(%/ 2 * fixed distance minimization The starting geometry for the four possible points of coordination of the iminium ion and the boroxinate core of the (S)-VANOL-B3 catalyst is shown in Figure 7.4. These geometries were minimized and the ONIOM extrapolated energies were compared in order to determine the lowest energy complex. 117 Interestingly, the optimizations initiated from the O1, O2 and 03 bound iminium ion converged to the same 02 bound minimized geometry. In order to obtain a geometry corresponding to the iminium ion bound to 03 and 01, two calculations were initiated with the iminium ion in proximity to 03 and 01 respectively, with the distance of the iminium proton to 02 fixed at 3 A. This calculation gives us a crude idea of what the energy of these species would be, if indeed they could be located as local minima. Starting from the optimized geometries from these fixed distance calculations and releasing the iminium proton-02 distance resulted in the 02 bound species. This preference for the 02 bound species probably results from a combination of the stronger H—bonding to the oxygen atom with the highest electron density and favorable interactions with the VANOL ligand. The O4 bound species lacked these catalyst interactions and was consequently found to be significantly higher in energy. The O1 bound species, though H-bonded to a less electron rich oxygen, probably benefits from intimate stabilizing interactions with the catalyst making it the second most preferred geometry of the catalyst imine complex. The relative energy of each of the four species either from complete minimization or fixed distance minimizations is also shown in Figure 7.4. The biaryl system with the S-configuration appears to effectively shield the He face of the iminium ion, keeping the Si face accessible for nucleophilic attack. This is consistent with the absolute configuration of the cis-aziridine 74 in reactions of 9a and 2. However one cannot rationalize, based on the 02 bound species in Figure 7.4, the Re facial attack that must occur in order to form the 118 observed enantiomer of the trans-aziridine 60a in reactions of 9a and 14a. There clearly has to be some interaction between 14a and the catalyst, that is absent in reactions of 2, at the stereochemistry determining transition state, that reverses both the diastereoselectivity and the facial selectivity to the imine in this reaction. 7.4 Transition state models Transition structures for the key carbon-carbon bond forming step of the reactions of 9a and either 2, Me or 67 catalyzed by the (S)-VAN0L-B3 catalyst were located using 0N|0M(B3LYP/6-31G*:AM1) calculations.87 The color scheme in Figure 7.4 illustrates the division of layers for the ONIOM calculations. In addition to the portions shown in red, the diazo nucleophile was also calculated using the DFT method. All distances are reported in angstroms. All reported energetics are single point energies of fully optimized geometries from the ONIOM calculations computed at the B3LYP/6-31+G* level of theory. This approach has been reasonably successful in qualitative predictions of stereoselectivity in similar reactions.88 The lowest energy transition structures leading to the observed enantiomer of the cis- (T81) and trans- (T52) aziridine in the reaction of 9a and 2 are shown in Figure 7.5. The key observation in both these structures (and in all structures discussed below) is that, unlike in the catalyst-imine complex depicted in Figure 7.4 (OZ-bound species), the iminium proton is no longer closest to 02. As a general trend, protonated 9a is H-bonded to 01 in all cis-, and to 03 in all trans- transition structures. There also exists a stabilizing non-covalent interaction between the acidic d-CH of 2 and 02/01 of the catalyst core in T81 119 and T82. The acidity of the d-CH of diazo compounds is well established (even a simple base such as DBU has been shown to cause deprotonation).89 Numerous other transition structures similar to T81 and T82 were located that did not have this non-covalent interaction. While they reproduced the diastereoselectivity, they were on an average 24 kcal/mol higher in energy than either T81 or T82. In order to accommodate this interaction, attack of 2 occurs via a syn-clinical approach relative to the iminium double bond in T81 and via a trans- antiperiplanar approach in T82 (similar to the cisoid and transoid transition structures in Scheme 7.2). T81 is 3.1 kcal/mol lower in energy than T82 and this difference is qualitatively consistent with the experimentally obsen/ed >50:1 cis:trans ratio for this reaction at room temperature. T81 (ent.) in Figure 7.5 is the transition structure leading to the minor enantiomer of the cis-aziridine 74 and corresponds to a Fla-facial attack of 2 with 9a H-bonded to 03. This geometry is similar to T82 with regard to the points of contact of the two key non-covalent interactions (9a bound to 03 and the a-CH of 2 bound to 01), the only difference being that the face of 2 is now switched with respect to T82 to now give the cis-aziridine. The energy of this transition structure relative to T81 is shown and it is in good agreement to the 98% ee observed experimentally. 120 Figure 7.5 Transition structures T81, T82 and T81 (ent.) accounting for the diastereoselectivity and enantioselectivity in reactions of 9a and 2 TS l (cis) like. : 0 kcall’mol TS 2 (trans) like. = 3.1 kcal/mol Ph0\ PhD 8 o _ /B o _ 0< 2>e. 0\ 2>e /a-—o 3 /B—0 PhO I latto~~~ 3 1.99,; N‘ 2J4 ‘H/h'N I < + 5 : PG PG 1 x N?- “ ...... 3“ pmu‘ ’i.79 l.87 H TS] (ent.) (cis) ERCI = 1.9 kcalr’mol Ph0\ a o 0< 2\ 3 /B—0 Ph0\ 2.12‘~ PG /,, i N. |I”’ \,.c 1. Ph\\\\ 1 H 121 Figure 7.6 Transition structures T83, T84 and T84 (ent.) accounting for the diastereoselectivity and enantioselectivity in reactions of 9a and 14a TS 4 (trans) ERel = 0 kcalt’l'nol TS 3 (cis) ERG. = 2.6 kcal‘mol Ph0\ PhD 8 o _ B—O _ / \ / \ C§\l3—<23/B""" %\B—C2)/ PhO/ ' " P“ Ph0/ ‘271 + ’11 95 \H \\ PG\\ .2. 2 04 \‘ N2 *4 NL‘PG l 99 \H/" r \H 7 ‘ l‘ p. l: .54 --- ‘C"’ N/n, 1-86 I 198! Ph/ K H h‘\l N2 0 H + TS 4 (ent.) (trans) ERCI = l 1.4 koal‘mol PhO B O _ / \ ’ O 2 B. ’ 3\B o/ PhO l 2.02 ‘. .' 2 09N, ’ \H :«1PG Ph’N F N; O [\llz 1.9... ‘ + H Transition structures T83 and T84 were then located for the reaction of 93 and 14a (Figure 7.6). Both T83 and T84 are characterized by non-covalent H- bonding interactions between (a) the iminium proton and 01/03, (b) the a-CH of 14a and 02, and (c) the amidic hydrogen of 14a and 03/01. While H-bonding interactions (a) and (b) are also present in T81 and T82, (c) is exclusive to T83 122 and T84. Therefore, the reversal of diastereoselectivity must have its origins in the relative strength of the H-bonding interaction (c) in T83 versus T84. Hydrogen bond strengths are characterized both by the bond distances and the donor-H-acceptor angle — with short, linear hydrogen bonds being the strongest interactions.90 The amide hydrogen-oxygen H-bond is shorter (1.94 A versus 2.04 A) and closer to linearity (176° versus 159°) in T84 as compared to T83. Consequently, T84 is 2.6 kcal/mol lower in energy than T83 and this is consistent with the experimental trans-selectivity. T84 (ent.) is the transition structure leading to the minor enantiomer of the trans-aziridine 60a and corresponds to a Si-facial attack of 14a with 9a H-bonded to 01. This geometry is similar in all respects to T83 with the only difference being that the face of 14a is now switched with respect to T83. The energy of this transition structure relative to T84 is shown. This difference is qualitatively consistent with the experimentally observed >95°/o ca. 7.5 Mechanistic probes for the proposed transition state models As a mechanistic probe for the importance of this third H-bonding interaction in impacting diastereoselectivity, we decided to explore the aziridination reaction of 9a and N-methyl-N-benzyldiazoacetamide 67 (Scheme 7.1). Being a 3° diazoamide, 67 lacks the key amide proton and we expected to see the reaction of 9a and 67 to revert to a cis-selective reaction, analogous to the reaction of 9a and 2. Not surprisingly, this was indeed the case — the reaction carried out at room temperature gave almost exclusively the cis-aziridine (Scheme 7.1). Transition structures T85 and T86 were then located for the 123 reaction of 93 and 67 (Figure 7.7). Comparing the pairs of transition structures T83/T 85 and TS4/TS6, all key distances are almost identical and clearly the only difference of note is the absence of the H-bond between the amide hydrogen and 03/01 in T85 and T86. Remarkably, T85 is now favored over T86 by 4.3 kcal/mol, once again in complete accord with the experimental (>50:1) cis:trans ratio. Figure 7.7 Transition structures T85 and T86 accounting for the diastereoselectivity in reaction of 9a and 67 TS 5 (cis) ERG. = 0 kcaI/mol TS 6 (trans) FRel : 4.3 kcal/mol PhO PhO B—O - B—O - O / \ / \ ’ O\ Z/B'luull O\ 2/B-u,,,” 3 /B—0 3 /B—Q phO :2 08 H pro (2 11 + r. ' ~\\ 7 0.7 \\ PG \‘ N23 N"PG H/"N' :1 (EH3 0: ..... (Ifep i: /(i:‘< Ph 1 93 («0'1 87 / NIH, ‘ \\\ . ‘- \/ H Ph\ 1 N2 0 H + Jacobsen and co-workers have recently illustrated the concept of ‘cooperative catalysis’ in Bronsted acid catalyzed reactions using chiral ureas/thioureas in a series of elegant publications.91 Based on our understanding of the non-covalent interactions that stabilize the transition states in the aziridination reactions catalyzed by the B3-catalyst, and the idea that triflic acid 91d W could function as a H-bonding counterion (as in the Jacobsen system), e decided to explore the aziridination reactions of 1b and 2,86b 14a or 67 catalyzed 124 by triflic acid (Chapter 3, Section 3.4.9, Scheme 3.7). Our hypothesis was that in the event that the three oxygen atoms of the triflate anion could stabilize the aziridination transition state in a manner similar to our B3-catalyst, we could have tunable diastereoselectivity even in this simple reaction, depending on the diazo nucleophile used. To our delight, identical to the trends observed in our system, we observed trans-selective aziridination in the reaction of 1b and 14a and cis- selective aziridination in reactions of 1b and 2/67 (Chapter 3, Section 3.4.9, Scheme 3.7). Figure 7.8 Transition structures T87 and T88 accounting for the diastereoselectivity in reaction of 1b and 14a TS 7 (cis) TS 8 (trans) ERG] = 2.0 kcal/mol EReI = O kcal/mol 0 FC\ 3 /S\517H7 187 UN PGII, ,"N H//:’ ‘H’ Hlllt /.81 We then sought to reproduce this experimental observation based on the transition state model for the B3-catalyzed reaction (Figure 7.8). The trans- antiperiplanar orientation of the double bonds of 1b and 14a in T88 sets up the three strong H-bonding interactions with the triflate anion, virtually identical to T84. The only transition structure located for the formation of the cis-aziridine in the reaction of 1b and 14a is T87 and it lacks one of the three H-bonding 125 interactions present in T88. Consequently it is 2.0 kcanol higher in energy than T88. While this result reinforces the validity of our model, it also emphasizes the importance of considering multiple non-covalent interactions as a control element in the other Bronsted acid catalyzed aziridinations.13"5'17 7.6 Conclusions and future direction Ours is a unique template in asymmetric catalysis. We have shown that the polyborate catalyst self-assembles only in the presence of the imine substrate.11 During a catalytic cycle, the boroxinate core executes key functions that are quintessential for asymmetric catalysis. It activates the imine electrophile by protonation and imparts enantioselection in nucleophilic additions to the imine by serving as a chiral counterion. Diastereoselection is achieved when the polyborate core directs the orientation and approach of the diazo nucleophile to the ‘active site’. It also lowers the energy of the transition state via multiple stabilizing H-bonding interactions with both substrates. Finally, it disassembles upon product formation and enters into another catalytic cycle by self-assembling with another molecule of the imine. This mode of catalysis is reminiscent of nature’s strategy of lowering reaction barriers. ‘Counterion catalysis’ has emerged as a powerful strategy in asymmetric proton catalysis.92 The mode of catalysis described in this chapter adds a new dimension to counterion catalysis by integrating into it some of the key features of H-bonding catalysis. This theoretical analysis of the catalyst-substrate interactions lays the groundwork for the rational development of newer reaction 126 types using our catalyst. Experimental characterization of the transition state geometry and the rate-limiting step in these reactions is detailed in Chapter 8. 127 CHAPTER EIGHT KINETIC ISOTOPE EFFECTS AND MECHANISM OF THE AZIRIDINATION REACTION The work described in this chapter was carried out in collaboration with Dr. Mathew Vetticatt (Albert Einstein College of Medicine, New York). 8.1 Transition state theory and kinetic Isotope effects Within the framework of conventional transition state theory (TST), selectivity observed in reactions is associated with relative energies of competing transition states, with the preferred product in a reaction arising from the lower energy transition state. Catalysis is explained in terms of lowering of the energy of the transition state relative to that of the uncatalyzed reaction. In short, TST has formed the basis of our understanding of how reactions work. Kinetic isotope effect (KIE) measurements are powerful mechanistic probes. The origin of KlEs lies in how isotopic substitution affects the vibrational modes associated with the reaction coordinate. The magnitude of the change in the vibrational normal modes, caused by isotopic substitution, is different at the stage of reactants and at the transition state. It is this difference that results in an isotope effect. It follows therefore that KlEs can be used to experimentally probe the transition state geometry, i.e. the extent of bond formation/bond breaking occurring as the reaction goes over the transition state. Each individual carbon and hydrogen atom in an organic molecule contains at natural abundance 1.109% of 13C and 0.015% of 2H. As a reaction 128 progresses, the starting materials are enriched in the slower reacting isotope and the products in the faster reacting ones. If this isotopic enrichment at every position in a molecule can be measured, KlEs can be determined without the use of explicitly labeled substrates. The Singleton method uses 13C NMR at natural abundance in order to measure this isotopic change that determines the magnitude of the KIEs.93 This method has been used for the elucidation of several important organic and organometallic reactions.94 There are mainly two approaches to measure KIEs by this method; these are described below. (A) Intermolecular starting material KlEs: Reactions are taken to high conversion (typically ~80°/o) and the starting material of interest is recovered. The isotopic composition of this recovered material is determined by NMR methodology at natural abundance and compared to that of unreacted starting material (drawn from the bottle originally used for the reaction). The enrichment (depletion) thus measured can be used to determine the KlEs. (B) Intermolecular product KlEs: Reactions are taken to low conversion (typically ~20%) and the product of interest is isolated. The isotopic composition of this isolated product is compared to that of a product isolated from a 100% conversion reaction (no isotopic fractionation), and the KlEs are thus determined. Having measured the experimental KlEs, the next step is to assume a mechanism, develop a theoretical model and make predictions for the isotope effects. These calculations will be used to predict KlEs for a variety of mechanistic possibilities. The match of experimental and theoretical KlEs gives 129 valuable insight to the reaction mechanism and provides an ‘experimental’ picture of the transition state geometry of the KIE determining step of the reaction. This step is either the first irreversible step or the rate-limiting step of the reaction. 8.2 Design of experiment The aziridination reaction of imine 9a and ethyldiazoacetate 2 provides us with a robust reaction to measure 13C KIEs. At room temperature, this reaction has been shown to give 97% yield of the cis-aziridine 74 with 99% ee, with a cis:trans ratio of >50:1.10 The advantage of such high diastereoselection and asymmetric induction is that one needs to consider only one transition state for the theoretical interpretation of KlEs. Scheme 8.1 Design of intermolecular product KIE measurement B(0Ph)3 (4 equiv) 0.1 mm 9 H20 (1 equw) 0.5 h, 80 °C‘ toluene_ (R)-VANOL = 7 stock solution of 1 equiv 80 °C, toluene, 1 h catalyst REACTION 1 0 20 mol% MEDAM (R)-VANOL-B catalyst PhAN.MEDAM + (Moe 3 = .23., N2 toluene, 25 °C, 15 h Ph“ ’C02Et 9“ 2 74 (0.2 equiv) 1.0 equiv (5.29 mmol) 0.2 equiv (1.06 mmol) 1st run' 95% yield 99% ee 2nd run: 93% yield, 99% ee REACTION 2 0 20 mol% It'llEDAM (R)-VANOL-B catalyst PhANMEDAM + (805, 3 : £5 N2 toluene, 25 °C, 15 h Ph“ ’CozEt 9‘ 2 74 (0.2 equiv) 0.2 equiv (1.06 mmol) 1.0 equiv (5.29 mmol) 1st run' 90% yield 99% ee 2nd run: 94% yield, 99% ee 130 Isolation of 9a or 2 from a reaction mixture is a tedious task and hence intermolecular starting material KlEs was excluded as a possible strategy. However 74 can be isolated relatively easily by column chromatography and hence we chose to perform intermolecular product KIE measurements to determine the isotope effects and thereby the mechanism of this reaction. Shown in Scheme 8.1 is the design of experiment for making this measurement. The first reaction shown in this scheme is run using 2 as the limiting reagent (0.2 equiv with respect to 1 equiv of 9a). The sample of 74 isolated from this reaction will correspond to a 20% reaction of imine and 100% reaction of ethyldiazoacetate. In the second reaction the stoichiometry is reversed and we will now have a sample that corresponds to 20% reaction of ethyldiazoacetate and 100% reaction of imine. By comparing the 13C composition of the carbon atoms that originally belonged to 9a, in the sample of 74 isolated from reaction 1 versus reaction 2, one can determine the 13C KIE for all the carbon atoms belonging to 9a. From the same two NMR spectra by simply reversing the standard for comparison, one can also get the 13C KIE for all the carbon atoms belonging to 2 (Le. by comparing the 13C composition of the carbon atoms that originally belonged to 2 in the sample of 74 isolated from reaction 2 versus reaction 1). One can thus calculate the experimental 13C KlEs at every position (with separated 13C NMR signal) of 74, using the fractional conversion and the relative abundance of 13C in sample versus standard NMR spectra. This measurement is made in duplicate (from two independent sets of samples). This novel process eliminates the need 131 for extra product isolation and analysis, and provides all of the 13C KlEs for the reaction from the analysis of two product samples. 8.3 Experimental KIEs The reactions of imine 9a with ethyldiazoacetate 2 proceeded smoothly at room temperature and afforded the cis-aziridine 74 in near-quantitative yields and asymmetric inductions (Scheme 8.1). The 13C KlEs for both components in this reaction were determined from NMR analysis of the products at natural abundance. Separate reactions were run to low conversion (~20°/o) in 9a (using limiting 2) and in 2 (using limiting 9a). The KlEs were then determined by comparison of the 13C composition of the product 74 to product samples derived from reactions in which the same starting material was taken to 100% conversion as described in the previous section. Figure 8.1 Experimental 13C KIEs (k120/k13C, 25 °C) for the reactions of 9a with 2, with 95% confidence limits on the last digit shown in parentheses. 1.008(9) Ar\rAr 1.050(8) 1.009(4) >N /O1 047(5) O i x 1.000 (assumed) The 13C KlEs based on two independent sets of reactions of 9a and 2 as described in the previous section are shown in Figure 8.1. The methyl group on the ester moiety was used as the standard for the measurement under the assumption that there is no isotopic fractionation at this position at the transition state. For clarity, only the KIEs of the key bond forming centers are shown. The 132 results are remarkable and help to qualitatively eliminate two mechanistic possibilities. The near unity KIE on the carbon that originally belonged to the imine suggests that it is not involved in the rate limiting transition state. This would imply that the carbon-carbon bond forming event is not rate-limiting. It does not tell us anything about the stepwise or concerted nature of this first necessary event in the reaction. The KIE on the ethyldiazoacetate carbon is large and answers this question. A large KIE on one of the bond forming centers and a minimal KIE on the other is clear indication that a two-step process is operational. And by extension, a two-step process precludes a concerted mechanism. The qualitative interpretation of this set of KIEs is that carbon- carbon bond formation is not rate-limiting and that ring closure to form the aziridine ring is likely the rate-limiting step of the reaction. The large carbon KIE on the diazoacetate carbon onto which the imine nitrogen ring closes is consistent with this scenario. One can now predict the KlEs for these two events being rate-limiting and a match between experimental and theoretical KlEs will lend support to this qualitative analysis. 8.4 Predicted KIEs and interpretation As a first step in the interpretation of the experimental KIEs, the reactions of 9a with 2 were explored using ONIOM(B3LYP/6-31G*:AM1) calculations. Transition structures for the carbon-carbon bond forming step (TS1c-c) and the ring-closing step (TS1RC) are shown in Figure 8.2. KlEs were predicted assuming each of these TSs as rate-limiting. 133 Figure 8.2 Relevant transition structures for the theoretical interpretation of experimental KlEs TS 1(‘-(.‘ Figure 8.3 Comparison of experimental and predicted KlEs for the two key transition structures Ar\r Ar N PhACO Et / \ ’ 1.008(9) 1.050(8) EXP' 1.009(4) 1.047(5) TS1C-C 1.033 1.031 TSiRC 1.006 1.050 Figure 8.3 shows the predicted KlEs for each of the transition structures shown in Figure 8.2. Consistent with our qualitative analysis of the KIEs, the predicted KlEs for T8100 are significantly different from our experimentally 134 determined values. The predicted KIE (1.033) for the bond-forming carbon of the imine 9a in T8104; is significantly higher than experiment. The predicted KIE for the bond-forming carbon of the diazoacetate 2 in T8100 is 1.031, almost 2% lower than the observed KIE at this position. These results clearly lend no support to the carbon-carbon bond forming event being the rate-limiting step of the reaction. Once the initial bond is formed, the carbon atom of the imine does not undergo rehybridization at the transition state for the ring closure to the aziridine. The bond-forming event in T8190 is between the imine nitrogen and the carbon atom of the diazo nucleophile. There is also a slight loss of bond order between the same carbon and the N2 leaving group. This concomitant bond-making and bond-breaking event at the diazo carbon should amplify the KIE at this position. The KlEs predicted for TSRC are consistent with this analysis and are shown in Figure 8.3 in blue. These values are distinct from those for T8100 and are in remarkable agreement with our experimental KIEs at both positions. Thus our experimental KlEs are qualitatively and quantitatively consistent with the ring- closure stop being rate limiting. 8.5 Discussion and future experiments We have presented compelling evidence that the rate-limiting step in the Wulff aziridination is the second bond-forming event in the catalytic mechanism — the 8N2 type elimination of N2 and ring closure to form the aziridine. In a multi- step reaction, one imagines the slow step to be the one with the largest entropic cost. Bringing together two molecules that are free in solution into a near-attack 135 conformation requires significant organization at the transition state. An intramolecular step in a catalytic mechanism, like the ring-closing step, is expected to be much faster and is rarely thought of as the rate-limiting event. We believe that the answer to this puzzle lies in the unique structure and mode of catalysis of the self-assembled B3 catalyst. From the theoretical analysis of the key interactions occurring at the transition state for the initial carbon-carbon bond formation (Chapter 7), we know that in forming the cis-aziridine 74, the diazo nucleophile approaches the catalyst-imine complex in a syn-clinical geometry. The anionic oxygen atoms of the boroxinate core form key H-bonding interactions with both 9a and 2 and significantly lower the barrier of this transition state. Now, having formed the bond, the a—diazonium B—amino ester intermediate also enjoys the same interactions with the catalyst, leading to a stabilized intermediate. In order to eliminate N2 and ring-close to form the aziridine, this intermediate needs to rotate and orient the leaving group N2 in a trans- antiperiplanar orientation to the carbon-nitrogen bond of the original imine. There are two factors that make this bond rotation unfavorable: (1) The d-CH to 0 interaction that stabilizes T81 and the intermediate has to be compromised as the bond-rotation occurs and (2) in the anti-periplanar orientation, the ester group might have steric interactions with the boroxinate core. The combined effect of stabilizing the carbon-carbon bond forming transition state (and the resulting intermediate) by non-covalent interactions with the catalyst and the energetic penalty of bond rotation and completion of the ring closure likely makes the second step rate-limiting. 136 One final question needs to be addressed here and will be the subject of future mechanistic work of this reaction. If the ring-closing step is slow because of the energetic penalty of bond rotation, then what about the trans-selective aziridinations where bond rotation is not required since the initial attack itself is in the trans-antiperiplanar orientation? Is there a possibility that the rate-limiting step for the formation of the trans-aziridine is different from the cis-selective reactions? This is an intriguing question and can quite easily be addressed by performing the same experiments described in this chapter, but using N-phenyl diazoacetamide instead of ethyldiazoacetate and analyzing the trans-aziridine product. A change in the rate-limiting step for two similar reactions mediated by the same catalyst is rare in solution chemistry but is often the hallmark of enzymatic catalysis. 137 CHAPTER NINE RAMBLING FANTASIES OF AN ASYMMETRIC CATALYSIS AFICIONADO A doctoral degree is a long drawn process which usually involves the following steps: proposal of an idea, the design of experiments, subsequent execution of these experiments, analysis of data, and validation of the initial proposal. This process more often than not breaks down along the chain, and the student has to start from the first step all over again, which is the proposal of a new idea. Having gone through this process several times, quite a few ideas were generated during the course of the present dissertation, many straight out absurd, some with slim chances of success. A few ideas belonging to the latter class, which have not been evaluated in this dissertation, will be briefly summarized here. There have been several sections in this dissertation where potential future work has been suggested, these will be mentioned first. (1) Ways to further improve the asymmetric inductions in the 2,3- dicarbonyl cis-aziridination project have been suggested (Chapter 2, Section 2.4, Scheme 2.5). An interesting idea would be to combine this with the study of the aziridination of the same imines with diazoacetamides, where surprisingly the cis- aziridine was observed as the major diastereomer (Chapter 3, Section 3.4.6, Scheme 3.5). An entire project could be constructed by combining these two experimental studies with a mechanistic understanding of the origins of the strange cis-selectivity with the diazoacetamides, with the aid of computational chemistry in collaboration with Dr. Mathew Vetticatt. 138 (2) An unprecedented catalytic asymmetric synthesis of tri-substituted aziridines has been proposed (Chapter 2, Section 2.6). Evaluating this should be straightforward, once the requisite diazo compound is prepared. (3) An aziridination protocol with a different “carbene” source has been proposed, mediated by the VAPOLNANOL-B3 catalysts (Chapter 3, Section 3.2, Scheme 3.1). (4) Previously our laboratory has studied the reactions of alkynyl imines with diazoacetates to afford cis-aziridines?"40 Surprisingly again, the reaction of an alkynyl imine and a diazoacetamide, with the same 83 catalyst, also afforded the corresponding cis-aziridine as the major diastereomer (Chapter 3, Section 3.4.6, Scheme 3.5). These reactions were especially clean. If pursued satisfactorily, this could make a nice addition to the experimental alkynyl imine aziridination study. Again with this project, a theoretical investigation could be initiated in collaboration with Dr. Mathew Vetticatt, to understand this strange switch in diastereoselectivity to favor the cis-aziridine in the reaction of diazoacetamides. (5) More efficient deprotection of the trans-aziridines, than what has been obtained during this dissertation (Chapter 3, Section 3.4.11), should be developed. (6) A few suggestions for further optimization and development of asymmetric transfer hydrogenation mediated by the VAPOLNANOL-B3 catalysts have been made (Chapter 4, Section 4.7). 139 (7) Multi-gram quantities of the new chiral ligands and Bronsted acid catalysts based on the framework of VAPOL and VANOL have been made (Chapter 5). These will be available in the research group. Detailed procedures have been described. These are structurally distinct ligands and catalysts, and should give singular profiles for reactivity and asymmetric inductions as compared to the traditionally used BINOL derivatives. It would be interesting to screen them for different reactions. (8) Ways to further improve the catalytic asymmetric Darzens reaction have been suggested (Chapter 6, Section 6.3). There have been several ideas that have been generated from general literature reading through these years, which are related to the kind of asymmetric catalysis being pursued in our group. Some of these ideas will be summarized herein. (1) lshikawa and co-workers have recently reported interesting applications of non-activated trans-ester aziridines of the type shown in Scheme 9.1.95 Their starting aziridines are very similar to the aziridines of the type 73 prepared in Chapter 3 (Section 3.4.8, Scheme 3.6); thus these would make for worthwhile applications of our trans-selective aziridination protocol. 140 Scheme 9.1 Ishikawa’s applications of non-activated trans-ester aziridines r ‘ Ph Phj freshly prepared 8 N EtzAlCN HN .. {DUQWCOZ‘Bu PhH, 0 °C, 2.5 n NC“. L O . 92% >=< ~78 °C. 2 h CF3C02H, CHZCIZ 40 °c, 5 n OMe ’ 82% ‘ 87% ,, Ph \\ '\\C02tBU CN OX' 0 ’ COztBu \ O < > om O (2) Ackermann in 2008 reported an intramolecular (racemic) hydroamination protocol for non-activated alkenes, catalyzed by racemic chiral phosphoric acid catalysts prepared from 3,3’-disubstituted BINOL ligands.96 They had one enantioselective example, providing the product in only 17% ee (Scheme 9.2). Scheme 9.2 Ackermann’s proof of principle for intramolecular hydroamination 00 " Bn 0\ o I ” Ph NH 20 mol% catalyst _ Ph ”’8” “0’ ROH Ph \ 1.4-dioxane. 130 °C, 20 h Ph CO 17% e N catalyst Ar = 3,5-(CF3)2C6H3 There is no example of a metal-free catalytic asymmetric hydroamination of non-activated alkenes in the literature. Thus, Ackermann’s study is a proof of principle for this field. With the appropriate N-substitution (benzyl, benzhydryl, 141 MEDAM or even no substitution), it would definitely be worthwhile to attempt to catalyze the above reaction with our VAPOLNANOL-B3 catalysts. Alternately, the phosphoric acid and N-triflyl phosphoramide derivatives of VAPOL/VANOL prepared in Chapter 5 would be interesting to evaluate under the same reaction conditions. (3) Lectka and co-workers in 2009 reported an interesting synthesis of trans-fl-lactams catalyzed by fluoride salts (Scheme 9.3, eq 1).97 In the proposed mechanism, the fluoride from the catalyst cleaves the trimethylsilyl ketene acetal 147 generating the enol in-situ which attacks the imine 143, leading to an intermediate which subsequently cyclizes on what was originally the trimethylsilyl ketene acetal carbon eliminating phenoxide, and leading to the formation of the fl-lactam 148. To the best of our knowledge, an enantioselective variant of this reaction would be unprecedented in the field of ,B-lactam synthesis. Scheme 9.3 Lectka’s ,B-lactam and Akiyama’s Mannich-type systems PMP OMe R OPh 10 mol% PPh4F ‘N O + )=( — (e 1 ref 97) A ' . q . - 143 147 148 OH 13.821291818 (I ArAN + >—‘=< ’ > NH (eq 2, ref. 98) OH OMe A, Ar/'>2 e 1e N-(2-bromobenzylidene)-1,1-diphenylmethanamine 19.25 Crystallization (1:5 ethyl acetate/hexanes) afforded 1e in 81% isolated yield as a white solid (mp. 113-114 °C). Spectral data for 1e: 1H NMR (CDCI3, 300 MHz) 6 5.71 (s, 1H), 7.27-7.81 (m, 13H), 8.27 (dd, 1H, J = 8, 2 Hz), 8.88 (s, 1H); 13c NMR (CDCI3, 75 MHz) 6 78.06, 127.06, 127.53, 127.61, 128.47, 129.23, 131.89, 132.96, 143.58, 159.80; IR (thin film) 3061m, 3026m, 16318, 14933, 10283, 7563 cm"; mass spectrum, m/z (% rel intensity) 351 M“ (4, 81Br), 349 M+ (5, 79Br), 165 148 (100), 152 (53), 151 (84), 88 (52). Anal calcd for C20H16BrN: C, 68.58; H, 4.60; O ,U" 0 1f N, 4.00. Found: C, 68.39; H, 4.73; N, 3.93. N-(4-bromobenzylidene)-1,1-diphenylmethanamine 1 {6'26 Crystallization (1 :5 ethyl acetate/hexanes) afforded 1f in 70% isolated yield as a white solid (mp. 98-97 °C). Spectral data for 1f: 1H NMR (CDCI3, 300 MHz) 8 5.23 (s, 1H), 7.15- 7.35 (m, 10H), 7.47 (d, 2H, J = 7 Hz), 7.84 (d, 2H, J = 7 Hz), 8.28 (s, 1H). 13c NMR (CDCI3, 75 MHz) 5 77.85, 127.05, 127.60, 128.46, 129.84, 131.75, 143.62, 0 WU” O 19 159.51. N-(4-nitrobenzylidene)- 1, 1 -diphenylmethanamine 1g.26 Crystallization (1 :1 ethyl acetate/hexanes) afforded 19 in 80% isolated yield as an off-white solid: mp. = 132-134 °C (lit27 134-135 °C). Spectral data for 19: 1H NMR (CDCI3, 300 MHz) 5 5.76 (s, 1H), 7.30-7.40 (m, 10H), 8.08 (d, 2H, J: 8 Hz), 8.31 (d, 2H, J: 8 Hz), 8.52 (s, 1H). "‘0 NMR (CDCI3, 75 MHz) (1 sp2 carbon missing) 8 78.09, 123.80, 127.28, 127.55, 128.57, 129.10, 141.65, 143.14, 158.51. 149 O U “ 0 1h N-(4-methoxybenzy/idene)-1,1-diphenylmethanamine 1h. Crystallization (1:5 ethyl acetate/hexanes) afforded 1h in 85% isolated yield as white crystals: mp. 108-109 °c (lit27 108-109 °C). Spectral data for 1h: 1H NMR (CDCI3, 300 MHz) 5 3.82 (s, 3H), 5.55 (s, 1H), 6.91 (d, 2H, J = 8.8 Hz), 7.28-7.40 (m, 10H), 7.78 (d, 2H, .1 = 8.8 Hz), 8.34 (s, 1H); 13c NMR (CDCI3, 75 MHz) 8 55.32, 77.77, 113.88, 126.85, 127.67, 128.37, 129.99, 144.11, 160.01; IR (thin film) 2849m, 1632s, 1493m, 1028m, 7569 cm"; mass spectrum, m/z (% rel intensity) 301 M+ (18), 188 (10), 187 (100), 184 (41), 152 (22), 78 (11). Anal calcd for C21H19NO: C, 83.69; H, 6.35; N, 4.65. Found: C, 83.60; H, 6.35; N, 4.52. O MOD/SN O AcO 1i 4-((benzhydlylimino)methyl)-1,2-phenylene diacetate 1i.6 Crystallization (1:5 ethyl acetate/hexanes) afforded 1i in 66% isolated yield as white crystals (mp. 138-139 °C). Spectral data for 1i: 1H NMR (CDCI3, 300 MHz) 6 2.29 (s, 3H), 2.30 (s, 3H), 5.62 (s, 1H), 7.24 (m, 3H), 7.33 (t, 4H, J = 8 Hz), 7.38 (d, 4H, J = 8 Hz), 7.88 (dd, 1H, J = 8, 2 Hz), 7.77 (d, 1H, .1 = 2 Hz), 8.37 (s, 1H); ”C NMR (CDCI3, 75 MHz) 8 20.64, 20.70, 77.62, 122.88, 123.60, 126.99, 127.11, 127.68, 128.50, 135.16, 142.44, 143.59, 144.07, 158.85, 168.02, 168.22; IR (thin film) 150 1775s, 16408 cm"; mass spectrum, m/z (% rel intensity) 387 M+ (10), 167 (100). Anal calcd for C24H21NO4: C, 74.46; H, 5.47; N, 3.62. Found: C, 74.17; H, 5.66; M: o N-butylidene-1,1-diphenylmethanamine 11.6 Crude product obtained as a N, 3.58. light yellow oil in 74% yield. Spectral data for 1]: 1H NMR (CDCI3, 500 MHz) 6 0.95 (t, 3H, J = 7.5 Hz), 1.60 (q, 2H, J = 7.5 Hz), 2.33 (dt, 2H, J = 7.5, 5 Hz), 5.35 (s, 1H), 7.1-7.4 (m, 10H), 7.84 (t, 1H, J: 5 Hz). cc N-(cyclohexy/methylene)-1,1-diphenylmethanamine 1k.6'23 Crystallization (1:5 ethyl acetate/hexanes) afforded 1k in 74% isolated yield as an off-white solid: mp. 49-51 °c (lit23 48-49 °C). Spectral data for 1k: 1H NMR (CDCI3, 300 MHz) 6 1.10-1.90 (m, 10H), 2.20 (bs, 1H), 5.21 (s, 1H), 7.00-7.60 (m, 10H), 7.59 (d, 1H, J = 5.5 Hz). 13c NMR (CDCI3, 75 MHz) 8 25.82, 28.41, 30.13, 43.91, 78.35, 127.20, 127.97, 128.73, 144.41, 169.51. 151 m 0 N-(2,2-dimethylpropylidene)-1,1-diphenylmethanamine 1l.6 Crystallization (1:9 ethyl acetate/hexanes) afforded 1| in 35% isolated yield as white crystals (mp. 51-515 °C). Spectral data for 1|: 1H NMR (CDCI3, 300 MHz) 8 1.27 (s, 9H), 5.50 (s, 1H), 7.34 (t, 2H, J = 7 Hz), 7.44 (t, 4H, J = 7 Hz), 7.49 (d, 4H, J = 7 Hz), 7.85 (s, 1H); 13c NMR (CDCI3, 75 Hz) 8 26.94, 38.38, 77.38, 126.68, 127.44, 128.25, 144.23, 171.48; IR (thin film) 1888s cm"; mass spectrum, m/z (% rel intensity) 251 M“ (<1), 167 (100). Anal calcd for C13H21N: C, 86.08; H, 8.43; N, 5.58. Found: C, 85.82; H, 8.58; N, 5.53. General procedure for the Wulff catalytic asymmetric cis-aziridination — illustrated for the synthesis of (28,3S)-ethyl 1-benzhydryI-3-phenylaziridine- 2-carboxylate 3b 5 mol% PhYPh (K (R)-VANOL-B3 catalyst N OEt ./_\. U: toluene, 25 °C, 24 h E)“ "C02Et (28,3S)-3b (28,3S)-ethyl 1-benzhydryl-3-phenylaziridine-Z-carboxylate 3b.6 The catalyst was prepared by the following method. A magnetic stir bar was added to a 25 mL pear shaped flask that had its 14/20 joint replaced by a high vacuum threaded T-shaped Teflon valve and then the flask was flame-dried and cooled 152 under argon. To the flask was added (Fl)-VANOL (21.9 mg, 0.05 mmol) and triphenylborate (58 mg, 0.2 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 (0.9 ,uL, 0.05 mmol). The Teflon value was closed and the flask was heated at 80 °C for 1 h. The threaded Teflon value was opened to gradually apply high vacuum (0.05 mm Hg) and to remove the solvent. The vacuum is maintained for a period of 30 min at a temperature of 80 °C. 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 imine 1b (271 mg, 1 mmol) and then dry toluene (2 mL). Upon addition of the imine and solvent the reaction mixture turned a yellow color. Ethyl diazoacetate (124 ,uL, 1.2 mmol) was added via syringe and the Teflon value was closed and the reaction mixture was stirred at room temperature for 24 h. Immediately upon addition of ethyl diazoacetate the reaction mixture became an intense yellow and the formation of bubbles from the release of nitrogen was noted. The mixture was then diluted with 15 mL of hexanes and 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 round bottom flask. Rotary evaporation of the solvent followed by exposure to high vacuum (0.05 mm Hg) for 30 minutes gave the crude aziridine as an off-white solid. The conversion was determined from the 1H NMR spectrum of the crude reaction mixture by integration of the aziridine ring methine protons relative to either the imine benzhydryl methine proton or the methine of the imine carbon. The cis:trans ratio was determined on the crude reaction mixture to be 153 2100:1 by 1H NMR integration of the ring methine protons for each aziridine. 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 products (26b) were determined from the 1H NMR spectrum of the crude reaction mixture by integration of the N-H proton of the enamine relative to the aziridine ring methine protons with the aid of the isolated yield of the cis-aziridine: 2% yield of 26b. Purification of the crude aziridine by chromatography (35 mm x 400 mm column) on silica gel with an eluent mixture of ethyl acetatezhexanes (1 :9) gave the pure aziridine 3b in 87% isolated yield (310.2 mg, 0.87 mmol). The optical purity of (28,3S)-3b was determined to be 93% ee by HPLC analysis (CHIRALCEL OD-H column, 90:10 hexanes/2-propanol, 222 nm, flow rate 0.7 mL/min). Retention times: R; = 4.44 min (major enantiomer) and R, = 8.18 min (minor enantiomer). Spectral data for (28,3S)-3b: R; = 0.3 (1:9 ethyl acetate/hexanes). 1H NMR (CDCI3, 500 MHz) 6 1.03 (t, 3H, J = 7 Hz), 2.76 (d, 1H, J: 7 Hz), 3.30 (d, 1H, J: 7 Hz), 4.00 (m, 2H), 4.08 (s, 1H), 7.25 (m, 2H), 7.33 (m, 5H), 7.41 (t, 2H, J = 7 Hz), 7.49 (d, 2H, J = 7 Hz), 7.57 (d, 2H, J = 7 Hz), 7.89 (d, 2H, J = 7 Hz); 13c NMR (CDCI3, 125 Hz) 6 13.88, 46.34, 47.98, 60.48, 77.64, 127.17, 127.27, 127.35, 127.49, 127.71, 127.74, 128.43, 135.00, 142.35, 142.48, 167.65; IR (thin film) 3030m, 2981m, 1737s, 1600s, 1200s, 10978 cm“; mass spectrum, m/z (% rel intensity) 357 M+ (<1), 190 (100), 167 (60), 117 (34). Anal calcd for C24H23NO2: c, 80.84; H, 8.48; N, 3.92. Found: c, 80.92; H, 8.70; N, 3.88. [c1230 - 41.0 (c 1.0, CH2CI2) on 99.4% as material (HPLC). White solid: mp. 128-129 °C on 99.4% ee material. 154 Optical purity enhancement by crystallization. The chemically pure aziridine (28,35‘)-3b (261 mg, 0.73 mmol, 94% ee) obtained from column chromatography was placed in a 100 mL round bottom flask. An air condenser with an argon balloon was attached to the round bottom flask. A small amount of a 1:9 mixture of EtOAc:hexanes (~10-20 mL) was added via syringe and the solvents brought to boil with a heat gun as the flask was swirled. Additional solvent mixture was added and mixture was returned to a boil. This process was continued until a clear solution was obtained (10-20 mL solvent mixture). The flask was then kept in an insulated place untouched for 10-15 h, upon which the aziridine 3b crystallized out. The first crop was collected (162 mg, 0.45 mmol, 62% recovery) and determined to be 99.4% ee by HPLC (see conditions above). The above procedure for the preparation of the aziridine 3b was also repeated with a slight modification of the procedure in which the catalyst solution was transferred to a solution of the imine and identical results were obtained. Each imine 1a-I was subjected to the catalytic asymmetric aziridination reaction with the procedure described above in four different variations: with catalysts derived from (Fl)-VANOL and (8)-VAPOL ligands and with the solvents toluene and CH2CI2. The results for all these reactions can be found in Tables 2.3 and 2.4 (in Chapter 2). lmines 1g, 1], 1k and 1| were also subjected to the catalytic asymmetric aziridination reaction at a reaction temperature of 0 °C and these results are presented in Table 2.5 (in Chapter 2). 155 PhYPh 0 N \‘LA'I O“ [0023 (28,3S)-3a (28,38)-ethyl 1-benzhydryl—3-(naphthalen-1-yl)aziridine-2—carboxylate 39.6 lmine 1a (321 mg, 1 mmol) was reacted according to the general procedure described above with (R)-VANOL as ligand. Purification by column chromatography on silica gel (1 :9 ethyl acetate/hexanes) gave the pure aziridine (28,38)-3a in 80% isolated yield (325 mg, 0.80 mmol); cis/trans: 51:1. Enamine side products: 2% yield of 26a. The optical purity of (28,38)-3a was determined to be 93% as by HPLC analysis (CHIRALCEL OD-H column, 99:1 hexanes/2- propanol, 222 nm, flow rate 0.7 mL/min). Retention times: R. = 32.89 min (major enantiomer) and R; = 25.62 min (minor enantiomer). A single crystallization (1 :15 ethyl acetatezhexanes) of 89% ee material gave 38 with 55% recovery and 99.9% 89. Spectral data for (28,3S)-3a: R; = 0.25 (1:9 ethyl acetate/hexanes). 1H NMR (CDCI3, 300 MHz) 8 0.85 (t, 3H, J = 7 Hz), 2.94 (d, 1H, J = 7 Hz), 3.75 (m, 2H), 3.77 (d, 1H, J: 7 Hz), 4.10 (s, 1H), 7.22 (m, 1H), 7.30 (m, 3H), 7.38 (m, 3H), 7.48 (m, 2H), 7.58 (d, 2H, J = 7 Hz), 7.70 (m, 4H), 7.81 (d, 1H, J = 7 Hz), 8.12 (d, 1H, J = 7 Hz); 13C NMR (CDCI3, 75 MHz) 6 13.55, 45.98, 46.36, 60.35, 77.91, 122.93, 125.29, 125.40, 125.82, 126.51, 127.10, 127.14, 127.58, 127.85, 128.48, 128.54, 130.48, 131.38, 133.01, 142.22, 142.45, 167.75; IR (thin film) 3030w, 2980w, 1737s, 1598m, 11913 cm"; mass spectrum, m/z (% rel intensity) 407 M+ (5), 240 (59), 167 (100), 139 (9). Anal calcd for C28H25NO2: C, 82.59; H, 156 8.19; N, 8.44. Found: c, 81.88; H, 6.37; N, 3.28. [81230 = +16.0 (01.0, CH2CI2) on 99.9% 99 material. White solid: mp 128-129 °C on 99.9% ee material. Ph Ph Y N \‘ LA .I (5“ ’COzEt (28,3S)-3c (28,3S)-ethyl 1-benzhydryl-3-o-tolylaziridine-Z-carboxylate .3c.6 Imine 1c (285 mg, 1 mmol) was reacted according to the general procedure described above with (Fl)-VANOL as ligand. Purification by column chromatography on silica gel (1 :9 ethyl acetate/hexanes) gave the pure aziridine 3c in 67% isolated yield (250 mg, 0.67 mmol); cis/trans: 12:1. Enamine side products: 11% yield of 26c. The optical purity of (28,38)-3c was determined to be 90% as by HPLC analysis (CHIRALCEL OD-H column, 99:1 hexanes/2-propanol, 222 nm, flow rate 1 mL/min). Retention times: R; = 6.02 min (major enantiomer) and R; = 7.47 min (minor enantiomer). A single crystallization (1 :19 ethyl acetatezhexanes) of 91% ee material gave 3c with 74% recovery and 99.3% ee. Spectral data for (28,3S)-3c: n, = 0.33 (1 :9 ethyl acetate/hexanes). 1H NMR (c0013, 500 MHz) 8 1.00 (t, 3H, J = 7 Hz), 2.43 (s, 3H), 2.86 (d, 1H, J = 7 Hz), 3.34 (d, 1H, J = 7 Hz), 4.00 (q, 2H, J = 7 Hz), 4.07 (s, 1H), 7.15 (d, 1H, J = 7 Hz), 7.22 (m, 2H), 7.28 (m, 1H), 7.38 (m, 3H), 7.45 (t, 2H, J = 7 Hz), 7.65 (d, 2H, J = 7 Hz), 7.68 (d, 1H, J = 7 Hz), 7.75 (d, 2H, J = 7 Hz); 130 NMR (CDCI3, 125 Hz) 8 13.73, 18.70, 45.53, 46.81, 60.33, 77.76, 125.26, 127.04, 127.06, 127.43, 127.63, 128.39, 128.41, 129.01, 133.05, 135.90, 142.33, 142.48, 167.80; IR (thin film) 3054m, 2982m, 1740s, 1600m, 11849 cm“; mass spectrum, m/z (% rel intensity) 371 M" (<1), 157 204 (100), 167 (43), 131 (41). Anal calcd for C25H25NO2: c, 80.83; H, 8.78; N, 3.37. Found: c, 80.84; H, 8.94; N, 3.84. [c1230 = -42.8 (01.0, CH2CI2) on 99.3% ee material. White solid: mp 164-165 °C on 99.3% ee material. Ph Ph Y N [A (28,3S)-3d (28,3S)-ethyl 1-benzhydryl-3—p-tolylaziridine-Z-carboxylate 3d. Imine 1d (285 mg, 1 mmol) was reacted according to the general procedure described above with (FD-VANOL as ligand. The only difference in the procedure was that 2 mL of a 4:1 toluenezCH2Cl2 solvent system was used for the reaction. Purification by column chromatography on silica gel (1 :9 ethyl acetate/hexanes) gave the pure aziridine 3d in 79% isolated yield (293 mg, 0.79 mmol); cis/trans: 250:1. Enamine side products: 2% yield of 26d. The optical purity of (28,3S)-3d was determined to be 94% ee by HPLC analysis (CHIRALCEL OD-H column, 90:10 hexanes/2-propanol, 222 nm, flow rate 0.7 mL/min). Retention times: R; = 4.29 min (major enantiomer) and R; = 7.60 min (minor enantiomer). A single crystallization (1:19 ethyl acetatezhexanes) of 94% ee material gave 3d with 80% recovery and 99.2% ee (HPLC). Spectral data for (28,35‘)-3d: R; = 0.30 (1:9 ethyl acetate/hexanes). 1H NMR (CDCI3, 300 MHz) 8 1.00 (t, 3H, J = 7.1 Hz), 2.28 (s, 3H), 2.64 (d, 1H, J: 6.9 Hz), 3.17 (d, 1H, J: 6 Hz), 3.93 (s, 1H), 3.95 (q, 2H, J = 7.2 Hz), 7.05 (d, 2H, J = 8 Hz), 7.13-7.36 (m, 8H), 7.48 (d, 2H, J = 7.2 Hz), 7.80 (d, 2H, J = 7.3 Hz); ‘30 NMR (CDCI3, 75 Hz) 8 13.94, 21.09, 48.29, 47.98, 60.47, 76.57, 127.13, 127.19, 127.31, 127.47, 127.63, 128.41, 131.94, 158 136.84, 142.41, 142.51, 167.75; IR (thin film) 3030m, 2980m, 17398, 1454m, 1197s, 11788, 1066m cm“; mass spectrum, m/z (% rel intensity) 371 M+ (<1), 204 (83), 203 (58), 167 (40), 164 (46), 131 (58), 130 (100), 129 (58), 77 (26). Anal calcd for C25H25NO2: C, 80.83; H, 6.78; N, 3.77. Found: C, 80.67; H, 6.50; N, 3.88. [(1]230 = -27.8 (01.0, CH2CI2) on 99.2% ee material. White solid: mp 164- 165 °C on 99.2% 98 material. Ph Br I LA (28,3S)-3e Ph (28,3S)-ethyl 1benzhydryl-3-(2-bromophenyl)aziridine-203rboxylate 3e. lmine 1e (349 mg, 1 mmol) was reacted according to the general procedure described above with (FD-VANOL as ligand, the only difference being the reaction time which was 48 h for this reaction. Purification by column chromatography (1:9 ethyl acetate/hexanes) gave the pure aziridine 3e in 43% isolated yield (188 mg, 0.43 mmol); cis/trans: 2100:1. Enamine side products: 24% yield of 269. The optical purity of (28,3S)-3e was determined to be 82% 89 by HPLC analysis (CHIRALCEL OD-H column, 98:2 hexanes/2-propanol, 222 nm, flow rate 0.7 mL/min). Retention times: R; = 6.06 min (major enantiomer) and R; = 7.91 min (minor enantiomer). A single crystallization (1:19 ethyl acetate) of 85% ee material gave 3e with 65% recovery and 98.6% 99. Spectral data for (28,38)-3e: R; = 0.33 (1 :9 ethyl acetate/hexanes). 1H NMR (CDCI3, 300 MHz) 8 0.94 (t, 3H, J: 7.1 Hz), 2.77 (d, 1H, J = 7.0 Hz), 3.32 (d, 1H, J = 6.8 Hz), 3.92 (q, 2H, J = 7.2 Hz), 3.98 (s, 1H), 7.12 (t, 1H, J = 7.6 Hz), 7.22-7.44 (m, 7H), 7.48 (d, 159 1H, J = 8.0 Hz), 7.56 (d, 2H, J = 7.1 Hz), 7.64 (d, 3H, J = 7.8 Hz); 1to NMR (CDCI3, 75 MHz) 8 13.85, 45.88, 48.77, 80.58, 76.57, 123.22, 128.71, 128.98, 127.18, 127.57, 127.85, 128.49, 128.54, 128.77, 130.78, 131.54, 134.40, 142.11, 142.34, 167.54; IR (thin film) 1738s, 1199s, 1028m, 748m cm"; mass spectrum, m/z (% rel intensity) 437 M+ (<1, 81Sr), 435 M+ (<1, 798r), 270 (22), 288 (31), 187 (100), 165 (50). Anal calcd for C24H22BrNO2: C, 66.06; H, 5.08; N, 3.21. Found: c, 88.01; H, 4.98; N, 3.08. [a]230 = -28.0 (01.0, CH2CI2) on 98.8% ee material (HPLC). White solid: mp 147-148 °C on 98.6 % ee material. \I/ N /_8 Br (28,3S)-3f Ph Ph (23, 3S)-ethyl 1-benzhydryI-3-(4-bromophenyl)aziridine-2-carboxylate 31:6 lmine 1f (349 mg, 1 mmol) was reacted according to the general procedure described above with (R)-VANOL as ligand. Purification by column chromatography on silica gel (1 :9 ethyl acetate/hexanes) gave the pure aziridine at in 86% isolated yield (373 mg, 0.86 mmol); cis/trans: 220:1. Enamine side products: 14% yield of 261. The optical purity of (28,3S)-3f was determined to be 94% as by HPLC analysis (CHIRALCEL OD-H column, 98:2 hexanes/2- propanol, 222 nm, flow rate 1 mL/min). Retention times: R; = 5.37 min (major enantiomer) and R; = 13.48 min (minor enantiomer). A single crystallization (1:19 ethyl acetatezhexanes) of 94% ee material gave at with 76% recovery and 99.4% 98. Spectral data for (28,3S)-3f: R; = 0.33 (1 :9 ethyl acetate/hexanes). 1H NMR (CDCI3, 500 MHz) 6 1.07 (t, 3H, J: 7 Hz), 2.74 (d, 1H, J: 7 Hz), 3.19 (d, 1H, J: 160 7 Hz), 4.00 (q, 2H, J = 7 Hz), 4.01 (s, 1H), 7.23 (t, 1H, 7 Hz), 7,297.45 (m, 9H), 7.50 (d, 2H, J = 7 Hz), 7.65 (d, 2H, J = 7 Hz); ”C NMR (CDCI3, 125 MHz) (1 sp2 carbon missing) 6 13.96, 46.44, 47.31, 60.67, 77.55, 121.31, 127.11, 127.25, 127.40, 127.48, 128.49, 129.52, 130.88, 134.08, 142.12, 142.29, 187.37; IR (thin film) 1734s, 1201s, 1067m cm"; mass spectrum, m/z (% rel intensity) 437 M+ (<1, 818r), 435 M+ (<1, 79hr), 270 (42, 81Br), 288 (43, 79Br), 187 (100, 81Sr), 185 (19, 79Br). Anal calcd for C24H22BrNO2: C, 66.06; H, 5.27; N, 3.09. Found: C, 66.06; H, 5.08; N, 3.21. [ot123D = -12.5 (c 1.0, CH2CI2) on 99.4% ee material. White solid: mp 155-157 °C on 99.4% 89 material. Ph Ph Y N \‘£_A ' I OZN (28,38)-3g (28, 3S)-ethyl 1-benzhydryI-3-(4-nitrophenyl)aziridine-2-carboxylate 39.6 lmine 19 (316 mg, 1 mmol) was reacted according to the general procedure described above with (R)-VANOL as ligand. The only difference was that the reaction was carried out at 0 °C. Purification by column chromatography on silica gel (1 :5 ethyl acetatezhexanes) gave the pure aziridine 39 in 93% isolated yield (371 mg, 0.92 mmol); cis/trans:100:1. Enamine side products: <1% yield of 269. The optical purity of (28,38)-3g was determined to be 93% as by HPLC analysis (CHIRALCEL OD-H column, 90:10 hexanesz2-propanol, 222 nm, flow rate 0.7 mL/min). Retention times: R; = 8.70 min (major enantiomer) and R; = 11.37 min (minor enantiomer). A Single crystallization (1:15 ethyl acetatezhexanes) of 94.5% ee material gave 39 with 74% recovery and 99.7% ee. Spectral data for (28,38)- 161 39: R; = 0.3 (1 :5 ethyl acetate:hexanes); 1H NMR (CDCI3, 500 MHz) 8 1.08 (t, 3H, J = 7 Hz), 2.84 (d, 1H, J = 7 Hz), 3.30 (d, 1H, J = 7H2), 3.98 (q, 2H, J = 7 Hz), 4.04 (s, 1H), 7.23 (t, 1H, J = 7 Hz), 7.29 (m, 3H), 7.38 (t, 2H, J = 7 Hz), 7.55 (d, 2H, J: 8 Hz), 7.83 (m, 4H), 8.15 (d, 2H, J: 8 Hz); 13c NMR (CDCI3, 125 MHz) 8 13.96, 29.64, 46.88, 47.02, 60.89, 123.00, 127.02, 127.34, 127.40, 127.64, 128.57, 128.60, 128.74, 141.09, 142.03, 142.49, 166.92; IR (thin film) 2980w, 1742s, 1605s, 1520s, 1346s, 1340s, 1202s cm"; mass spectrum, m/z (% rel intensity) 402 M+ (<1), 167 (100), 165 (12), 152 (8), 89 (3). Anal calcd for C24H22N2O4: c, 71,63; H, 5.51; N, 8.98. Found: c, 71.58; H, 5.71; N, 8.82. [8:123D = +112 (0 1.0, CH2CI2) on 99.7% 89 material. White solid: mp 139-140 °C on 99.7% ee material. Ph Ph N “A" D“ ’COzEI MeO (28,38)-3h (28, 38)-ethyl 1-benzhydryI-3-(4-methoxyphenyl)aziridine-2—carboxylate 3h. lmine 1h (301 mg, 1 mmol) was reacted according to the general procedure described above with (Fl)-VANOL as ligand. The silica gel for column chromatography was pre-conditioned by preparing a slurry in a 1:9 mixture of EtaNzCH2CI2 which was loaded into a column, 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:hexanes, the crude aziridine was loaded onto the column and then elution with the same solvent mixture gave the pure aziridine 3h in 61% isolated yield (236 mg, 0.61 mmol); 162 cis/trans: 34:1. Enamine side products: <1% yield of 26h. The optical purity of (28,38)-3h was determined to be 87% ee by HPLC analysis (CHIRALCEL OD-H column, 95:5 hexane822-propanol, 222 nm, flow rate 0.7 mL/min). Retention times: R; = 6.35 min (major enantiomer) and R; = 15.00 min (minor enantiomer). A single crystallization (1 :25 ethyl acetate:hexanes) of 87% ee material gave 3h with 81% recovery and 99.9% 99. Spectral data for (28,38)-3h: R; = 0.2 (1:9 ethyl acetate:hexanes). 1H NMR (CDCI3, 300 MHz) 8 1.03 (t, 3H, J = 7.0 Hz), 2.66 (d, 1H, J = 6.8 Hz), 3.19 (d, 1H, J = 6.7 Hz), 3.74 (s, 3H), 3.96 (s, 1H), 3.97 (q, 2H, J = 7.2 Hz), 6.82 (d, 2H, J = 8.8 Hz), 7.15-7.39 (m, 8H), 7.51 (d, 2H, J: 7.3 Hz), 7.83 (d, 2H, J = 7.3 Hz); 130 NMR (CDCI3, 75 MHz) 8 13.94, 48.28, 47.67, 55.06, 60.45, 76.57, 113.16, 127.05, 127.15, 127.31, 127.46, 128.40, 128.82, 142.38, 142.53, 158.84, 167.80; IR (thin film) 3030w, 2934w, 17388, 1614m, 15168, 12508, 10338 cm“; mass spectrum, m/z (% rel intensity) 388 M+1 (0.9), 315 (10), 222 (12), 221 (100), 167 (21), 166 (20), 147 (25), 146 (19), 91 (19). Anal calcd for C25H25N03: C, 77.49; H, 6.50; N, 3.61. Found: C, 77.67; H, 6.63; N, 3.58. [04230 = -27.6 (c 1.0, CH2CI2) on 99.9% 88 material. White solid: mp 136-137 °C on 99.9% 98 material. Ph Ph N .LA. MOD)“ "C02Et AcO (28,38)-3i 4-((28, 3S)- 1-benzhydryI-3-(ethoxycarbonyl)aziridin—2-yl)- 1,2-phenylene diacetate 3i.6 Imine 1i (387 mg, 1 mmol) was reacted according to the general procedure described above with (Fl)-VANOL as ligand. Purification by column 163 chromatography on silica gel (1 :2 ethyl acetate:hexanes) gave the pure aziridine 3i in 84% isolated yield (214 mg, 0.45 mmol); cis/trans: 2100:1. Enamine side products: <1 % yield of 26i. The optical purity of (28,3S)-3i was determined to be 93% ee by HPLC analysis (CHIRALCEL OD column, 85:15 hexanesz2-propanol, 222 nm, flow rate 0.7 mL/min). Retention times: R; = 28.62 min (major enantiomer) and R; = 25.38 min (minor enantiomer). A single crystallization (1 :5 ethyl acetate:hexanes) of 92.5% 98 material gave 3i with 67% recovery and 99% ee. Spectral data for (28,3S)-3i: R; = 0.28 (1:2 ethyl acetate:hexanes). 1H NMR (CDCI3, 300 MHz) 6 0.99 (t, 3H, J = 7 Hz), 2.24 (s, 3H), 2.25 (s, 3H), 2.68 (d, 1H, J = 7 Hz), 3.18 (d, 1H, J = 7 Hz), 3.95 (s, 1H), 3.95 (m, 2H), 7.07 (d, 1H, J = 9 Hz), 7.19 (m, 1H), 7.28 (m, 7H), 7.45 (d, 2H, J: 7 Hz), 7.81 (d, 2H, J: 7 Hz); "*0 NMR (CDCI3, 75 MHZ) 6 13.84, 20.64, 46.57, 47.03, 60.89, 77.49, 122.75, 122.78, 126.05, 127.18, 127.30, 127.45, 127.61, 128.55, 128.65, 133.97, 141.35, 141.57, 142.21, 167.45, 168.07, 168.24; IR (thin film) 3030w, 2980w, 1770w, 1731s, 1600m cm"; mass spectrum, m/z (% rel intensity) 474 M+1 (21), 306 (12), 195 (10), 167 (100). Anal calcd for C28H27N06: C, 71.02; H, 5.75; N, 2.96. Found: c, 71.23; H, 5.88; N, 2.94. [ot12‘3D = -19.7 (c 1.0, CH2CI2) on 99% ee material. White solid: mp 141-143 °C on 99% ee material. Ph Ph Y N A J "'c02Et (28,38)-3j (28, 38)-ethyl 1-benzhydryl-3-propylaziridine~2-carboxylata 3).6 lmine 1] (237 mg, 1 mmol) was reacted according to the general procedure described 164 above with (H)-VANOL as ligand. The only differences were that the reaction was carried out at 0 °C, 10 mol% catalyst loading was used and the reaction time was 48 h. Purification by column chromatography (1:19 ethyl acetate:hexanes) gave the pure aziridine 3j in 60% isolated yield (194 mg, 0.60 mmol); cis/trans: 33:1. Enamine side products: 4% yield of 26]. The optical purity of (28,38)-3j was determined to be 83% 99 by HPLC analysis (CHIRALCEL OD-H column, 99:1 hexaneszz-propanol, 222 nm, flow rate 1 mL/min). Retention times: R; = 3.51 min (major enantiomer) and R; = 7.44 min (minor enantiomer). A single crystallization (hexanes) of 86% ee material gave 3] with 40% recovery and 96.6% 98. Spectral data for (28,38)-3j: R; = 0.33 (1:9 ethyl acetate:hexanes). 1H NMR (CDCI3, 500 MHz) 6 0.74 (t, 3H, J: 7 Hz), 1.05 (m, 1H), 1.10 (m, 1H), 1.25 (t, 3H, J: 7 Hz), 1.45 (m, 1H), 1.52 (m, 1H), 2.05 (q, 1H, J: 7 Hz), 2.28 (d, 1H, J = 7 Hz), 3.66 (s, 1H), 4.17 (m, 2H), 7.27 (m, 2H), 7.33 (m, 4H), 7.39 (d, 2H, J = 7 Hz), 7.49 (d, 2H, J = 7 Hz); 130 NMR (CDCI3, 125 MHz) 8 13.57, 14.21, 20.28, 29.85, 43.32, 46.62, 60.62, 77.88, 126.94, 127.10, 127.30, 127.82, 128.27, 128.29, 142.42, 142.77, 169.46; IR (thin film) 3040m, 2959m, 17328, 11948 cm“; mass spectrum, m/z (% rel intensity) 323 M+ (2), 167 (100), 156 (91), 152 (15), 128 (23), 82 (17). Anal calcd for C2; H25NO2: C, 77.98; H, 7.79; N, 4.33. Found: C, 78.06; H, 7.94; N, 4.21. [c1230 = -112.2 (c 1.0, CH2CI2) on 988% cc material. White solid: mp 93-95 °C on 96.6% ee material. Ph Ph Y N LA 01- (28,3S)-3k 165 (28, 3S)-ethyl 1-benzhydryl—3-cyclohexylaziridine-Z—carboxylate 3k.6 lmine 1k (277 mg, 1 mmol) was reacted according to the general procedure described above with (FD-VANOL as ligand. The only difference was that the reaction was carried out at 0 °C. Purification by column chromatography on silica gel (1:15 ethyl acetate:hexanes) gave the pure aziridine 3k in 81% isolated yield (295 mg, 0.81 mmol); cis/trans: 100:1. Enamine side products: 6% yield of 26k. The optical purity of (28,3S)-3k was determined to be 82% ee by HPLC analysis (CHIRALCEL OD-H column, 99:1 hexanes:2-propanol, 222 nm, flow 1 mL/min). Retention times: R; = 3.45 min (major enantiomer) and R; = 6.99 min (minor enantiomer). A single crystallization (1:19 ethyl acetate:hexanes) of 83% ee material gave 3k with 80% recovery and 99.1% 99. Spectral data for (28,38)-3k: R; = 0.2 (1 :15 ethyl acetate:hexanes). 1H NMR (CDCI3, 500 MHZ) 6 0.52 (dq, 1H, J = 10, 3 Hz), 0.95-1.66 (m, 10H), 1.28 (t, 3H, J = 7 Hz), 1.83 (dd, 1H, J = 7, 3 Hz), 2.29 (d, 1H, J = 7 Hz), 3.83 (s, 1H), 4.25 (m, 2H), 7.24 (m, 2H), 7.31 (m, 4H), 7.37 (m, 2H), 7.45 (d, 2H, J = 7 Hz); 13C NMR (CDCI3, 125 MHz) 6 14.27, 25.34, 25.53, 30.11, 30.71, 36.27, 43.39, 52.12, 60.67, 78.18, 126.80, 126.82, 127.06, 127.49, 128.26, 128.30, 128.35, 142.33, 142.72, 169.63; IR (thin film) 2927m, 2917m, 2850m, 17318, 11908, 11808; mass spectrum, m/z (% rel intensity) 363 M+ (1), 196 (100), 167 (64), 102 (18), 95 (29). Anal calcd for C24H29NO2: c, 79.44; H, 8.07; N, 3.64. Found: c, 79.30; H, 8.04; N, 3.85. [(1]230= -145.2 (0 1.0, CH2CI2) on 99.1% ee material. White solid: mp 165-166 °C on 99.1% ee material. 166 Ph Ph T EWLA'TOZEt (28,3S)-3I (2S,3S)-ethyl 1-benzhydryl-3-tert-butylaziridine-Z-carboxylate 316 |mine1l (251 mg, 1mmol) was reacted according to the general procedure described above with (FD-VANOL as ligand. Purification by column chromatography on silica gel (1:9 ethyl acetate:hexanes) gave the pure aziridine 3| in 89% isolated yield (300 mg, 0.89 mmol); cis/trans: 2100z1. Enamine side products: 4% yield of 26i. The optical purity of (28,3S)-3I was determined to be 85% ee by HPLC analysis (CHIRALCEL OD-H, 99:1 hexanes:2-propanol, 222 nm, flow rate 1 mL/min). Retention times: R; = 3.60 min (major enantiomer) and R; = 9.76 min (minor enantiomer). A single recrysallization (1 :19 ethyl acetate:hexanes) of 87% as material gave 3| with 76% recovery and 99.7% 99. Spectral data for (28,38)- 3|: R; = 0.33 (1:9 ethyl acetate:hexanes). 1H NMR (CDCI3, 300 MHz) 8 0.70 (s, 9H), 1.29 (t, 3H, J = 7 Hz), 1.76 (d, 1H, J = 7 Hz), 2.16 (d, 1H, J: 7 Hz), 3.59 (s, 1H), 4.09 (m, 1H), 4.24 (m, 1H), 7.20 (m, 2H), 7.28 (m, 4H), 7.40 (d, 2H, J = 7 Hz), 7.87 (d, 2H, J = 7 Hz); ‘30 NMR (CDCI3, 75 MHZ) 8 14.09, 27.39, 31.59, 43.37, 56.07, 60.58, 79.19, 126.83, 127.24, 127.36, 128.17, 128.19, 128.26, 142.07, 143.43, 169.72; mass spectrum, m/z (% rel intensity) 338 M+1 (14), 195 (15), 167 (100). Anal calcd for C22H27NO2: C, 78.30; H, 8.06; N, 4.15. Found: C, 78.27; H, 8.27; N, 4.13. [00230 = -149.4 (c 1.0, CH2CI2) on 99.7% ee material. White solid: mp 150-152 °C on 99.7% as material. 167 General procedures for the recovery and recycling of VAPOL from the catalytic asymmetric aziridination reaction N ACOzEt 2 Ph Ph Ph EDA Y 4 Ph/TN/kph 5 mol% T LAN + recovered (3)-VAPOL-B3 Ph COZEt (3)-V9POL 1b catalyst (2R,3R)-3b >99 0 99 toluene, 24 h, 25 °C 27 VAPOL-EDA adduct Recovery of VAPOL-EDA adduct 27. The aziridination reaction of the imine 1b (542 mg, 2 mmol) with ethyl diazoacetate 2 (250 pL, 2.4 mmol) was carried out in toluene, for 24 h at room temperature and with 5 mol% of the (S)- VAPOL-borate catalyst generated according to the general procedure described above. Thus for the preparation of the catalyst, (8)-VAPOL (54 mg, 0.1 mmol), B(0Ph)3 (116 mg, 0.4 mmol), H2O (1.8 pL, 0.1 mmol) and toluene (2 ml) were heated at 80 °C for 1 h, then a vacuum (0.2 mm Hg) was applied carefully. Upon removal of solvent, the vacuum was kept for 30 minutes with continual heating at 80 °C. After the aziridination reaction, the crude reaction mixture obtained was subjected to separation by column chromatography with an eluent mixture of 1:9 EtOAc:hexanes, which afforded the pure aziridine 3b in 73% yield (522 mg, 1.46 mmol) as well as the VAPOL-EDA adduct 27 in 98% yield (61 mg, 0.098 mmol). No VAPOL was detected under these reactions conditions. The R; values for VAPOL, the aziridine 3b and the VAPOL-EDA adduct 27 with the eluent mixture of 1:9 EtOAc:hexanes are 0.34, 0.30 and 0.25 respectively. The characterization data for 27 was identical to that previously reported by our group.“ The amount 168 of the VAPOL-EDA adduct 27 that is formed is variable and depends on the amount of excess ethyl diazoacetate that is used. For example, if 1.1 equivalents of ethyl diazoacetate is used then the adduct 27 is isolated in 49% yield along with a 46% recovery of unreacted VAPOL that is >99% ee. Smlz-THF HMPA, EtOH p), THF, 25 °c, 1 h 7 Ph... 27 4 91 % yield 99.8% ee Samarium Diiodidez’ Reduction of EDA -Adduct 27. A 25 mL round- bottom flask was flame dried and cooled under argon and charged with samarium metal (128 mg, 0.85 mmol) and dry THF (5.2 ml). The flask was then fitted with a rubber septum and an argon balloon. Freshly distilled diiodomethane (63 ,uL, 0.784 mmol) was then added via syringe. The reaction mixture was stirred for 2 h at room temperature to give a dark blue slurry. To another 25 mL round-bottom flask which had been flame dried and cooled under argon was added the VAPOL—EDA adduct 27 (61 mg, 0.098 mmol) and dry THF (1 mL). After fitting the flask with a rubber septum and an argon balloon, ethanol (reagent grade, 17 yL, 0.294 mmol) and hexamethylphosphoramide (HMPA, 153 ,uL, 0.882 mmol) were added via syringe. The Sml2-THF solution (0.392 mmol, 2.6 mL) was then transferred via syringe to the solution of 27. The reaction mixture was stirred at room temperature for 1 h, during which time the reaction went to 169 completion (TLC, 1:9 ethyl acetate:hexanes). To the reaction flask was then added saturated NaHCOa solution (20 mL) and the mixture extracted with ethyl acetate (4 x 20 mL). The organic layers were combined, washed with brine, dried over M9804 and the solvent removed by rotary evaporation to afford the crude VAPOL ligand 4. The ligand was then purified by column chromatography on silica gel with an eluent mixture of 1:19 ethyl acetate/hexanes, which afforded the pure (8)-VAPOL product 4 in 91% yield (48 mg, 0.089 mmol). The optical purity of the recovered VAPOL was determined to be 99.8% ee by chiral HPLC analysis (Regis Pirkle Covalent D-Phenylglycine column, 75:25 hexanes:2- propanol, 260 nm, flow rate 2 mL/min). Retention times: (8)-VAPOL = 18.54 min, (Fl)-VAPOL = 12.50 min. t.20 Liberation of the VAPOL Ligand via Curtius rearrangemen NaOH, EtOH ACOZEt 25 °C, 1h _ Ph "’0 27 28 98% yield Hydrolysis of the EDA-Adduct to the Acid 28. A 100 mL round bottom flask was flame dried and cooled under argon and then the VAPOL-EDA adduct 27 (232 mg, 0.372 mmol) was introduced into the flask. The adduct was dissolved in ethanol (20 mL) and then 20 mL of 20% (w/v) aqueous solution of NaOH was added. This resulted in an instant color change from colorless to intense yellowish green. The reaction mixture was stirred at room temperature for 170 1 h. Thereafter, 140 mL 1 N HCl was added to adjust the pH of the mixture to pH = 1, upon which the product carboxylic acid 28 precipitated from the reaction mixture. The product was isolated by vacuum filtration and then dissolved in ethyl acetate. The filtrate was extracted once with ethyl acetate (30 mL) and the organic layers combined, washed with brine (2 X 30 mL), dried over M9804 and then the solvent was removed via rotary evaporation to afford the crude carboxylic acid product 28 as a yellow solid in 98% yield (217.2 mg, 0.36 mmol). Spectral data for 28: 1H NMR (c0013, 500 MHz) 8 4.29 (d, 1H, J = 15.7 Hz), 4.39 (d, 1H, J = 15.7 Hz), 8.51 (bs, 1H), 8.78-8.88 (m, 4H), 8.95-7.04 (m, 4H), 7.04-7.13 (m, 2H), 7.43 (s, 1H), 7.47-7.84 (m, 7H), 7.71-7.84 (m, 3H), 7.82 (d, 1H, J = 8.7 Hz), 7.92 (d, 1H, J: 7.7 Hz), 9.31 (d, 1H, J = 8.1 Hz), 9.71 (d, 1H, J = 8.7 Hz); 13c NMR (CDCI3, 125 MHz) (1 sp2 0 missing) 8 87.72, 115.25, 118.70, 119.92, 120.74, 123.01, 123.13, 126.03, 126.09, 126.63, 126.73, 126.84, 126.99, 127.05, 127.12, 127.30, 127.62, 127.71, 127.73, 128.08, 128.19, 128.53, 128.77, 128.86, 128.90, 129.02, 129.07, 129.23, 129.61, 130.40, 132.84, 133.10, 134.55, 135.15, 139.19, 139.76, 140.41, 142.32, 152.07, 154.63, 171.64. a) NEI3 (Ph0)2P0N3 ' /\ b) H20, reflux Ph "0 COZH c) acid : 4 + Ph,, (8)-VAPOL 56% yield 28 29. 98% yield 34% weld 171 Curtius Rearrangement?” of Acid 28. A 25 mL round bottom flask was flame dried and cooled under argon and then charged with the crude carboxylic acid 28 (41.2 mg, 0.069 mmol). The solid was then dissolved by the addition of toluene (3 mL) and DMF (1 mL). This was followed by the addition of triethyl amine (11 pL, 0.079 mmol) and diphenylphosphoryl azide (DPPA, 15.7 pL, 0.072 mmol). The flask was then fitted with a water condenser and an argon balloon and the reaction mixture was refluxed for 3 h. After cooling down to room temperature, water (3 mL) was added via syringe and the reaction mixture was refluxed again for 2 h. After cooling to room temperature, 2 N HCI (5 mL) and ethyl acetate (10 mL) were added and the layers separated. The aqueous layer was extracted with ethyl acetate (2 x 10 mL), the organic layers combined, washed twice with brine, dried over M9804 and the solvent evaporated by rotary evaporation to afford the crude reaction product. This crude product was then subjected to column chromatography on silica gel with an eluent mixture of 1:9 ethyl acetate:hexanes to afford (8)-VAPOL 4 (56% yield, 20.8 mg, 0.039 mmol, >99% ee) and the Iactone 29 (34% yield, 13.6 mg, 0.024 mmol). Spectral data for 29: 1H NMR (CDCI3, 500 MHz) 8 4.92 (d, 1H, J = 13.5 Hz), 5.25 (d, 1H, J = 13.5 Hz), 6.54 (d, 2H, J = 7.1 Hz), 8.87 (d, 2H, J = 7.1 Hz), 8.89-8.98 (m, 4H), 7.04—7.10 (m, 2H), 7.60 (s, 1H), 7.64-7.76 (m, 7H), 7.79-7.85 (m, 2H), 7.95-8.0 (m, 2H), 9.29-9.34 (m, 2H); 13c NMR (CDCI3, 125 MHz) 8 71.29, 121.14, 122.01, 126.74, 126.82, 126.93, 127.01, 127.10, 127.25, 127.40, 127.49, 127.55, 127.83, 128.28, 128.37, 128.67, 128.84, 128.93, 128.94, 128.99, 129.12, 129.18, 129.21, 133.21, 133.47, 134.20, 135.03, 139.14, 139.24, 140.06, 140.45, 147.74, 154.25, 172 166.31; IR (thin film) 3055w, 2920w, 1761m, 1641m cm"; mass spectrum, m/z (% rel intensity) 578 M* (32), 295 (17), 294 (100), 221 (25). K2CO3 29 4 27 4 Ethanolysis of the Lactone 29. A 25 mL round bottom flask was flame dried and cooled under argon and then the crude reaction mixture (29+4) from the Curtius rearrangement reaction (77.8 mg, 0.0975 mmol (scale determined from the amount of the original starting material — the carboxylic acid 28)) was added which was dissolved in EtOH (4 mL) and THF (1.2 mL) to obtain a clear yellow solution. To this mixture was added K2C03 (134.7 mg, 0.975 mmol) and the reaction mixture stirred for 6 h to obtain a brownish green slurry at which point the TLC indicated complete disappearance of the Iactone 29. To this solution was then added 2N HCI (5 mL) and diethyl ether (10 mL) and the layers separated. The aqueous layer was extracted with diethyl ether (2 x 10 mL), the organic layers combined and washed twice with brine, dried over M9804 and the solvent removed by rotary evaporation to give the crude reaction mixture. This was then subjected to purification by column chromatography on silica gel with an eluent mixture of 1:19 ethyl acetate:hexanes to afford (8)-VAPOL 4 (38% yield, 26.1 mg, 0.042 mmol, >99% ee) and the VAPOL-EDA adduct 27 (32% yield, 26.7 mg, 0.05 mmol). 173 Section 2.2 Aziridinations with o-bromophenyl benzhydryl imine: First glimpses of trans-aziridines Bh Bh \ Bh EDA 2 (1.2 eq) N N N’ 5 mol% ligand-B3 cat; + 5 5 Br toluene, 25 °c, 90 h (:{A‘COfit E): CO2Et Br Br 1° (2R,3R)-3e (2R,3S)-30 Bh 0 ° 0 NH2 N—\ 36 Ph 182 lmine 36. The standard procedure described above for the preparation of imine 1b was followed with 5H-dibenzo[a,d]cyclohepten-5-amine (0.75 g, 3.63 mmol). The crude product was purified by crystallization (1 :10 EtOAc:hexanes, 2 crops) to give 36 as white crystals (mp 136-139 °C) in 49% yield (0.62 g, 2.10 mmol). Spectral data for 38: 1H NMR (CDCI3, 500 MHz) 8 4.98 (bs, 1H), 7.14 (bs, 2H), 7.21 (t, 2H, J = 7.4 Hz), 7.33-7.36 (m, 4H), 7.46 (bs, 3H), 7.75-7.94 (m, 4H), 8.33 (bs, 1H); "’0 NMR (CDCI3, 125 MHZ) 8 72.13, 124.59, 125.97, 127.84, 128.51, 128.52, 128.63, 130.88, 131.23, 133.29, 136.39, 141.36, 161.52; IR (thin film) 3083w, 3024w, 1849m, 1483w, 798m cm"; Mass spectrum: m/z (% rel intensity) 296 M+1+ (19), 192 (37), 191 (100); Anal calcd for C22H;7N: C, 89.46; H, 5.80; N, 4.74. Found: C, 89.16; H, 5.84; N, 4.59. o o o o (8)-VAP0L-B3 catalyst H C02Et ‘ + o ' l/,N \ll/ CH2Cl2, 25 c, 24 h N ph N2 Ph C02Et 35 2 (2R,3R)—38 (2R, 3R)-ethyl 1-(dicyclohexylmethyl)-3—phenylaziridine~2-carboxy/ate 38. The standard procedure for the preparation of aziridine 3b described above was followed from imine 35 (283 mg, 1 mmol). The crude product was purified by silica gel chromatography (1:40 EtOAc/hexanes as elute) to give 38 as a white solid (mp 64-66 °C) in 18% yield (65 mg, 0.18 mmol). An optical purity of 74% ee was determined by HPLC analysis (Chiralcel OD-H column, 222 nm, 99:1 hexane/i-PrOH, flow rate: 0.7 mL./min). Retention times: R; = 3.43 min for (2R,3R)-38 and R; = 3.86 min for (28,38}38. 183 Spectral data for 38: R; = 0.32 (1:19 EtOAc/hexanes); 1H NMR (CDCI3, 500 MHz) 6 0.99 (t, 3H, J: 7.1 Hz), 1.13-1.35 (m, 10H), 1.58-1.94 (m, 13H), 2.46 (d, 1H, J = 6.7 Hz), 2.88 (d, 1H, J = 6.8 Hz), 3.92-3.99 (m, 2H), 7.21-7.24 (m, 1 H), 7.27-7.30 (t, 2H, J = 7.2 Hz), 7.41-7.44 (m, 2H); 13C NMR (CDCI3, 125 MHz) 6 13.96, 26.56, 26.70, 26.91, 26.94, 27.06, 27.18, 29.98, 30.03, 31.85, 32.48, 41.56, 42.03, 46.30, 46.90, 60.30, 79.29, 127.02, 127.63, 128.00, 135.74, 168.55; IR (thin film) 29488, 17438, 1195vs cm"; Mass spectrum: m/z (% rel intensity) M+1+ 370 (100), 301 (27), 217 (10); HRMS calcd for C24H36NO2 (M+H) m/z 370.2748, meas 370.2764; [a]230 = +4.1 (01.0, CH2CI2) on 70% ee (28,38)- 10 mol% (8)-VAPOL-B3 catalyst H COzEI = 38. + o l,/N \ll/ CH2Cl2, 25 c, 24h N ph N2 Fh’ ‘cozEt 34 2 (2R,3R)-37 (2R,3Fl)-ethyl 1 -(nonan-5-yl)-3-phenylaziridine-Z-carboxylate 37. The standard procedure for the preparation of aziridine 3b described above was followed from imine 34 (231 mg, 1 mmol). The crude product was purified by silica gel chromatography and prep TLC (1 :19 EtOAc/hexanes as elute) to give 37 as a colorless oil in 27% yield (86 mg, 0.27 mmol). An optical purity of 84% 89 was determined by HPLC analysis (Chiralcel OD-H column, 222 nm, 100% hexanes, flow rate: 1 mL/min). Retention times: R; = 2.59 min for (2R,3R)—37 and R; = 2.90 min for (28,3S}37. Spectral data for 37: n; = 0.30 (1:25 EtOAc/hexanes); 1H NMR (CDCI3, 500 MHz) 8 0.86-1.00 (m, 9H), 1.26-1.68 (m, 13H), 2.52 (d, 1H, J = 8.8 Hz), 2.96 184 (d, 1H, J = 8.8 Hz), 3.88-4.09 (m, 2H), 7.25-7.34 (m, 3H), 7.43-7.46 (m, 2H); ‘30 NMR (CDCI3, 125 MHZ) 6 13.84, 13.90, 13.99, 22.93, 23.05, 27.96, 28.03, 33.78, 34.05, 45.52, 47.11, 60.39, 69.55, 127.13, 127.71, 127.81, 135.70, 168.53; IR (thin film) 2986s, 1751s, 1297vs, 946m cm"; Mass spectrum: m/z (% rel intensity) M+1+ 318 (100), 217 (9); HRMS calcd for C20H32NO2 (M+H) m/z 318.2433, meas 318.2428; [81230 = +3.6 (01.0, CH2CI2) on 79% ee (28,3S)-37. O i O 1 | l% O i O (8)-VAPO -83 catalyst N r/N + HTCOZEt CH2Cl2, 25 °c, 24 h , ph N2 Ph’ ‘cozEt 36 2 (2R,3R)-39 Aziridine 39. The standard procedure for the preparation of aziridine 3b described above was followed from imine 36 (147 mg, 0.5 mmol). The crude product was purified by silica gel chromatography (1:19 EtOAc:hexanes as elute) to give 39 as a white solid (mp 174-176 °C) in 65% yield (124 mg, 0.33 mmol). An optical purity of 96% 89 was determined by HPLC analysis (Chiralcel OD-H column, 222 nm, 95:5 hexaneszi-PrOH, flow rate: 1 mL/min). Retention times: R; = 6.1 min for (2R,3Fl)-39 and R; = 3.2 min for (2S,38)-39. Spectral data for 39: R; = 0.21 (1:19 EtOAc/hexanes); 1H NMR (CDCI3, 500 MHz) 6 1.09 (t, 3H, J = 7.1 Hz), 2.60 (d, 1H, J = 7.1 Hz), 3.05 (d, 1H, J = 6.8 Hz), 3.38 (s, 1H), 4.03-4.10 (m, 2H), 7.13 (d, 2H, J = 2.2 Hz), 7.16-7.20 (m, 1H), 7.24-7.36 (m, 5H), 7.41 (t, 2H, J = 7.6 Hz), 7.50 (t, 1H, J = 7.1 Hz), 7.69 (d, 2H, J = 7.1 Hz), 7.91 (d, 1H, J = 7.8 Hz), 8.31 (d, 1H, J = 8 Hz); 13c NMR (CDCI3, 125 MHZ) 5 14.02, 47.68, 48.47, 60.68, 72.72, 124.03, 124.47, 125.99, 126.13, 185 127.46, 127.49, 127.51, 127.78, 127.93, 128.69, 127.88, 131.06, 131.11, 133.29, 133.32, 134.99, 138.92, 139.15, 167.44; IR (thin film) 30848, 30498, 1746m, 1263m cm"; Mass spectrum: m/z (% rel intensity) M+1+ 382 (100), 301 (26), 192 (25), 191 (83); HRMS calcd for C26H24NO2 (M+H) m/z 382.1807, meas 382.1798; [81230 = -81.1 (01.0, CH2CI2) on 98% ee (2R,3Fl)-39. Section 2.4 cis-2,3-Dicarbonylaziridines from the Wulff aziridination The procedures for the formation of the imines 40 and the aziridines 41 were identical to the general procedures reported above for the imine 1b and the aziridine 3b respectively. 'Butyl diazoacetate 19 is commercially available from Aldrich, and can also be prepared according to previously reported /N procedures.“32 COzEt 40a Ethyl 2-(benzhydrylimino)acetate 40a. This imine was prepared in a similar manner as described in the general procedure, from diphenylmethanamine (0.94 g, 5.16 mmol) and freshly distilled ethyl glyoxalate solution (50% in toluene), and was obtained as a viscous yellow oil from the reaction in 95% yield (1.31 g, 4.90 mmol). However, it solidified when kept in the refrigerator for 2 days and this light yellow crude solid was used in the aziridination reaction as such without further purification. Spectral data for 40a: 1H NMR (CDCI3, 500 MHz) 8 1.38 (t, 3H, J = 7.1 Hz), 4.37 (q. 2H, J: 7.1 Hz), 5.71 (s, 1H), 7.27-7.30 (m, 2H), 7.33-7.37 (m, 8H), 188 7.80 (d, 1H, J: 1 Hz); 13c NMR (CDCI3, 125 MHz) 8 14.09, 61.75, 77.42, 127.46, 127.77, 128.56, 141.53, 153.70, 163.10. /0 O O 0\ /N C02Et 405 Ethyl 2-(bis(4-methoxy-3,5-dimethy/phenyl)methylimino)acetate 40b. This imine was prepared in a similar manner as described in the general procedure, from the MEDAM amine (1.54 g, 5.16 mmol) and freshly distilled ethyl glyoxalate solution (50% in toluene), and was obtained as a viscous yellow oil from the reaction in 93% yield (1.83 g, 4.78 mmol). However, it solidified when kept in the refrigerator for 2 days and this light yellow crude solid was used in the aziridination reaction as such without further purification. Spectral data for 40b: 1H NMR (CDCI3, 500 MHz) 6 1.33 (t, 3H, J = 7.1 Hz), 2.23 (s, 12H), 3.87 (s, 6H), 4.32 (q, 2H, J: 7.1 Hz), 5.42 (s, 1H), 8.92 (s, 4H), 7.70 (s, 1H); 13c NMR (CDCI3, 125 MHZ) 8 14.15, 18.14, 59.81, 81.74, 77.25, 127.97, 130.93, 136.99, 153.22, 156.24, 163.27. ti-3u ttau /O O 0 °\ tBu tBu /N 002Et 40c 187 '3 ’n-_l u Ethyl 2-(bis(3,5-di-tert-butyl-4-methoxyphenyl)methylimino)acetate 40c. This imine was prepared in a similar manner as described in the general procedure, from the BUDAM amine (2.84 g, 6.10 mmol) and freshly distilled ethyl glyoxalate solution (50% in toluene). Crystallization (1 :20 ethyl acetate/hexanes) afforded imine 40c in 75% isolated yield as white crystals (mp 118-120 °C). Spectral data for 40¢: 1H NMR (CDCI3, 500 MHZ) 8 1.33 (t, 3H, J = 7.2 Hz), 1.36 (s, 36H), 3.62 (s, 6H), 4.33 (q, 2H, J = 7.1 Hz), 5.53 (s, 1H), 7.07 (s, 4H), 7.81 (s, 1H); 13C NMR (CDCI3, 500 MHz) 6 14.14, 32.01, 35.79, 61.68, 64.22, 77.79, 126.35, 134.97, 143.45, 152.94, 158.80, 163.52; IR (thin film) 29618, 2912w, 1753m, 1724m, 14148 cm"; Mass spectrum: m/z (% rel intensity) M+1+ 552 (10), 452 (100); Anal calcd for C35H53NO4: C, 76.18; H, 9.68; N, 2.54. Found: C, 75.94; H, 10.12; N, 2.53. Ph Ph Y N EtOflOtBu 0 0 41a (2R, 3S)-tert-butyl 1-benzhydryl-3—propionylaziridine-2-carboxylate 419. The standard procedure for the aziridination was followed from imine 40a (66 mg, 0.25 mmol). The reaction temperature was -40 0C for 24 h followed by room temperature for 12 h. The crude product was purified by silica gel chromatography with an eluent system of 1:9 EtOAc:hexanes to afford the pure product 41a as a white solid (mp 144-146 °C) in 65% isolated yield (62 mg, 0.16 mmol). An optical purity of 4% e9 was determined by HPLC analysis (Chiralcel 188 OD-H column, 222 nm, 95:5 hexanesz’PrOH, flow rate: 1 mUmin). Retention times: R; = 3.6 min for (28,3R)-41a and R; = 7.5 min for (2R,38)-41a. Spectral data for 41a: R; = 0.09 (1:15 EtOAc:hexanes); 1H NMR (CDCI3, 500 MHz) 6 1.23 (t, 3H, J: 7.1 Hz), 1.42 (s, 9H), 2.60-2.66 (m, 2H), 3.88 (8, 1H), 4.09-4.23 (m, 2H), 7.19-7.23 (m, 2H), 7.26-7.31 (m, 4H), 7.49-7.54 (m, 4H); “’0 NMR (CDCI3, 125 MHZ) 6 14.08, 27.90, 43.52, 44.59, 61.13, 76.74, 81.80, 127.33, 127.37, 127.38, 127.41, 128.34, 128.39, 141.76, 141.78, 166.02, 167.19; IR (thin film) 3065w, 2980w, 17458, 1732m, 1238m cm"; Mass spectrum: m/z(% rel intensity) M+1+ 382 (100), 326 (32), 167 (50); HRMS calcd for C23H28NO4 (M+H) m/z 382.2018, meas 382.2016. Me Me MeO I l OMe Me Me N EtOflOtBu O 0 41b (2R,3S)-tert-butyl 1-(bl's(4-methoxy-3,5-dimethylphenyl)methyl)-3- propionylaziridine-Z-carboxylate 41b. The standard procedure for the aziridination was followed from imine 40b (96 mg, 0.25 mmol). The reaction temperature was 0 °C for 24 h. The crude product was purified by silica gel chromatography with an eluent system of 1:5 EtOAc:hexanes to afford the pure product 41b as a light yellow solid (mp 82-85 °C) in 80% isolated yield (100 mg, 0.2 mmol). An optical purity of 14% ee was determined by HPLC (Chiralcel OD-H column, 222 nm, 99:1 hexanes:’PrOH, flow rate: 0.7 mL/min). Retention times: R; = 12.5 min for (28,3R)-41b and R; = 18.2 min for (2R,3S)-41 b. ‘ 189 Spectral data for 41 b: R; = 0.1 (1:9 EtOAc:hexanes); 1H NMR (0001;, 500 MHz) 8 1.23 (t, 3H, J = 7.1 Hz), 1.41 (s, 9H), 2.22 (s, 12H), 2.44-2.51 (m, 2H), 3.54 (s, 1H), 3.85 (s, 6H), 4.08-4.24 (m, 2H), 7.11 (s, 2H), 7.12 (s, 2H); ”C NMR (CDCI3, 125 MHz) 8 14.18, 18.14, 27.93, 43.93, 44.57, 59.58, 81.11, 78.24, 81.71, 127.52, 127.66, 130.55, 130.57, 137.12, 137.22, 156.04, 158.10, 188.29, 167.31; IR (thin film) 2980s, 2934s, 2866w, 2828w, 1751s, 1483m, 1389s cm"; Mass spectrum: m/z (% rel intensity) M+1+ 498 (100), 283 (45); HRMS calcd for C29H40N06 (M+H) m/z 498.2858, meas 498.2847; [a]230 = +0.8 (01.0, CH2CI2) on 46% ee (28,3R)-41b. (2R,3S)-tert-butyl 1-(bis(3,5-di-tert-butyI-4-methoxyphenyl)methyI)-3- propionylaziridine-2-carboxylate 41c. The standard procedure for the aziridination was followed from imine 40c (138 mg, 0.25 mmol). The reaction temperature was 0 °C for 24 h. The crude product was purified by silica gel chromatography with an eluent system of 1:19 EtOAc:hexanes to afford the pure product 41c as a light yellow solid (mp 96-99 °C) in 58% isolated yield (97 mg, 0.14 mmol). An optical purity of 15% ee was determined by HPLC analysis (Pirkle Covalent (R,Fl) Whelk 01 column, 222 nm, 99:1 hexanes:’PrOH, flow rate: 190 0.7 mUmin). Retention times: R; = 9.4 min for (28,3R)-41c and R; = 10.3 min for (2R,3S)-41c. 1 Spectral data for 41¢: R; = 0.2 (1:19 EtOAc:hexanes); 1H NMR (CDCI3, 500 MHZ) 8 1.27 (t, 3H, J = 7.1 Hz), 1.41 (s, 38H), 1.44 (s, 9H), 2.60-2.64 (m, 2H), 3.67 (s, 6H), 3.78 (s, 1H), 4.14-4.24 (m, 2H), 7.27 (s, 2H), 7.33 (s, 2H); ”C NMR (CDCI3, 125 MHZ) 6 14.19, 27.96, 32.09, 35.74, 44.26, 44.77, 61.15, 64.03, 76.60, 81.60, 125.65, 125.76, 135.67, 135.86, 143.03, 143.04, 158.43, 158.46, 166.17, 167.32; IR (thin film) 2983s, 2870w, 1757s, 1730m, 1414m cm"; Mass spectrum: m/z (% rel intensity) M+1+ 666 (2), 451 (100); HRMS calcd for C41H64N05 (M+H) m/z 888.4734, meas 888.4742; [81230 = +0.5 (01.0, CH2CI2) on 15% ee (2R,38)-41c. Section 2.5 A gram scale catalytic asymmetric aziridination process H C O CH2CI2, M9804 O O 0 . © ' \ U“ 0 Br Br 58.14 mmol scale 1.1 equiv 1f (10-54 9) 84-85% yield (17.04-17.36 9, single crop) 0.5 mol% 0 (8)-VANOL-B3 catalyst + 44 mg of (S)- VANOL used U” D 112 Br 1f . toluene, 22 C (rt), 8 h C 02Et 1.2 equrv Br 20 mmol scale (7 g) 31' 1St crop: 62-64% yield (5.41-5.59 g) 99% ee 2nd crop: 25-27% yield (2.20-2.35 9) 75-78% ee overall: 89% yield (776-779 9) 92-93% ee 191 N-(4-bromobenzylidene)-1,1-diphenylmethanaml'ne (11').8 A 250 mL round- bottom flask with a single 24/40 neck was fitted with a pear-shaped magnetic stir bar (2.5 x 1.3 x 1.3 cm) and a 24/40 vacuum adapter. This assembly was flame dried under high vacuum (0.1 mm Hg) and cooled under a slight positive pressure of Argon. To this flask was then sequentially added 4- bromobenzaldehyde (11.84 g, 63.95 mmol, 1.1 equiv) and M9804 (14 9, 116.28 mmol, 2 equiv) (Note 1). This was followed by the addition of 60 mL dry dichloromethane (Note 1), via a plastic syringe fitted with a metallic needle, along the neck and the sides of the flask such that all solids could be brought to the bottom of the flask. The vacuum adapter was then replaced with a rubber septum and an Argon balloon. The mixture was stirred at room temperature (22 °C) to get a white slurry. Aminodiphenylmethane (10 mL, 58.14 mmol, 1 equiv) was then added to the solution through the rubber septum, via a plastic syringe fitted with a metallic needle (Note 1). The resulting white slurry was stirred at room temperature (22 °C) for 20 h, at which time the reaction was complete (Note 2). A different 250 mL round bottom flask (24/40 single neck) was fitted with a filter adapter and a glass fritted funnel (60 mL, 4.5 x 5.5 cm) packed with Celite (1 cm height). The reaction mixture was then filtered through the fritted funnel; the reaction flask was rinsed with 15 mL dichloromethane three times and the rinse added to the funnel each time (Note 3). The fritted funnel and the Celite bed were then washed twice with 15 mL dichloromethane. The fritted funnel was removed, the filter adapter rinsed with 10 mL dichloromethane and the solution of the crude product was then subjected to rotary evaporation until drynress (20 mm Hg, 35- 192 45 °C) followed by high vacuum (0.1 mm Hg) for 3 h. This afforded the crude imine product 1f as an off-white solid (21.25-21.41 9). For crystallization, the 250 mL round bottom flask containing the crude product was fitted with a water condenser, a rubber septum and an Argon balloon. A mixture of 20 mL of 1:5 ethyl acetate:hexanes was added via a plastic syringe fitted with a metallic needle (Note 4). This solution was brought to a boil while swirling by hand over a heat gun. An additional 15 mL portion of the 1:5 ethyl acetate:hexanes mixture was then added slowly with continued boiling and swirling (total volume 35 mL). At this time, a clear pale yellow solution of the crude product was obtained; this was placed on a wooden cork and left untouched for 19 h. The resulting crystals were then broken up into small pieces by a spatula, and these were collected by filtration on a Biichner funnel (6 cm d x 3.5 cm h). The crystallization flask was rinsed twice with 10 mL cold (0 °C) hexanes and the rinse added each time to the Biichner funnel. The resulting crystals were transferred to a 50 mL single neck round bottom flask and subjected to high vacuum (0.1 mm Hg) for 4 h. This afforded the product imine 1f as white crystals (mp. 95-97 °C) in 84-85% yield (1704-1736 9, 48.69-49.60 mmol) (Notes 5, 6). (2R,3Fl)-ethyl 1 -benzhydryI-3-(4-bromophenyl)aziridine-2-carboxylate (31').8 A 100 mL glass Schlenk flask fitted with a magnetic stir bar (3.8 x 1 x 1 cm) was connected via a rubber tube to a double manifold vacuum line with an Argon ballast (Note 7, 8). The flask was then flame dried under high vacuum (0.05 mm Hg) and cooled under a slight positive pressure of Argon. To the flask was added sequentially (8)-VANOL (44 mg, 0.1 mmol, 0.005 equiv) and triphenyl borate 193 6.1!. “15.1. (116 mg, 0.4 mmol, 0.02 equiv) under a slight positive pressure of Argon (Note 9). Thereafter, 4 mL dry toluene (Note 1) was added along the sides of the Schlenk flask via a plastic syringe fitted with a magnetic needle which had been pre-flushed with Argon. This was followed by the addition of water (1.8 uL, 0.1 mmol, 0.005 equiv) via a glass syringe. The flask was then sealed and stirred at 80 °C in an oil bath (bath temperature) for 1 h. Thereafter, the valve on the double manifold connected to the Schlenk flask was turned to high vacuum (0.05 mm Hg). The threaded valve on the Schlenk flask was then carefully and gradually opened to the high vacuum, and the solvent was removed (Note 10). After all solvent was removed, the Schlenk flask was allowed to remain at 80 °C in the oil bath for an additional 0.5 h exposed to high vacuum. The flask was then removed from the oil bath and cooled to room temperature under a slight positive pressure of Argon (ca. 20 min) to afford the pre-catalyst as a colorless/off-white oil stuck to the sides of the Schlenk flask. To this was then added, under a slight positive pressure of Argon, the imine 1f (7.00 g, 20 mmol, 1 equiv), followed by the addition of 20 mL dry toluene along the sides of the Schlenk flask via a plastic syringe fitted with a magnetic needle (pre-flushed with Argon). The magnetic stir bar at this point was stuck to the Schlenk flask, the flask was swirled by hand until the stir bar became free (Note 11). Additional dry toluene (5 mL) was then added along the sides of the Schlenk flask, and the solution was stirred at room temperature for 5-10 min to obtain a clear pale yellow solution of the catalyst-imine complex. Under a slight positive pressure of Argon, ethyldiazoacetate (2.5 mL, 24 mmol, 1.2 equiv) was then added to the 194 In-‘- ' Schlenk flask via a plastic syringe fitted with a magnetic needle (pre-flushed with Argon) (Note 9). The clear solution in the Schlenk flask turned dark yellow/orange with this addition, and vigorous nitrogen evolution was observed. Within 1 h, the product aziridine started precipitating out, and the entire reaction mixture turned into a pale yellow semi-solid mass. The reaction was stirred at room temperature under a slight positive pressure of Argon for a total of 8 h, at which point the reaction was complete (Note 12). Dichloromethane (30 mL) was added to the Schlenk flask (Note 3) and the resulting mixture was stirred to obtain a clear yellow solution of the crude aziridine product. This was then added, via a plastic funnel, to a pre-weighed 250 mL round bottom flask with a single neck (24/40 joint). The Schlenk flask was rinsed twice with 20 mL dichloromethane, the plastic funnel with 5 mL dichloromethane, and the rinse added each time to the round bottom flask. This was then subjected to rotary evaporation (20 mm Hg, 35-45 °C) until ca. 25 mL of the crude product solution was left in the flask. Hexanes (50 mL) were added to the flask at this point, and the solution was again subjected to rotary evaporation to dryness and finally to high vacuum (0.1 mm Hg) for 12 h to afford the crude aziridine product at as an off-white solid (889-891 g). This was then dissolved in 30 mL dichloromethane to obtain a clear yellow solution and was allowed to stand at room temperature for 15 min. A different pre-weighed 250 mL round bottom flask (24/40 Single neck) was fitted with a filter adapter and a glass fritted funnel (30 mL, 3.5 x 5.0 cm) packed with Celite (1 cm height). The crude product solution was filtered through the fritted funnel; the flask was rinsed twice with 20 195 mL dichloromethane and the rinse added to the funnel. The sides of the fritted funnel and the Celite bed were then washed with 20 mL dichloromethane. The fritted funnel was removed and the filter adapter rinsed with 10 mL dichloromethane and this crude product solution was then subjected to rotary evaporation to dryness (20 mm Hg, 35-45 °C) followed by high vacuum (0.1 mm Hg) for 4 h. This afforded the crude aziridine product 31 again as an off-white solid. For crystallization, the 250 mL round bottom flask containing the crude product was fitted with a water condenser, a rubber septum and an Argon balloon. A mixture of 1:3 dichloromethanezhexanes (30 mL) was added via a plastic syringe fitted with a metallic needle (Note 3, 4). This solution was brought to a boil while swirling by hand over a heat gun. An additional portion (60 mL) of the 1:3 dichloromethanezhexanes solvent mixture was then added slowly (total volume 90 mL). The solution was continually heated at boil over the heat gun and swirled by hand until all the solids had dissolved and a clear pale yellow solution of the crude product was obtained; this was placed on a wooden cork and left untouched for 1 h. The condenser was then removed, and the crystallization flask allowed to stand open to air at room temperature for an additional 27 h. During this time, a very small amount of light cloudy material appeared at the bottom of the flask, followed by needle-like white crystals. After a total of 28 h, the supernatant was then carefully decanted, so as to not disturb the crystals, into another 500 mL round bottom flask (24/40 single neck) via a plastic funnel. Cold hexanes (-20 °C, 50 mL) was gently added to the 196 crystallization flask, the flask gently swirled by hand, and the supernatant solution was again added via decantation to the 500 mL round bottom flask. The hexane wash was repeated once more. Then, 80 mL of dichloromethane was added to the crystallization flask to completely dissolve the product crystals and afford a clear slightly pale yellow solution. A small aliquot (ca. 0.5 mL) was taken from this solution, diluted with ethyl acetate and hexanes, and subjected to chiral HPLC analysis, which revealed 99% ee for the first crop of aziridine 3f (Note 13). The solution of the first crop in the 250 mL round bottom flask was then subjected to rotary evaporation until dryness (35-45 °C, 20 mm Hg) and finally to high vacuum for 3-4 h to afford the first crop of aziridine 3f as a white solid (mp. 152-154 °C) in 82-84% yield (541-559 g, 12.41-12.82 mmol) (Note 13). The 500 mL round bottom flask with the mother liquor and the washes was then subjected to rotary evaporation to dryness (35-45 °C, 20 mm Hg) and the resulting solids were dissolved in 50 mL dichloromethane, and transferred to a different pre-weighed 250 mL round bottom flask (24/40 single neck) via a plastic funnel. The 500 mL round bottom flask was rinsed twice with 20 mL dichloromethane, the plastic funnel with 10 mL dichloromethane and the rinse added each time to the 250 mL round bottom flask. This mother liquor solution was then subjected to rotary evaporation until dryness (35-45 °C, 20 mm Hg) and finally to high vacuum for 3-4 h to afford the crude aziridine product 31 as a pale yellow solid (337-354 g). A second crop was then taken from this material in the same manner as the first crop, except that a total volume of 35 mL of a 1:4 mixture of dichloromethanezhexanes was used for the crystallization. Two similar 197 cold hexanes (-20 °C) washes were employed as in the first crop, with 25 mL hexanes each time. The second crop of aziridine 31 was obtained as a white/off- white solid (mp. 134-142 °C) in 25-27% yield (2.20-2.35 g, 5.05-5.39 mmol) and 75-78% 88. Thus, the overall yield of the reaction was 89% (7.76-7.79 g, 17.80- 17.87 mmol) and the overall asymmetric induction was 92-93% ee (Note 14). Notes 1. Aminodiphenylmethane (97%) and 4-bromobenzaldehyde (99%) were obtained from Aldrich, used as received and stored under nitrogen on the bench. M9804 (98+%, anhydrous) was obtained from Jade Scientific and used as received. Dichloromethane (99.5+%) was obtained from Mallinckrodt Chemicals and distilled from calcium hydride under nitrogen. Toluene (99.5+%) was obtained from Mallinckrodt Chemicals and distilled from sodium under nitrogen. 2. Determined from 1H NMR analysis of the crude reaction mixture. The stirring was stopped and the solids were allowed to settle from the reaction mixture to the bottom of the reaction flask. A small aliquot (<0.5 mL) was then taken from the solution with a glass pipette, which was subjected directly to high vacuum (0.01 mm Hg) for 15 min, and analyzed by 1H NMR. The disappearance of the singlet signal from the methine proton of aminodiphenylmethane was observed (6: 5.22 ppm, CDCI3); the reaction was judged complete. 3. The dichloromethane was not dried, regular dichloromethane (99.5+%) obtained from Mallinckrodt Chemicals was used. 198 4. Ethyl acetate (99.5+%) was obtained from Mallinckrodt Chemicals and used as received. Hexanes (98.5+%, total hexane isomers and methylcyclopentane) was obtained from EMD Chemicals and used as received. 5. lmine 1f can be stored for a long period of time sealed under Argon in a dry desiccator. Spectral data for imine 11:8 1H NMR (CDCI3, 500 MHz) 6 5.59 (s, 1H), 7.22-7.25 (m, 2H), 7.30-7.34 (m, 4H), 7.37-7.40 (m, 4H), 7.54 (d, J = 8.5 Hz, 2H), 7.70 (d, J = 8.5 Hz, 2H), 8.36 (s, 1H); 13C NMR (CDCI3, 125 MHz) 6 77.86, 125.17, 127.06, 127.61, 128.47, 129.85, 131.76, 135.20, 143.64, 159.52; IR (thin film) 3028w, 2845w, 1843s, 1485m, 700s cm"; HRMS calcd for C20H16798rN (M+H) m/z 350.0544, meas 350.0558; white crystals: mp. 95-97 °C. 6. A second crop of crystals could be taken to afford imine 1f in 6% yield (1.27 g, 3.63 mmol), but this was found to contain ~1% of 4-bromobenzaldehyde by 1H NMR analysis. 7. The Schlenk flask was made in a glass blowing shop by fusing together a high vacuum threaded Teflon valve (Chemglass, CG-960-03, Valve, Chem- VacTM, Chem-Cap®, Hi-Vac, 1-Arm, 0-12 mm Bore) and a 100 mL recovery flask (Chemglass, CG-622-04, 100 mL Glassblowers Flask Blank, Recovery). The Side-arm of the high vacuum valve was modified with a piece of 3/8th inch glass tubing to fit with the rubber tube attached to the double manifold. The double manifold had two-way high-vacuum valves, which could be alternated between high vacuum (0.05 mm Hg) and an Argon supply (ultra high purity, 99.999%). The large stir bar is needed for efficient stirring during the actual aziridination reaction. 199 8. For pictures of the set up after addition of ethyldiazoacetate, see published procedure. 9. (8)-VANOL is commercially available from Aldrich as well as Strem Chemicals, Inc. It was sealed under Argon and stored in a refrigerator away from light. Triphenyl borate was obtained from Aldrich, used as received and stored under nitrogen in a dry desiccator. Ethyl diazoacetate was obtained from Aldrich, used as received and stored under nitrogen in a refrigerator. Commercially available ethyldiazoacetate usually contains 515% dichloromethane, which was the reason behind using 1.2 equivalents in the procedure. 10. If the threaded valve on the Schlenk flask is not opened with care under high vacuum, the solvent might bump into the manifold and result in loss of catalyst. 11. If needed, the Schlenk flask may be gently tapped on a hard surface to aid in freeing the stir bar stuck inside. 12. Determined from 1H NMR analysis of the crude reaction mixture. A glass pipette was dipped into the Schlenk flask, and a small amount of the semi-solid reaction mass was collected at the tip of the pipette. This was directly rinsed with CDCI3 and analyzed by 1H NMR. The disappearance of the singlet signals from the methine protons of imine 1f was observed (6 = 5.59, 8.36 ppm, CDCI3); the conversion was 295% as determined from the relative integration of the aforementioned imine methine protons vs. the aziridine ring methine protons. 13. Aziridine 3f can be stored for a long period of time sealed under nitrogen on the bench. The optical purity of the first crop of (2R,3H)-3f was determined to 200 Ir be 99% ee by HPLC analysis (Chiralcel OD-H column, hexanes/2-propanol 98:2, 222 nm, flow rate 1 mL min"). Retention times: t;:; = 5.5 min (minor enantiomer) and tn = 13.3 min (major enantiomer). Spectral data for (2F?,3H)-3f:8 1H NMR (CDCI3, 500 MHz) 8 1.05 (t, J = 7.1 Hz, 3H), 2.72 (d, J = 8.8 Hz, 1H), 3.17 (d, J = 6.8 Hz, 1H), 3.98 (s, 1H), 3.98 (q, J = 7.1 Hz, 2H), 7.21 (t, J = 7.3 Hz, 1H), 7.28-7.42 (m, 9H), 7.48 (d, J = 7.1 Hz, 2H), 7.61 (d, J = 7.1 Hz, 2H); 13c NMR (CDCI3, 125 MHz) 6 13.98, 46.46, 47.33, 60.69, 77.58, 121.33, 127.13, 127.27, 127.41, 127.48, 128.50, 128.51, 129.53, 130.88, 134.07, 142.13, 142.30, 167.39; IR (thin film) 1734s, 1201s, 1067m cm"; Mass spectrum: m/z (%) 437 (<1, 8‘Br) [1141:3435 (<1, 798r) (My, 270 (42, 81Sr), 288 (43, 79Hr), 167 (100, 818r), 185 (19, 79Br); elemental analysis calcd (%) for C24H22BrNO2: C 66.06; H 5.27; N 3.09. Found: c 88.08; H 5.08; N, 3.21; [8:123D = +125 (0 = 1.0, CH2CI2) on 99% ee material; white solid: mp. 152-154 °C on 99% ee material. 14. During the optimization of this procedure, one particular run afforded the 1st crop of aziridine 3f in 59% yield (5.13 g, 11.77 mmol) and 99% ee, and the 2'"d crop in 24% yield (2.07 g, 4.75 mmol) and 78% ee. At this time, a 3rd crop was taken by simply washing the crude material remaining after the 2"d crop with cold hexanes (-20 °C, 2 x 10 mL) and swirling by hand followed by decantation. Thus, the 3rd crop of aziridine 3f was obtained in 5% yield (0.40 g, 0.92 mmol) and 96% ee. Subjecting the crude material remaining after collection of the 3rd crop to purification by column chromatography on regular silica gel (1 :9 EtOAc:hexanes) ' afforded negligible quantities of pure aziridine 3f (0.07 g, 0.16 mmol, <1% yield). 201 Section 2.6 Failed attempts for direct access to tri-substituted aziridines The di-substituted diazo compound 47 was prepared according to a reported procedure.33 The di-substituted MEDAM imine 45 was prepared in a similar manner to a reported procedure.34 5 mol% PTSA reflux, Dean Stark, FMEDAM benzene, 5 days 66% yield + MEDAM'NHZ F 1 (after column) 45 Ethyl 4,4-bis(4-methoxy-3,5-dimethylphenyl)-2-phenylbut-2-enoate 45. A 50 mL RBF, fitted with a Dean-Stark apparatus, was flame dried and cooled under Argon. The MEDAM amine (2.37 g, 7.92 mmol) was added to the flask and was dissolved in 20 mL of dry benzene. Thereafter, ethyl benzoylformate (0.89 mL, 5.618 mmol) was added via a syringe, which was followed by the addition of p-toluene sulfonic acid (54 mg, 0.28 mmol). The reaction mixture was heated to reflux with azeotropic distillation of water for 5 days, following which the reaction was judged complete by TLC. The reaction mixture was then cooled down to room temperature, all organic volatiles removed by rotary evaporation and subjected to high vacuum to afford the crude product 45 as a viscous oil. This was then subjected to column chromatography with an eluent mixture of 1:9 EtOAc:hexanes to afford the pure product 45 as a colorless viscous oil in 66% isolated yield (1.69 g, 3.69 mmol) and with a syn:anti ratio of 25:1 (the diastereomers were not assigned). Spectral data for 45: R; = 0.25 (1 :9 EtOAc:hexanes); 1H NMR (CDCI3, 500 MHz) 8 1.34 (t, 3H, J = 7.1 Hz), 2.24 (s, 12H), 3.67 (s, 6H), 4.41 (q, 2H, J = 7.1 202 Hz), 5.47 (s, 1H), 8.99 (s, 4H), 7.38-7.43 (m, 3H), 7.80-7.82 (m, 2H); ‘30 NMR (CDCI3, 500 MHZ) 6 14.23, 16.22, 59.56, 61.30, 70.79, 127.59, 127.80, 128.45, 130.57, 130.94, 134.56, 138.59, 155.95, 158.45, 165.55; IR (thin film) 30,63w, 2982w, 2943w, 17328, 1633m, 1483m cm"; Mass spectrum: m/z (% rel intensity) M+1+ 460 (100), 283 (85); Anal calcd for C29H33NO4: C, 75.79; H, 7.24; N, 3.05. Found: C, 75.34; H, 7.44; N, 3.03. i." 203 Appendix C Experimental Information for Chapter Three Section 3.4 Catalytic asymmetric trans-aziridination: Development of a universal aziridination protocol General procedure for the preparation of imines, and characterization data for new imines Procedures for the preparation of benzhydryla, MEDAM"), and BUDAM9 imines have been previously published by our group. All these procedures are similar in the reaction conditions, and that for the benzhydryl imines is also detailed in the experimental information for Chapter 2 of this dissertation. The new imines for the present study were also prepared using this general procedure. Benzhydryl imines 1b and 1k have been previously reported by our group (see also experimental information for Chapter 2).8 MEDAM imines Qa-e and 9k-l have been previously reported by our group.10 BUDAM imines 58a and 58k-m have also been previously reported by our group.9 OMe Me 0 Me 1, 1 -bis(4-methoxy-3,5-dimethylphenyI)-N-(3- methylbenzylidene)methanamine 9f. The MEDAM amine (1.00 g, 3.34 mmol) and m-methylbenzaldehyde (0.42 mL, 3.51 mmol) were reacted according to the 204 general procedure to afford crude 9f. The crude imine 9f was obtained as a thick colorless oil in quantitative yield (1.34 g, 3.34 mmol), and was used in the aziridination reaction as such. Spectral data for 9f: 1H NMR (CDCI3, 500 MHz) 6 2.24 (8, 12H), 2.38 (s, 3H), 3.68 (s, 6H), 5.35 (s, 1H), 6.99 (s, 4H), 7.21-7.30 (m, 2H), 7.57 (d, 1 H, J = 7.5 Hz), 7.68 (s, 1 H), 8.33 (s, 1 H). OMe Me 0 Me \N Me 0?. O 99 Me N-(2-chlorobenzylidene)- 1, 1—bis(4-methoxy-3,5— dimethy/phenyl)methanamine 9g. The MEDAM amine (1 .00 g, 3.34 mmol) and o- chlorobenzaldehyde (0.40 mL, 3.51 mmol) were reacted according to the general procedure to afford crude 9g. Crystallization (1:10 CH2Cl2zhexane8) afforded 99 as a pale yellow solid (mp. 100-102 °C) in 78% isolated yield (1.10 g, 2.61 mmol). Spectral data for 99: 1H NMR (CDCI3, 500 MHz) 8 2.25 (s, 12H), 3.68 (s, 8H), 5.42 (s, 1H), 7.02 (s, 4H), 7.28-7.35 (m, 3H), 8.22-8.24 (m, 1H), 8.82 (s, 1H); “’0 NMR (CDCI3, 125 MHz) 8 18.22, 59.80, 77.79, 128.87, 127.78, 128.90, 129.67, 130.71, 131.49, 133.35, 135.27, 139.03, 155.90, 156.99; IR (thin film) 2941m, 1633m, 14838, 12218, 11428, 10168 cm"; HRMS calcd for C25H2935C|NO2 (M+H, ES+) m/z 422.1887, meas 422.1898. 205 1, 1-bis(4-methoxy-3,5-dimethylphenyl)-N-(3- methoxybenzylidene)methanamine 9h. The MEDAM amine (0.50 g, 1.67 mmol) and m-rnethoxybenzaldehyde (0.22 mL, 1.76 mmol) were reacted according to the general procedure to afford crude 9h. The crude imine 9h was obtained as a thick colorless oil in quantitative yield (0.70 g, 1.67 mmol), and was used in the aziridination reaction as such. Spectral data for 9h: 1H NMR (CDCI3, 500 MHz) 6 2.24 (s, 12H), 3.67 (s, 6H), 3.84 (s, 3H), 5.36 (s, 1H), 6.94-6.96 (m, 1H), 6.99 (s, 4H), 7.28-7.34 (m, 2H), 7.42-7.43 (m, 1H), 8.32 (s, 1H); ‘30 NMR (CDCI3, 125 MHZ) 6 16.22, 55.41, 59.60, 77.32, 112.53, 116.95, 121.67, 127.89, 129.44, 130.64, 137.90, 139.12, 155.85, 159.82, 160.23. OMe M. O M. W“ 0 Me 9i 1, 1 -bis(4-methoxy-3,5-dimethylphenyI)-N-(naphthalen-2- ylmethylene)methanamine 9i. The MEDAM amine (0.50 g, 1.67 mmol) and 2- napthaldehyde (0.27 g, 1.76 mmol) were reacted according to the general procedure to afford crude 9|. The crude imine 9i was obtained as a non- 206 crystallizable white foamy solid in quantitative yield (0.73 g, 1.67 mmol), and was used in the aziridination reaction as such. Spectral data for 9i: 1H NMR (CDCI3, 500 MHz) 8 2.26 (s, 12H), 3.89 (s, 6H), 5.44 (s, 1H), 7.05 (s, 4H), 7.47-7.52 (m, 2H), 7.83-7.89 (m, 3H), 8.07 (s, 1H), 8.15 (dd, 1H, J = 1.7, 8.5 Hz), 8.51 (s, 1H); 13C NMR (CDCI3, 125 MHz) 6 16.23, 59.59, 77.45, 124.32, 126.36, 127.06, 127.84, 127.91, 128.27, 128.57, 130.16, 130.67, 133.07, 134.15, 134.73, 139.22, 155.86, 160.42. OMe Me 0 Me \N Me .U 0 Me 9] N-(4-bromo-2-fluorobenzylidene)- 1, 1-bis(4-methoxy-3,5- dimethy/phenyl)methanamine 9]. The MEDAM amine (0.50 g, 1.67 mmol) and 4- bromo-2-fluorobenzaldehyde (0.36 g, 1.76 mmol) were reacted according to the general procedure to afford crude 9]. Crystallization (hexanes, seeded with crude solid imine) afforded 9] as a light yellow solid (mp. 137-139 °C) in 80% isolated yield (0.65 g, 1.34 mmol). Spectral data for 9]: 1H NMR (CDCI3, 500 MHz) 6 2.25 (s, 12H), 3.68 (s, 6H), 5.37 (s, 1H), 6.98 (s, 4H), 7.25 (dd, 1H, J = 1.7, 9.6 Hz), 7.32 (dd, 1H, J = 1.7, 8.5 Hz), 8.05 (t, 1H, J = 8.1 Hz), 8.80 (s, 1H); 130 NMR (CDCI3, 125 MHz) 8 18.23, 59.81, 77.92, 119.28 (d, 1C, J = 24.4 Hz), 123.13 (d, 1C, J = 9.2 Hz), 125.14 (d, 1C, J = 9.7 Hz), 127.74, 127.79 (d, 1C, J = 3.7 Hz), 129.29 (d, 1C, J = 3.7 Hz), 130.78, 138.82, 152.81 (d, 1c, J = 4.8 Hz), 155.98, 207 161.84 (d, 10, J = 256.8 Hz); 19F NMR (CDCI3, 283 MHz) 8 -119.62; IR (thin film) 2941m, 1639m, 1481s, 1219s, 1016m cm"; HRMS calcd for C26H237QBI'FN02 (M+H, ES+) m/z 484.1287, meas 484.1284. 1, 1-bis(3,5-di-tert-butyl-4-methoxyphenyI)-N-(2- methy/propylidene)methanamine 58n. The BUDAM amine (2.00 g, 4.28 mmol) 1: and isobutyraldehyde (0.45 mL, 4.92 mmol) were reacted according to the general procedure to afford crude 58n. Crystallization (1:39 EtOAc:hexanes) afforded 58h as a white solid (mp. 128-130 °C) in 61% isolated yield (1.36 g, 2.61 mmol). Spectral data for 58n: 1H NMR (CDCI3, 500 MHz) 8 1.14 (d, 6H, J = 7.0 Hz), 1.38 (s, 36H), 2.53-2.60 (m, 1H), 3.65 (s, 8H), 5.21 (s, 1H), 7.05 (s, 4H), 7.72 (d, 1H, J = 5.1 Hz); 13C NMR (CDCI3, 125 MHZ) 8 19.57, 32.07, 34.11, 35.78, 64.13, 77.29, 126.10, 137.12, 142.95, 158.22, 169.31; IR (thin film) 2983s, 1666m, 1414m, 1221m, 1014m cm"; HRMS calcd for C35H56NO2 (M+H, ES+) m/z 522.431 1, meas 522.4317. 208 580 1, 1 -bi8(3,5-di-tert-butyl-4-methoxyphenyl)-N-(2,2-dimethylpent-4- enylidene)methanamine 580. The BUDAM amine (1.50 g, 3.20 mmol) and 2,2- dimethyl-4-pentenal (0.53 mL, 3.52 mmol) were reacted according to the general procedure to afford crude 580. The crude imine 580 was obtained as a thick colorless oil in quantitative yield (1.79 g, 3.20 mmol), and was used in the aziridination reaction as such. Spectral data for 580: 1H NMR (CDCI3, 500 MHz) 8 1.11 (s, 6H), 1.36 (s, 36H), 2.24 (d, 2H, J = 7.3 Hz), 3.65 (s, 6H), 4.97-5.01 (m, 2H), 5.23 (s, 1H), 5.78-5.84 (m, 1H), 7.06 (s, 4H), 7.70 (s, 1H); 13c NMR (CDCI3, 125 MHZ) 6 24.97, 32.09, 35.78, 39.21, 44.72, 64.11, 76.88, 117.14, 126.01, 135.10, 137.34, 142.87, 158.13, 170.61. General procedures for the preparation of the diazoacetamides, and their characterization data Diazoacetamides 14a and 14d-e were prepared in an identical manner as previously reported in the literature,13 and diazoacetamides 14b-c were prepared in an analogous manner. Diazoacetamide 14b is a known compound.45 Diazoacetamides 14f-g were prepared in an identical manner as previously reported in the literature.46 The starting material for the syntheses of 14f-g was 31 ,32b succinimidyl diazoacetate , and the starting material for the preparation of 209 succinimidyl diazoacetate was p-toluenesulfonylhydrazone of glyoxylic acid31'3za; these were all prepared in an identical manner as previously reported in the literature. N-methyl-N-benzyldiazoacetamide 67 was prepared in an identical manner as previously reported by our group.”31 0 0 DCM DBU (2 equiv) o 8’10,N§)l\ 0 °C, 2 h 0 ” c1 + PhNH2 2 ~th Me 1.1 equiv 2-diazo-N-phenylacetamide 14.11.13 A 100 mL round bottom flask fitted with a magnetic stir bar was flame dried and cooled under Argon. The p- toluenesulfonylhydrazone of glyoxylic acid chloride31'3za (3.6 g, 13.82 mmol, 1 equiv) was added to this flask followed by the addition of 30 mL dry dichloromethane. 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 (1.4 mL, 15.2 mmol, 1.1 equiv) and DBU (4.2 mL, 27.6 mmol, 2 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. NH4C| (~ 30 mL), and the layers separated. The aqueous layer was extracted with dichloromethane 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 (3 x 27 cm). An eluent mixture 210 of 1:50 MeOH:CH2CI2 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 148 as a yellow solid. This was then washed with ether 1-4 times until a single spot was observed on TLC (1 :29 MeOH2CH2CI2), this afforded pure 148 as a bright yellow solid in 40-52% yield (1.0 g, 6.2 mmol, 45% yield). Data for 14a:13 Ft; = 0.18 (1:50 MeOH:CH2CI2); 1H NMR (DMSD-oe, 500 MHz) 6 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); 13C NMR (DMSO-d6, 125 MHz) 6 48.01, 118.58, 122.66, 128.75, 139.52, 163.53; IR (thin film): 3086w, 20998, 1635w, 1371m cm' 1; Mass spectrum: m/z (% rel intensity) 161 M“ (4), 133 (60), 105 (55), 104 (100); Anal calcd for C3H7N302 C, 59.62; H, 4.38; N, 26.07. Found: C, 59.21; H, 4.15; N, 25.52; bright yellow solid: mp. dec. 147-149 °C. (EN/Ohm N2 H 14b 2-diazo-N-(4-nitrophenyl)acetamide 14b. The general procedure for the preparation of 14a described above was followed for the synthesis of 14b, starting from the p-toluenesulfonylhydrazone of glyoxylic acid chloride (1.80 g, 6.91 mmol) and p-nitroaniline (1.05 g, 7.6 mmol). After the reaction, only column chromatography on regular silica gel with an eluent system of 1:50 MeOH:CH2CI2 was sufficient to afford pure 14b as a yellow solid in 39% isolated yield (0.56 g, 2.72 mmol). The ether washes described for 148 were not necessary for 14b. 211 Data for 141::45 H, = 0.30 (1:50 MeOHzCHzClg); 1H NMR (oMso-ae, 500 MHz) 5 5.59 (s, 1H), 7.75 (d, 2H, J = 8.5 Hz), 8.18 (d, 2H, J = 8.5 Hz), 10.33 (s, 1H); 13c NMR (DMSO-06, 125 MHz) 5 49.11, 118.06, 125.06, 141.59, 145.70, 164.39. 14c 2-diazo-N-(4-(trifluoromethy/)phenyl)acetamide 140. The general procedure described above for the preparation and purification of 14a was followed for the preparation and purification of 14c, starting from the p- toluenesulfonylhydrazone of glyoxylic acid chloride (1.18 g, 4.52 mmol) and p- trifluoromethylaniline (0.62 mL, 4.97 mmol). This afforded pure 14c as a yellow solid in 34% isolated yield (0.36 g, 1.55 mmol). Data for 14¢: Fig = 0.20 (1:50 MeOHzCHzClz); 1H NMR (DMSO-d6, 500 MHz) 6 5.54 (s, 1H), 7.63 (d, 2H, J = 8.9 Hz), 7.72 (d, 2H, J = 8.9 Hz), 10.08 (s, 1H); 13c NMR (omso-ae, 125 MHz) 5 48.58, 118.34, 122.57 (q, 1c, J = 32.1 Hz), 124.38 (q, 10, J = 270.8 Hz), 126.07 (q, 10, J = 3.7 Hz), 143.04, 164.15; 19F NMR (CDCI3, 283 MHz) 6 -60.21; IR (thin film) 3418 bm, 3092w, 21053, 1605m, 1321m cm"; Mass spectrum: m/z (°/o rel intensity) 229 M” (18), 202 (10), 201 (95), 173 (79), 172 (100); Anal calcd for CgH6F3N30: C, 47.17; H, 2.64; N, 18.34. Found: C, 46.67; H, 2.45; N, 17.66; HRMS calcd for C9H7F3N30 (M+H, ES+) m/z 230.0541 , meas 230.0544; yellow solid. 212 14d 2—diazo-N-(4-methoxyphenyl)acetamide 14d.13 The general procedure described above for the preparation and purification of 143 was followed for the preparation and purification of 14d, starting from the p-toluenesulfonylhydrazone of glyoxylic acid chloride (1 .34 g, 5.14 mmol) and p-methoxyaniline (0.70 g, 5.66 mmol). This afforded pure 14d as a yellow solid in 21% isolated yield (0.21 g, 1.10 mmol). Data for 1451:13 H, = 0.30 (1:50 MeOH:CH2C|2); ‘H NMR (DMSO-d6, 500 MHz) 6 3.70 (s, 3H), 5.42 (s, 1H), 6.85 (d, 2H, J = 8.8 Hz), 7.42 (d, 2H, J = 8.8 Hz), 9.55 (s, 1H); 130 NMR (DMSO-oB, 125 MHz) 6 47.61, 55.11, 113.89, 120.20, 132.70, 154.86, 163.01. N2 14e N-(4-chlorophenyl)-2-diazoacetamide 14a.13 The general procedure described above for the preparation and purification of 1451 was followed for the preparation and purification of 14a, starting from the p-toluenesulfonylhydrazone of glyoxylic acid chloride (1.80 g, 6.91 mmol) and p-chloroaniline (0.97 g, 7.60 mmol). This afforded pure 148 as a yellow solid in 30% isolated yield (0.41 g, 2.10 mmol). 213 Data for 146:13 H, = 0.32 (1:50 MeOHzCHzclz); 1H NMR (DMSO-os, 500 MHz) 5 5.48 (s, 1H), 7.32 (d, 2H, J = 8.7 Hz), 7.54 (d, 2H, J = 8.7 Hz), 9.84 (s, 1H); ‘30 NMR (DMSO-oe, 125 MHz) 5 48.23, 120.08, 126.15, 128.64, 138.47, 163.68. N-benzyl—2-diazoacetamide 14f. Diazoacetamide 14f was prepared in an identical manner as previously reported in the literature.46 The starting material 3"32", and the starting for the synthesis of 14f was succinimidyl diazoacetate material for the preparation of succinimidyl diazoacetate was p- toluenesulfonylhydrazone of glyoxylic acid31'32a; these were all prepared in an identical manner as previously reported in the literature. Thus, pure 14f was obtained as a yellow solid in 85% isolated yield (0.41 g, 2.33 mmol), starting from succinimidyl diazoacetate (0.50 g, 2.73 mmol) and benzylamine (0.60 mL, 5.46 mmol). Data for 14f:46 Fit = 0.33 (1 :1 EtOAc:hexanes); 1H NMR (CDCI3, 500 MHz) 5 4.37 (d, 2H, J = 5.5 Hz), 4.82 (s, 1H), 6.22 (bs, 1H), 7.23-7.32 (m, 5H); 13c NMR (CDCI3,125 MHZ) 6 43.74, 46.99, 127.34, 127.43, 128.56, 138.36, 165.51. 0 H/lkN/m N2 H 149 N-butyI-Z-diazoacetamide 14g. Diazoacetamide 149 was prepared in an identical manner as previously reported in the literature.46 The starting material 214 3"32", and the starting for the synthesis of 149 was succinimidyl diazoacetate material for the preparation of succinimidyl diazoacetate was p- toluenesulfonylhydrazone of glyoxylic acid31'328; these were all prepared in an identical manner as previously reported in the literature. Thus, pure 149 was obtained as a yellow solid in 80% isolated yield (0.31 g, 2.20 mmol), starting from succinimidyl diazoacetate (0.50 g, 2.73 mmol) and n-butylamine (0.54 mL, 5.46 mmol). Data for 149:“6 H. = 0.33 (1 :1 EtOAc:hexanes); 1H NMR (CDCI3, 500 MHz) 6 0.90 (t, 3H, J = 7.3 Hz), 1.29-1.36 (m, 2H), 1.44-1.50 (m, 2H), 3.26 (bs, 2H), 4.68 (bs, 1H), 5.10 (bs, 1H); “’0 NMR (CDCI3,125 MHz) 5 13.69, 19.96, 32.01, 39.76, 46.95, 165.34. The issue of trans-aziridine invertomers 1H NMR analysis of almost all isolated pure trans-aziridines reveals the presence of aziridine invertomers (two species). The ratio of these invertomers depends on the deuterated NMR solvent used, and also on the aziridine substrate itself. The ratio of invertomers for aziridine 606 in CDCI3 is usually 1:0.31, while the same ratio in'DMSO-ds is 1:0.06. DMSO'da gives predominantly one invertomer for almost all trans-aziridines, and is the solvent of choice for characterization of the trans-aziridines by NMR analysis. However, there have been certain trans-aziridines in this study for which even DMSO—da indicates a significant presence of both invertomers in the NMR analysis. The conversions, trans:cis ratios and yields of enamines for the trans- selective aziridinations are usually calculated on the basis of the 1H NMR 215 analysis of the crude reaction mixture in CDCI3. For the relative integrations, the trans-aziridine ring methine proton signals are taken into consideration. For the major invertomer, these methines usually exhibit sharp doublets (J = 2-3 Hz) in the region of 2-4 ppm. For the minor invertomer, these are small broad singlets in the same region. The minor diastereomers, the cis aziridines, are single species and do not show invertomers as the trans-aziridines. Thus, for the relative integrations, the cis-aziridine ring methine proton signals (sharp doublets, J = 6-8 Hz, 2-4 ppm) are taken into consideration. For the enamines, the signals from the NH proton (doublets or doublet of doublets, 8-10 ppm) are considered. Before the practitioners get comfortable with the trans-aziridination protocol, they are advised to isolate the trans-aziridine, confirm the location of the signals from the two invertomers, and then revert to the crude 1H NMR analysis to calculate the necessary ratios of products. General procedure for the catalytic asymmetric trans-aziridination (illustrated for the preparation of trans-aziridine 60a), and characterization data for the products All trans-aziridines (major diastereomers) have been characterized. Two cis-aziridines (minor diastereomers, 65a and 69) and one enamine side-product (from the reaction of imine 9a and diazoacetamide 140) have been characterized. Cis-aziridine 68 has been previously reported by our group.”31 216 Me 5 mol% Me MeO OMe O (8)-VANOL-B3 catalyst toluene (0.2 M) A ,MEDAM + HL .1311 Me Me ' N Ph N N 7 N H 24 h, 0 °C 2 Ph\,..L\rNHPh 9a 14a (0.2 mmol) 1.4 equiv 0 60a (2H, 38)- 1-(bis(4-methoxy-3, 5-dimethylphenyl)methyl)-N, 3- diphenylaziridine-Z-carboxamide 60a. Preparation of catalyst stock solution. A 50 mL glass Schlenk flask fitted with a magnetic stir bar was connected via a rubber tube to a double manifold with an Argon ballast. The Schlenk flask was made in a glass blowing shop by fusing together a high vacuum teflon valve and a 50 mL recovery flask. The side- arm of the high vacuum valve was modified with a piece of 3/8th inch glass tubing to fit with the rubber tube attached to the double manifold. The double manifold had two-way high-vacuum valves, which could be alternated between high vacuum (0.1 mm Hg) and an Argon supply (ultra high purity, 99.999%). The Schlenk flask was then flame dried under high vacuum and cooled under a low flow of Argon. To the flask was added sequentially (8)-VANOL (44 mg, 0.1 mmol), phenol (19 mg, 0.2 mmol), dry toluene (2.5 mL), BHaoSMez (2 M solution in toluene, 150 uL, 0.3 mmol) and water (5.4 11L, 0.3 mmol) under a low flow of Argon. The threaded Teflon valve on the Schlenk flask was then closed, and the mixture heated at 100 °C for 1 h. The valve was opened to gradually apply high vacuum (0.1 mm Hg) and the solvent was removed. The vacuum was maintained for a period of 30 min at 100 °C. The flask was then removed from the oil bath 217 and allowed to cool to room temperature under a low flow of Argon. This was then completely dissolved in 10 mL of dry toluene to afford the stock solution of the catalyst. The actual aziridination reaction. A 5 mL round-bottom single-neck (14/20) flask fitted with a magnetic stir bar was flame dried under high vacuum and cooled down under a low flow of Argon. For the aziridination reactions at -20 °C, a 14/20 glass extender was attached to the round bottom flask with a Teflon sleeve to prevent moisture from entering the reaction medium. To the flask was then added imine 9a (77 mg, 0.2 mmol, 1 equiv). The flask was then fitted with a rubber septum and an Argon balloon. To this flask was added 1.00 mL of the catalyst stock solution (5 mol% catalyst) via a plastic syringe fitted with a metallic needle. This catalyst-imine complex was cooled to 0 °C with the help of a chiller for 15-20 min. Diazoacetamide 14a (45 mg, 0.28 mmol, 1.4 equiv) was then added to the reaction flask, and the reaction stirred at 0 °C for 24 h. The work-up and crude ’H NMR analysis. The reaction mixture was added to ca. 7-10 mL of cold saturated aq. NaHCOa. The reaction flask was rinsed three times with EtOAc and the rinse added each time to the aq. NaHCOa solution. The layers were separated, the aqueous layer was washed once with EtOAc and the organic layers were then combined. This was dried over Na2804, filtered through a pad of Celite, rinsed with EtOAc, subjected to rotary evaporation till dryness and finally to high vacuum to afford the crude product as a foamy light yellow solid. Crude 1H NMR analysis was performed in CDCI3 to calculate the conversion, trans:cis ratio and yields of the enamine side-products (vide supra). 218 The purification. Column chromatography with regular silica gel and an eluent mixture of 1:6 EtOAc:hexanes afforded the trans-aziridine 60a which was 95% pure. Subsequent column chromatography with regular silica gel and an eluent mixture of 1:25 EtOAczbenzene afforded analytically pure 606 as a white foamy solid in 84% isolated yield (87 mg, 0.17 mmol). The optical purity of 60a was determined to be 90% ee by HPLC analysis (Chiralcel OD-H column, hexanes:2-propanol 97:3, 222 nm, flow rate 0.7 mL min"). Retention times were 22 min (minor enantiomer, (2S,3H)-60a) and 31 min (major enantiomer, (2R,3S)- 60a) The absolute configurations for the major diastereomer of this reaction, the trans-aziridine 60a, and the minor diastereomer of this reaction, the cis- aziridine 658, were determined by chemical correlation (vide infra). The absolute configurations for the rest of the aziridines in this study were assigned by analogy. Data for 60a: F?) = 0.2 (1:6 EtOAc:hexanes); Fig = 0.27 (1:25 EtOAczbenzene); 1H NMR (DMSO-oB, 500 MHz) 6 2.01 (s, 6H), 2.06 (s, 6H), 2.91 (d, 1H, J = 2.6 Hz), 3.34 (d, 1H, J: 2.5 Hz), 3.48 (s, 3H), 3.54 (s, 3H), 5.04 (s, 1H), 6.98 (s, 2H), 7.04 (s, 2H), 7.04-7.06 (m, 1H), 7.25-7.35 (m, 7H), 7.48 (d, 2H, J = 7.7 Hz), 10.28 (s, 1H); 13c NMR (DMSO-06, 125 MHz) 5 15.70, 15.88, 45.89, 47.41, 58.94, 59.07, 65.35, 119.21, 123.51, 126.02, 127.21, 127.30, 127.84, 128.31, 128.62, 129.64, 129.68, 138.59, 138.67, 138.84, 138.87, 155.11, 155.23, 164.83; IR (thin film) 3318m, 2941m, 1684s, 1539s, 1485s, 1444s, 1221m cm“; Mass spectrum: m/z (% rel intensity) 520 M“ (1), 401 (9), 400 (31), 219 _._- _. __ -91.. 298 (25), 284 (78), 283 (100); Anal calcd for C34H36N203: c, 78.43; H, 6.97; N, 5.38. Found: C, 77.77; H, 6.78; N, 5.32; HRMS calcd for C34H37N203 (M+H, ES+) m/z 521.2804, meas 521.2823; [81230 = +5.1 (0 = 1, CH2CI2) on 96% ee (2R,3S)- 608; white foamy solid: mp. 92-96 °C. Me Me MeO O l OMe Me Me N Ph Ph/LW NH 0 65a (2R, 3F?)- 1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-N, 3- dlphenylaziridine-2-carboxamide 653. Cis-aziridine (the minor diastereomer) 658 was isolated (74 mg, 0.14 mmol, 14% yield) in a reaction run as described above with (S)~VANOL-Ba catalyst (5 mol%), at room temperature and at a 1 mmol scale of imine 9a (Section 3.4.10, Chapter 3). The trans:cis ratio of the reaction was 5:1. The optical purity of 65a was determined to be 77% ee by HPLC analysis (Chiralcel OD-H column, hexanes:2-propanol 97:3, 222 nm, flow rate 0.7 mL min"). Retention times were 10 min (major enantiomer, (2R,3Fl)-65a) and 24 min (minor enantiomer, (2S,3S)-65a). Data for 65a: Fl; = 0.25 (1 :3 EtOAc:hexanes); 1H NMR (CDCI3, 500 MHz) 6 2.25 (s, 12H), 2.73 (d, 1H, J = 7.2 Hz), 3.28 (d, 1H, J = 7.1 Hz), 3.67 (s, 6H), 3.81 (s, 1H), 7.01 (t, 1H, J = 7.4 Hz), 7.08 (s, 2H), 7.10-7.12 (m, 2H), 7.13 (s, 2H), 7.15-7.24 (m, 5H), 7.28-7.29 (m, 2H), 8.07 (s, 1H); “’0 NMR (CDCl3, 125 MHz) 5 16.24, 16.33, 47.30, 48.73, 59.61, 59.63, 76.72, 120.30, 124.42, 127.49, 127.55, 220 127.64, 127.72, 128.28, 128.79, 130.91, 131.12, 134.92, 136.66, 137.16, 137.23, 156.27, 156.34, 165.96; IR (thin film) 3360w, 2926w, 16843, 1525s, 14428, 1223m cm"; Mass spectrum: m/z (% rel intensity) 520 M+ (<1), 400 (10), 384 (8), 400 (10), 284 (78), 283 (100); Anal calcd for C34H36N203: C, 78.43; H, 6.97; N, 5.38. Found: C, 77.95; H, 7.11; N, 5.32; HRMS calcd for C34H37N203 (M+H, ES+) m/z 521.2804, meas 521.2814; [61230 = +4.0 (0 = 1, CH2Cl2) on 13% ee (23,319)- 658; white solid: mp. 168-172 °C. NI Ph,...L\rNHPh 0 59a (2R,3S)-1benzhydryl-N,3—diphenylaziridine-2-carboxamide 59a. Imine 1b (54 mg, 0.2 mmol) and diazoacetamide 14a (45 mg, 0.28 mmol) were reacted according to the general procedure described above (0 °C, 5 mol% (5)-VANOL- B3 catalyst) to afford crude product 59a. Column chromatography with regular silica gel and an eluent mixture of 1:9 EtOAc:hexanes afforded pure 59a as a white foamy solid in 47% isolated yield (38 mg, 0.09 mmol). The optical purity of 59a was determined to be 77% ee by HPLC analysis (Chiralcel OD-H column, hexanes:2-propanol 95:5, 222 nm, flow rate 0.7 mL min"). Retention times were 13 min (minor enantiomer, (2S,3Fl)-59a) and 18 min (major enantiomer, (2R,38)- 59a) Data for 59a: Ft, = 0.22 (1:9 EtOAc:hexanes); 1H NMR (DMso-ae, 500 MHz) 5 2.98 (d, 1H, J = 2.5 Hz), 3.44 (d, 1H, J = 2.2 Hz), 5.41 (s, 1H), 7.03 (t, 221 1H, J = 7.5 Hz), 7.11-7.14 (m, 2H), 7.20-7.28 (m, 7H), 7.31-7.36 (m, 4H), 7.43- 7.45 (m, 6H), 10.28 (s, 1H); ‘30 NMR (DMSO-06, 125 MHz) (2 sp2 carbons missing) 5 45.96, 47.31, 65.85, 119.33, 123.60, 125.94, 126.78, 127.15, 127.30, 128.13, 128.25, 128.37, 128.66, 138.46, 138.82, 143.65, 143.88, 165.00; IR (thin film) 3308m, 3030m, 2924w, 1662s, 1601s, 1531s, 1444s cm"; Mass spectrum: m/z (% rel intensity) 404 M+ (<1), 283 (15), 236 (36), 181 (30), 166 (100); HRMS calcd for C23H25N20 (M+H, ES+) m/z 405.1967, meas 405.1982; [0t]230 = -7.5 (c = 1, CH2CI2) on 78% ee (2R,3.S’)-59a; white foamy solid: mp. 68-72 °C. tBu tBu M80 0 O OMe tBu tBu N NHPh a. W 0 61a (2R, 3S)- 1-(bis(3, 5-di-tert—butyl-4-methoxyphenyl)methyl)-N, 3- diphenylaziridine-Z—carboxamide 61a. lmine 58a (111 mg, 0.2 mmol) and diazoacetamide 14a (45 mg, 0.28 mmol) were reacted according to the general procedure described above (0 °C, 5 mol% (8)-VANOL-83 catalyst) to afford crude 61a. Column chromatography with regular silica gel and CH2CI2 as an eluent afforded pure 618 as a white foamy solid in 75% isolated yield (103 mg, 0.15 mmol). The optical purity of 61a was determined to be 91% ee by HPLC analysis (Chiralcel OD-H column, hexanes:2-propanol 99:1, 222 nm, flow rate 0.7 mL min"). Retention times were 18 min (minor enantiomer, (28, 3R)-61 a) and 28 min (major enantiomer, (2R, 38)-61 a). 222 Data for 61a: 19,: 0.38 (CH2Clg); 1H NMR (DMSO-06, 500 MHz) 5 1.21 (s, 18H), 1.22 (s, 18H), 2.98 (d, 1H, J = 2.2 Hz), 3.37 (d, 1H, J = 2.2 Hz), 3.41 (s, 3H), 3.52 (s, 3H), 5.21 (s, 1H), 7.01 (t, 1H, J: 7.3 Hz), 7.18 (s, 2H), 7.22-7.26 (m, 3H), 7.29 (s, 2H), 7.31-7.36 (m, 4H), 7.49 (d, 2H, J = 8.1 Hz), 10.26 (s, 1H); ”C NMR (DMSO-d62CDCI3 2:1, referenced with DM3o-os, 125 MHz) 5 31.62, 31.64, 35.04, 35.08, 46.33, 46.38, 47.52, 63.44, 63.49, 63.59, 63.65, 65.35, 65.42, 118.89, 123.13, 125.03, 125.64, 125.90, 126.93, 127.98, 128.21, 137.58, 137.59, 138.61, 138.89, 142.00, 142.05, 157.18, 157.28, 165.08; lR (thin film) 3325w, 2961s, 16843, 15393, 14443, 1221m cm"; Mass spectrum: m/z (% rel intensity) 688 M+ (1), 568 (24), 568 (24), 452 (48), 451 (100); Anal calcd for C46H60N203: c, 80.19; H, 8.78; N, 4.07. Found: c, 79.62; H, 8.81; N, 4.07; HRMS calcd for 046H61N203 (M+H, ES+) m/z 689.4682, meas 689.4709; [61230 = +112 (0 = 1, CHzclz) on 91 % ee (2R, 3S)-61a; white foamy solid: mp. 98-100 °C. Me Me MeO ] i OMe Me Me 0 66¢ CF13 (2H, 38)- 1 -(bi3(4-methoxy-3,5-dimethy/phenyl)methyl)-3-phenyl-N-(4- (trifluoromethyl)phenyl)aziridine-2-carboxamide 66c. lmine 9a (77 mg, 0.2 mmol) and diazoacetamide 14c (64 mg, 0.28 mmol) were reacted according to the general procedure described above (0 °C, 5 mol% (8)-VANOL-B3 catalyst) to afford crude 66c. Column chromatography with regular silica gel and an eluent 223 mixture of 1:5 EtOAc:hexanes afforded 66c which was 95% pure. Subsequent column chromatography with regular silica gel and an eluent mixture of 1:25 EtOAc:benzene afforded analytically pure 66c as a white foamy solid in 40% isolated yield (47 mg, 0.08 mmol). The optical purity of 66c was determined to be 80% ee by HPLC analysis (Chiralcel OD-H column, hexanes:2-propanol 98:2, 222 nm, flow rate 1 mL min"). Retention times were 14 min (minor enantiomer, (28,3Fl)-66c) and 53 min (major enantiomer, (2R,3S)-66c). Data for 660: R; = 0.3 (1:5 EtOAc:hexanes); Rf = 29 (1:25 EtOAc:benzene); 1H NMR (DMso-oe, 500 MHz) 5 1.98 (s, 6H), 2.06 (s, 6H), 2.93 (d, 1H, J = 2.2 Hz), 3.39 (d, 1H, J = 2.4 Hz), 3.44 (s, 3H), 3.54 (3, 3H), 4.96 (s, 1H), 6.97 (s, 2H), 7.05 (3, 2H), 7.26-7.35 (m, 5H), 7.65-7.70 (m, 4H), 10.62 (s, 1H); 13C NMR (DMSO-oB, 125 MHz) 6 15.70, 15.97, 46.26, 47.44, 58.92, 59.11, 65.72, 118.96, 123.49 (q, 1c, J = 31.8 Hz), 124.37 (q, 10, J = 271.1 Hz), 126.06, 126.10, 127.31, 127.39, 127.83, 128.42, 129.75, 129.82, 138.56, 138.65, 138.78, 142.12, 155.20, 155.28, 165.50; 19F NMR (DMSO-oB, 283 MHz) 5 6033; IR (thin film) 3424m, 2928w, 1674m, 1529m, 13253 cm"; Mass spectrum: m/z (% rel intensity) 588 M+ (<1), 400 (25), 284 (58), 283 (100); HRMS calcd for 035H35N203F3 (M+H, ES+) m/z 589.2678, meas 589.2697; [81230 = +8.0 (0 = 1, CHzclz) on 80% ee (2R, 38)-66c; white foamy solid: mp. 94-98 °C. OMe Me I Me “6 o 0"“ MeO 19th Me H 3—(bis(4-methoxy—3,5-dimethylphenyl)methylamino)-3-phenyl-N-(4- (tnfluoromethyl)phenyl)acrylamide. Enamines are common side products in all acid catalyzed aziridinations of imines. The enamine shown above was isolated in 2% yield (2.0 mg, 0.0034 mmol) as a white solid, during the reaction between imine 9a and diazoacetamide 14c; only the clean fractions were collected from the column chromatography. Data for enamine side product: R; = 0.32 (1:5 EtOAc:hexanes); 1H NMR (CDCl3, 500 MHz) 5 2.20 (s, 12H), 3.67 (s, 6H), 4.56 (s, 1H), 5.24 (d, 1H, J = 9.7 Hz), 6.75 (s, 4H), 6.81 (s, 1H), 7.19-7.21 (m, 2H), 7.30-7.39 (m, 3H), 7.52 (d, 2H, J = 8.5 Hz), 7.58 (d, 2H, J = 8.8 Hz), 9.84 (d, 1H, J = 9.7 Hz); 13C NMR (CDCI3, 125 MHz) (1 carbon — CF3 missing) 6 16.24, 59.63, 61.27, 88.82, 118.84, 126.15, 127.41, 127.77, 128.24, 128.32, 129.14, 130.81, 136.09, 137.93, 142.06, 155.91, 163.35, 168.22; IR (thin film) 3319w, 2926w, 1593m, 1317s, 1066m cm"; HRMS calcd for C35H36N203F3 (M+H, ES+) m/z 589.2678, meas 589.2657; white solid. Me Me MeO O O OMe Me Me W O O OMe 66d (2H, 38)- 1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-N-(4- methoxyphenyl)-3-phenylaziridine-2-carboxamide 66d. lmine 9a (77 mg, 0.2 mmol) and diazoacetamide 14d (53 mg, 0.28 mmol) were reacted according to the general procedure described above (0 °C, 5 mol% (8)-VANOL-Ba catalyst) to 225 “~wa afford crude 66d. Column chromatography with regular silica gel and an eluent mixture of 1:5 EtOAc:hexanes afforded 66d which was 95% pure. Subsequent column chromatography with regular silica gel and an eluent mixture of 1:15 EtOAc:benzene afforded analytically pure 66d as a white foamy solid in 75% isolated yield (83 mg, 0.15 mmol). The optical purity of 66d was determined to be 91% ee by HPLC analysis (Chiralpak AD column, hexanes:2-propanol 95:5, 222 nm, flow rate 1 mL min"). Retention times were 28 min (major enantiomer, (2R,3S)-66d) and 49 min (minor enantiomer, (2S,3R)-66d). Data for 66d: Fl; = 0.2 (1:5 EtOAc:hexanes); Fl; = 0.21 (1:15 EtOAc:benzene); 1H NMR (DMSD-oe, 500 MHz) 5 2.04 (s, 6H), 2.06 (s, 6H), 2.86 (d, 1H, J = 2.7 Hz), 3.31 (d, 1H, J = 2.4 Hz), 3.50 (s, 3H), 3.54 (s, 3H), 3.71 (s, 3H), 5.05 (s, 1H), 6.86 (d, 2H, J = 9.1 Hz), 6.98 (s, 2H), 7.03 (s, 2H), 7.25- 7.37 (m, 7H), 10.13 (s, 1H); 13c NMR (DMso-oe, 125 MHz) (1 sp2 carbon missing) 6 15.74, 15.86, 45.72, 47.37, 55.15, 58.97, 59.06, 65.24, 113.75, 120.85, 126.00, 127.16, 127.30, 127.82, 128.27, 129.60, 129.64, 131.75, 138.74, 138.91, 155.08, 155.22, 155.43, 164.34; IR (thin film) 3306m, 2932m, 16533, 15123, 12233, 10163 cm"; Mass spectrum: m/z (% rel intensity) 550 M+ (2), 384 (16), 298 (35), 284 (65), 283 (100); HRMS calcd for C35H39N204 (M+H, ES+) m/z 551.2910, meas 551.2933; [81230 = +145 (0 = 1, CH2CI2) on 91% ee (211,33)- 66d; white foamy solid: mp. 89-92 °C. 226 Me Me MeO O O OMe Me Me N H 0 Cl 669 (2H, 38)- 1 -(bis(4-methoxy-3, 5—dimethylphenyl)methyl)-N-(4-chlorophenyl)- 3-phenylaziridine-2-carboxamide 66e. lmine 9a (77 mg, 0.2 mmol) and diazoacetamide Me (55 mg, 0.28 mmol) were reacted according to the general procedure described above (0 °C, 5 mol% (8)-VANOL-B3 catalyst) to afford crude 66e. Column chromatography with regular silica gel and an eluent mixture of 1:6 EtOAc:hexanes afforded 66c which was 95% pure. Subsequent column chromatography with regular silica gel and an eluent mixture of 1:50 EtOAc:benzene afforded analytically pure 66e as a white foamy solid in 82% isolated yield (91 mg, 0.16 mmol). The optical purity of 66a was determined to be 92% ee by HPLC analysis (Chiralcel OD-H column, hexanes:2-propanol 97:3, 222 nm, flow rate 1 mL min"). Retention times were 15 min (minor enantiomer, (28,3Fl)-66e) and 39 min (major enantiomer, (2R,3S)-66e). Data for 66e: Fl; = 0.22 (1:6 EtOAc:hexanes); Flt = 0.27 (1:50 EtOAc:benzene); 1H NMR (DMSO-06, 500 MHz) 6 2.01 (s, 6H), 2.06 (s, 6H), 2.89 (d, 1H, J = 2.4 Hz), 3.35 (d, 1H, J = 2.6 Hz), 3.48 (s, 3H), 3.54 (s, 3H), 4.99 (s, 1H), 6.97 (s, 2H), 7.03 (s, 2H), 7.24-7.29 (m, 1H), 7.34-7.35 (m, 6H), 7.50 (d, 2H, J = 8.8 Hz), 10.41 (s, 1H); ”C NMR (DMSO-06, 125 MHz) (1 sp2 carbon missing) 8 15.70, 15.87, 46.02, 47.34, 58.94, 59.06, 65.50, 120.67, 126.02, 227 _ urbane-5.1: 1: 127.08, 127.27, 127.80, 128.31, 128.55, 129.65, 129.69, 137.51, 138.58, 138.70, 138.77, 155.13, 155.25, 164.95; IR (thin film) 3319w, 2924m, 1666m, 1597m, 1493m, 1221m cm"; Anal calcd for Ca4H350IN203: C, 73.56; H, 6.36; N, 5.05. Found: C, 72.74; H, 6.27; N, 4.86; HRMS calcd for C34H36CIN203 (M+H, ES+) m/z 555.2414, meas 555.2420; [61230 = +172 (0 = 1, CH20I2) on 92% ee (2R,38)-66e; white foamy solid: mp. 88-94 °C. Me Me MeO O O OMe Me Me N H Ph““L\rN\/Ph (2R, 3S)-N-benzyl- 1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3- phenylaziridine-Z-carboxamide 66f. lmine 9a (77 mg, 0.2 mmol) and diazoacetamide 14f (35 mg, 0.28 mmol) were reacted according to the general procedure described above (0 °C, 5 mol% (5)-VANOL-83 catalyst) to afford crude 66f. Column chromatography with regular silica gel and an eluent mixture of 1:5 EtOAc:hexanes afforded pure 66f as a white foamy solid in 62% isolated yield (66 mg, 0.12 mmol). The optical purity of 66f was determined to be 94% ee by HPLC analysis (Chiralcel OD-H column, hexanes:2-propanol 92:8, 222 nm, flow rate 0.4 mL min"). Retention times were 32 min (minor enantiomer, (28,3Fl)- 66f) and 35 min (major enantiomer, (2R,3S)—66f). Data for 66f: R. = 0.18 (1:5 EtOAc:hexanes); 1H NMR (DMSO-o6, 500 MHz) 5 2.06 (s, 6H), 2.17 (s, 6H), 2.82 (d, 1H, J = 2.5 Hz), 3.27 (d, 1H, J = 2.4 228 Hz), 3.53 (s, 3H), 3.62 (s, 3H), 4.03 (dd, 1H, J = 4.7, 15.4 Hz), 4.43 (dd, 1H, J: 7.1, 15.2 Hz), 5.16 (s, 1H), 6.85-6.87 (m, 2H), 7.03 (s, 2H), 7.08 (s, 2H), 7.16- 7.31 (m, 8H), 8.75 (t, 1H, J = 4.6 Hz); ‘30 NMR (DMSO-oB, 125 MHz) (1 sp‘2 carbon missing) 6 15.86, 16.03, 42.11, 45.42, 46.62, 59.03, 59.12, 64.88, 125.99, 126.66, 126.89, 127.05, 127.39, 128.07, 128.21, 129.64, 129.66, 138.72, 139.13, 139.17, 137.37, 155.09, 155.29, 166.25; IR (thin film) 3310w, 2945w, 1653m, 1483m, 1221m cm"; Mass spectrum: m/z (% rel intensity) 534 M+ (<1), 400 (26), 309 (18), 283 (88), 91 (100); Anal calcd for C35H38N203: C, 78.62; H, 7.16; N, 5.24. Found: C, 78.06; H, 6.90; N, 4.98; HRMS calcd for C35H39N203 (M+H, ES+) m/z 535.2961, meas 535.2974; [5423D = -40.1 (c = 1, CH2CI2) on 98% ee (2R,3S)- 66f; white foamy solid: mp. 74-84 °C. Me Me MeO OMe Me O 0 Me N H Ph/Qmfivph o 69 (2R, 3R)-N-benzyl- 1—(bis(4—methoxy-3,5-dimethylphenyl)methyl)-3- phenylaziridine-2-carboxamide 69. Cis-aziridine (the minor diastereomer) 69 was isolated, in a reaction run as above at room temperature and at a 0.1 mmol scale in imine 9a, as a white solid in 21% isolated yield (11 mg, 0.02 mmol). The optical purity was determined to be 70% ee by HPLC analysis (Regis Rexchrom Pirkle Covalent D-Phenylglycine column, hexanes:2-propanol 90:10, 222 nm, flow 229 rate 1 mL min"). The retention times were 42 min (major enantiomer, (2R,3S)- 69) and 49 min (minor enantiomer, (28,3Fl)-69). Data for 69: R; = 0.25 (1:2 EtOAc:hexanes); 1H NMR (CDCI3, 500 MHz) 6 2.23 (s, 6H), 2.25 (s, 6H), 2.71 (d, 1H, J: 7.1 Hz), 3.24 (d, 1H, J: 7.2 Hz), 3.68 (s, 3H), 3.72 (s, 3H), 3.75 (s, 1H), 4.08 (dd, 1H, J: 6.1, 15.3 Hz), 4.23 (dd, 1H, J = 6.1, 15.2 Hz), 6.63 (t, 1H, J = 6.1 Hz), 6.78-6.80 (m, 2H), 7.02 (s, 2H), 7.11 (s, 2H), 7.20-7.27 (m, 8H); 13c NMR (CDCI3, 125 MHz) (1 sp2 carbon missing) 5 16.18, 16.23, 29.69, 42.57, 46.91, 48.44, 59.61, 77.09, 127.08, 127.11, 127.50, 127.80, 127.83, 128.25, 128.49, 130.81, 130.92, 130.93, 135.23, 137.21, 137.43, 137.86, 156.28, 167.76; IR (thin film) 3404m, 2924w, 1653s, 1525m, 1485m, 1221m cm"; Mass spectrum: m/z (% rel intensity) 534 M+ (<1), 400 (22), 309 (24), 283 (100); HRMS calcd for C35H39N203 (M+H, ES+) m/z 535.2961, meas 535.2937; white solid: mp. 178-180 °C. Me Me M80 0 O OMe Me Me Ph‘wLfir W O 669 (2R,3S)- 1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-N-butyl-3- phenylaziridine-Z-carboxamide 669. lmine 9a (77 mg, 0.2 mmol) and diazoacetamide 14g (40 mg, 0.28 mmol) were reacted according to the general procedure described above (0 °C, 5 mol% (S)-VANOL-Ba catalyst) to afford crude 66g. Column chromatography with regular silica gel and an eluent mixture 230 of 1:5 EtOAc:hexanes afforded pure 669 as a white foamy solid in 62% isolated yield (62 mg, 0.12 mmol). The optical purity was determined to be 95% ee by HPLC analysis (Regis Rexchrom Pirkle Covalent D-Phenylglycine column, hexanes:2-propanol 98:2, 222 nm, flow rate 1 mL min"). Retention times were 79 min (major enantiomer, (2R,3S)-66g) and 91 min (minor enantiomer, (28,3R)- 669) Data for 669: R; = 0.2 (1:5 EtOAc:hexanes); 1H NMR (DMSO-oB, 500 MHz) 6 0.77 (t, 3H, J = 7.4 Hz), 1.03-1.22 (m, 4H), 2.04 (s, 6H), 2.16 (s, 6H), 2.70 (d, 1H, J = 2.4 Hz), 2.79-2.85 (m, 1H), 3.08-3.14 (m, 1H), 3.19 (d, 1H, J = 2.5 Hz), 3.53 (s, 3H), 3.58 (s, 3H), 5.06 (s, 1H), 7.00 (s, 4H), 7.21-7.32 (m, 5H), 8.21 (t, 1H, J = 5.3 Hz); “’0 NMR (DMSO-d6, 125 MHz) 5 13.52, 15.84, 15.92, 19.28, 30.87, 38.32, 45.15, 46.83, 59.02, 59.04, 64.94, 125.94, 126.99, 127.31, 127.62, 128.20, 129.45, 129.58, 139.05, 139.21, 139.28, 155.02, 155.22, 165.86; IR (thin film) 3316w, 2930m, 1647m, 1483m, 1221m cm"; Mass spectrum: m/z (% rel intensity) 500 M+ (2), 401 (31), 400 (82), 384 (40), 309 (27), 283 (100); HRMS calcd for 032H41N203 (M+H, ES+) m/z 501.3117, meas 501.3113; [61230 = +398 (0 = 1, CHZCIZ) on 98% ee (28,3F?)-66g; white foamy solid: mp. 74-80 °C. Me Me MeO ] ] OMe Me Me N D“ ‘CONHPh Me 60b 231 (2R, 3S)- 1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-N-phenyl-3-p- tolylaziridine-Z-carboxamide 60b. lmine 9b (80 mg, 0.2 mmol) and diazoacetamide 14a (45 mg, 0.28 mmol) were reacted according to the general procedure described above (0 °C, 5 mol% (8)-VANOL-Ba catalyst) to afford crude 60b. Column chromatography with regular silica gel and an eluent mixture of 1:6 EtOAc:hexanes afforded 60b which was 95% pure. Subsequent column chromatography with regular silica gel and an eluent mixture of 1:40 EtOAc:benzene afforded analytically pure 60b as a foamy white solid in 84% isolated yield (90 mg, 0.17 mmol). The optical purity of GOD was determined to be 95% ee by HPLC analysis (Chiralcel OD-H column, hexanes:2-propanol 97:3, 222 nm, flow rate 1 mL min"). Retention times were 9 min (major enantiomer, (2R,3S)-60b) and 14 min (minor enantiomer, (28,3Flj-60b). Data for 60b: Fl; = 0.22 (1:6 EtOAc:hexanes); R; = 0.22 (1:50 EtOAc:benzene); 1H NMR (DMSO-06, 500 MHz) 5 2.00 (s, 6H), 2.07 (s, 6H), 2.28 (s, 3H), 2.87 (d, 1H, J = 2.5 Hz), 3.30 (m, 1H, with DMSO water peak), 3.47 (s, 3H), 3.55 (s, 3H), 5.01 (s, 1H), 6.97 (s, 2H), 7.02-7.05 (m, 3H), 7.14 (d, 2H, J = 7.8 Hz), 7.22 (d, 2H, J = 8.1 Hz), 7.28 (t, 2H, J = 7.8 Hz), 7.46 (d, 2H, J = 8.3 Hz), 10.24 (s, 1H); 130 NMR (DMSO-d6, 125 MHz) 5 15.67, 15.89, 20.67, 45.81, 47.25, 58.92, 59.05, 65.38, 119.19, 123.46, 125.91, 127.30, 127.81, 128.58, 128.84, 129.58, 129.65, 135.80, 136.28, 138.59, 138.69, 138.89, 155.10, 155.19, 164.91; IR (thin film) 3320w, 2924w, 1680m, 1601 m, 1529m, 1444m, 1221m cm' ‘; Mass spectrum: m/z (% rel intensity) 534 M+ (<1), 414 (15), 298 (17), 284 (23), 283 (100); HRMS calcd for C35H39N203 (M+H, ES+) m/z 535.2961, meas 232 535.2959; [81230 = -3.1 (c = 1, CH2Cl2) on 95% ee (23,3R)-60b; white foamy solid: mp. 82-90 °C. Me Me M80 0 O OMe Me Me N 0 ‘CONHPh Br 60c (2H, 38)- 1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3—(4-bromophenyl)- N-phenylaziridine-2-carboxamide 60c. Imine 9c (93 mg, 0.2 mmol) and diazoacetamide 14a (45 mg, 0.28 mmol) were reacted according to the general procedure described above (0 °C, 5 mol% (8)-VANOL-B3 catalyst) to afford crude 60c. Column chromatography with regular silica gel and an eluent mixture of 1:6 EtOAc:hexanes afforded pure 60c as a white foamy solid in 87% isolated yield (104 mg, 0.17 mmol). The optical purity of 60c was determined to be 97% ee by chiral HPLC analysis (Chiralcel OD-H column, hexanes:2-propanol 97:3, 222 nm, flow rate 1 mL min"). The retention times were 12 min (major enantiomer, (2R,35')-60c) and 28 min (minor enantiomer, (28,3R)-60c). Data for 60¢: R = 0.28 (1:6 EtOAc:hexanes); 1H NMR (DMso-oe, 500 MHz) 6 2.00 (3, 6H), 2.07 (3, 6H), 2.89 (d, 1H, J = 2.5 Hz), 3.36 (d, 1H, J = 2.4 Hz), 3.47 (s, 3H), 3.55 (s, 3H), 5.02 (s, 1H), 6.97 (s, 2H), 7.03 (s, 2H), 7.05 (t, 1H, J = 7.3 Hz), 7.27-7.33 (m, 4H), 7.46 (d, 2H, J = 7.8 Hz), 7.53 (d, 2H, J = 8.6 Hz), 10.27 (s, 1H); 13c NMR (DMso-oe, 125 MHz) 5 15.67, 15.87, 45.11, 47.57, 58.92, 59.05, 65.30, 119.21, 120.14, 123.53, 127.23, 127.76, 128.21, 128.59, 233 129.63, 129.74, 131.19, 138.39, 138.49,138.51, 138.72, 155.16, 155.23, 164.52; IR (thin film) 3318m, 2963s, 1668s, 1601s, 1533s, 1444s, 1263s, 1010s cm"; HRMS calcd for C34H35N203798r (M+H, ES+) m/z 599.1909, meas 599.1891; [5:123D = +12.6 (c = 1, CH2Cl2) on 99% ee (2R,3S)-60c; white foamy solid: mp. 98- 104 °C. Me Me M90 3 O OMe Me Me N O ‘CONHPh OZN 60d (2R, 3S)- 1-(bis (4-methoxy-3, 5 -dimeth ylphen yl)meth yl)-3- (4-nitrophen yl)-N- phenylaziridine-2—carboxamide 60d. lmine 9d (86 mg, 0.2 mmol) and diazoacetamide 14a (45 mg, 0.28 mmol) were reacted according to the general procedure described above (0 °C, 5 mol% (S)-VANOL-B3 catalyst) to afford crude 60d. Column chromatography with regular silica gel and an eluent mixture of 1:6 EtOAc:hexanes afforded pure 60d as a pale yellow foamy solid in 80% isolated yield (90 mg, 0.16 mmol). The optical purity of 60d was determined to be 92% ee by HPLC analysis (Chiralcel OD-H column, hexanes:2-propanol 93:7, 222 nm, flow rate 1 mL min"). Retention times were 15 min (major enantiomer, (2R,3S)-60d) and 54 min (minor enantiomer, (2S,3Fl)-60d). Data for 60d: Fl; = 0.18 (1:6 EtOAc:hexanes); 1H NMR (DMso-os, 500 MHz) 5 2.01 (s, 6H), 2.07 (s, 6H), 3.00 (d, 1H, J = 2.4 Hz), 3.48 (s, 3H), 3.54 (s, 3H), 3.55 (d, 1H, J = 2.5 Hz), 5.07 (s, 1H), 6.99 (s, 2H), 7.04 (s, 2H), 7.05 (t, 1H, 234 J = 7.3 Hz), 7.29 (t, 2H, J = 7.6 Hz), 7.46 (d, 2H, J = 7.6 Hz), 7.65 (d, 2H, J = 8.8 Hz), 8.21 (d, 2H, J = 8.7 Hz), 10.32 (s, 1H); 130 NMR (DMso-os, 125 MHz) 5 15.67, 15.85, 44.96, 48.36, 58.93, 59.05, 65.35, 119.24, 123.54, 123.63, 127.16, 127.25, 127.73, 128.62, 129.70, 129.83, 138.29,138.43, 138.55, 146.68,146.97, 155.20, 155.29, 164.09; IR (thin film) 3323w, 2928w, 1686m, 1601s, 1522s, 1444m, 13463, 1223m cm"; HRMS calcd for 034H36N305 (M+H, ES+) m/z 566.2655, meas 566.2638; [(1]230 = +6.8 (0 = 1, CH2Cl2) on 93% ee (2R,3S)-60d; pale yellow foamy solid: mp. 104-110 0C. Me Me MeO O O OMe Me Me N D ‘coNHPh MeO 606 (2B, 38)- 1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-(4- methoxyphenyl)-N-phenylaziridine-2-carboxamide 609. Imine 9e (83 mg, 0.2 mmol) and diazoacetamide 14a (45 mg, 0.28 mmol) were reacted according to the general procedure described above (0 0C, 10 mol% (8)-VANOL-Ba catalyst) to afford crude 60e. For chromatography, the column was packed with regular silica gel with a solvent mixture of 1:9 NEt3ICH2Cl2, completely dried and then re- slurried in the column with a solvent mixture of 1:15 EtOAc:hexanes. Subsequent column chromatography with an eluent mixture of 1:3 EtOAc:hexanes afforded pure 60e as a white foamy solid in 61% isolated yield (67 mg, 0.12 mmol). The optical purity of 60e was determined to be 89% ee by HPLC analysis (Chiralcel 235 OD-H column, hexanes:2-propanol 97:3, 222 nm, flow rate 0.7 mL min"). Retention times were 22 min (major enantiomer, (2R,38)-60e) and 36 min (minor enantiomer, (2S,3Fl)-60e). Data for 60e: R = 0.22 (1:3 EtOAc:hexanes); 1H NMR (DMSO-d6, 500 MHz) 6 2.00 (s, 6H), 2.07 (3, 6H), 2.86 (d, 1H, J = 2.2 Hz), 3.28 (d, 1H, J = 2.4 Hz), 3.48 (s, 3H), 3.55 (s, 3H), 3.73 (s, 3H), 5.01 (s, 1H), 6.90 (d, 2H, J: 8.5 Hz), F“ 6.96 (s, 2H), 7.02 (s, 2H), 7.04 (t, 1H, J = 7.6 Hz), 7.24-7.30 (m, 4H), 7.47 (d, 2H, " J = 8.1 Hz), 10.24 (s, 1H); 130 NMR (DMSO-OB, 125 MHz) 6 15.68, 15.89, 45.59, 47.05, 55.05, 58.93, 59.06, 65.33, 113.75, 119.18, 123.45, 127.13, 127.32, 127.83, 128.59, 129.58, 129.64,130.67,138.61, 138.72, 138.91, 155.09,155.19, 158.52, 165.00; IR (thin film) 3315w, 2937m, 1679m, 1601m, 1514s, 1443m, 1249m cm"; HRMS calcd for 035H39N204 (M+H, ES+) m/z 551.2910, meas 551.2896; [a]230 = +61.1 (c = 1, EtOAc) on 90% ee (2R,33)-60e; white foamy solid: mp. 84-92 °C. Me Me M60 0 O OMe Me Me N E?“ ‘CONHPh 60f Me (2R, 3S)- 1-(bis(4-methoxy-3, 5-dimethylphenyl)methyl)-N-phenyl-3-m- tolylaziridine-Z-carboxamide 60f. lmine 9f (80 mg, 0.2 mmol) and diazoacetamide 14a (45 mg, 0.28 mmol) were reacted according to the general procedure described above (0 °C, 5 mol% (8)-VANOL-Bs catalyst) to afford crude 60f. 236 Column chromatography with regular silica gel and with an eluent mixture of 1:5 EtOAc:hexanes afforded 60f which was 95% pure. Subsequent column chromatography with regular silica gel and an eluent mixture of 1:35 EtOAc:benzene afforded pure 60f as a white foamy solid in 82% isolated yield (88 mg, 0.16 mmol). The optical purity of 60f was determined to be 87% ee by HPLC analysis (Chiralcel OD-H column, hexanes:2-propanol 98:2, 222 nm, flow rate 1 mL min"). Retention times were 18 min (minor enantiomer, (2S,3Fi)-60f) and 22 min (major enantiomer, (2R,3S)-60f). Data for 60f: R; = 0.25 (1:5 EtOAc:hexanes); Ft; = 0.28 (1:35 EtOAc:benzene); 1H NMR (DMSO-06, 500 MHz) 6 2.01 (s, 6H), 2.07 (s, 6H), 2.29 (s, 3H), 2.90 (d, 1H, J = 1.7 Hz), 3.30 (m, 1H, with DMSO water peak), 3.48 (s, 3H), 3.55 (s, 3H), 5.02 (s, 1H), 6.97 (s, 2H), 7.03-7.08 (m, 4H), 7.13 (bs, 2H), 7.21-7.24 (m, 1H), 7.28 (t, 2H, J = 8.5 Hz), 7.47 (d, 2H, J = 8.3 Hz), 10.25 (s, 1H); 13C NMR (DMSO-06, 125 MHz) 6 15.68, 15.88, 20.94, 45.99, 47.14, 58.93, 59.06, 65.42, 109.24, 119.19, 123.08, 123.48, 126.76, 127.36, 127.80, 128.20, 128.60, 129.60, 129.65, 137.37, 138.59, 138.63, 138.71, 138.88, 155.13, 155.20, 164.89; IR (thin film) 3313w, 2925m, 1669m, 1602m, 1527s, 1484s, 1443s, 12213 cm"; HRMS calcd for C35H39N203 (M+H, ES+) m/z 535.2961, meas 535.2938; [81230 = +55.8 (c = 1, EtOAc) on 80% ee (2R,3S)-60f; white foamy solid: mp. 78-86 °C. 237 Me Me MeO OMe .. O O M. “ CONHPh CL... 609 (2R, 3S)- 1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3—(2-chlorophenyl)- N-phenylaziridlne-2-carboxamide 609. lmine 99 (84 mg, 0.2 mmol) and diazoacetamide 14a (45 mg, 0.28 mmol) were reacted according to the general procedure described above (0 °C, 5 mol% (3)-VANOL-83 catalyst) to afford crude 609. Column chromatography with regular silica gel and an eluent mixture of 1:5 EtOAc:hexanes afforded 609 which was 95% pure. Subsequent column chromatography with regular silica gel and an eluent mixture of 1:35 EtOAc:benzene afforded pure 609 as a white foamy solid in 78% isolated yield (87 mg, 0.16 mmol). The optical purity of 609 was determined to be 90% 99 by HPLC analysis (Chiralcel OD column, hexanes:2-propanol 95:5, 222 nm, flow rate 1 mL min"). Retention times were 17 min (minor enantiomer, (23,3Fl)-609) and 21 min (major enantiomer, (2R,3S)-609). Data for 609: R; = 0.2 (1:5 EtOAc:hexaneS); Ht = 0.28 (1:35 EtOAc:benzene); 1H NMR (DMSO-06, 500 MHz) 6 2.03 (s, 6H), 2.12 (s, 6H), 2.85 (d, 1H, J = 2.7 Hz), 3.47 (s, 3H), 3.56 (s, 3H), 3.61 (d, 1H, J = 2.7 Hz), 5.03 (s, 1H), 7.03 (s, 2H), 7.05 (t, 1H, J = 7.6 Hz), 7.13 (s, 2H), 7.27-7.30 (m, 3H), 7.37-7.41 (m, 2H), 7.46 (d, 2H, J = 7.5 Hz), 7.51 (dd, 1H, J = 1.5, 7.8 Hz), 10.27 (s, 1H); ”‘0 NMR (DMSO-06, 125 MHz) 5 15.71, 15.86, 43.56, 46.88, 58.93, 238 59.08, 65.61, 119.23, 123.59, 127.04, 127.37, 127.43, 127.61, 128.62, 128.82, 128.93, 129.67, 129.90, 132.46, 136.05, 138.38, 138.48, 138.65, 155.24, 155.32, 164.37; IR (thin film) 3310w, 2925W, 16853, 16013, 15398, 1444s, 12213 cm"; HRMS calcd for C34H36N20335C| (M+H, ES+) m/z 555.2414, meas 555.2428; [61230 = +48.1 (c = 1, EtOAc) on 85% ee (2R,3S)-609; white foamy solid: mp. 86- 94 °C. Me Me Meo OMe M. 0 0 M. N \“. ~ CONHPh OMe 60h (2H, 38)- 1 -(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-(3- methoxyphenyl)-N-phenylazlridine-2-carboxamide 60h. lmine 9h (83 mg, 0.2 mmol) and diazoacetamide 14a (45 mg, 0.28 mmol) were reacted according to the general procedure described above (0 °C, 5 mol% (S)-VANOL-83 catalyst) to afford crude 60h. Column chromatography with regular silica gel and an eluent mixture of 1:5 EtOAc:hexanes afforded pure 60h as a white foamy solid in 76% isolated yield (84 mg, 0.15 mmol). The optical purity of 60h was determined to be 92% ee by HPLC analysis (Chiralcel OD column, hexanes:2-propanol 98:2, 222 nm, flow rate 1 mL min“). Retention times were 52 min (minor enantiomer, (2S,3H)-60h) and 61 min (major enantiomer, (2R,3S)-60h). Data for 60h: R, = 0.2 (1:4 EtOAc:hexanes); 1H NMR (DMSO-06, 500 MHz) 5 2.01 (s, 6H), 2.08 (s, 6H), 2.89 (d, 1H, J = 2.4 Hz), 3.34 (d, 1H, J = 2.4 239 Hz), 3.47 (s, 3H), 3.55 (s, 3H), 3.74 (s, 3H), 5.01 (s, 1H), 6.81 (dd, 1H, J = 2.2, 8.1 Hz), 6.89 (s, 1H), 6.93 (d, 1H, J = 7.5 Hz), 6.98 (s, 2H), 7.04 (t, 1H, J = 7.6 Hz), 7.06 (s, 2H), 7.23-7.30 (m, 3H), 7.46 (d, 2H, J = 7.8 Hz), 10.25 (s, 1H); “’0 NMR (DMSO-06, 125 MHz) 5 15.68, 15.89, 45.87, 47.26, 54.97, 58.92, 59.05, 65.43, 111.46, 112.98, 118.15, 119.20, 123.49, 127.35, 127.78, 128.59, 129.39, 129.61, 129.69, 138.57,138.60, 138.86, 140.50, 155.15, 155.21, 159.32, 164.78; IR (thin film) 3313w, 2939w, 1670m, 1601s, 1529s, 1487s, 14443, 12213 cm"; HRMS calcd for 035H39N204 (M+H, ES+) m/z 551.2910, meas 551.2905; [04230 = -64.2 (c = 1, EtOAc) on 93% ee (28,3R)-60h; white foamy solid: mp. 76-84 °C. Me Me M80 0 O OMe Me Me N ‘CONHPh 60i (2R, 3S)- 1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-(naphthalen-2-yl)- N—phenylaziridine-Z-carboxamide 60i. lmine 9i (87 mg, 0.2 mmol) and diazoacetamide 14a (45 mg, 0.28 mmol) were reacted according to the general procedure described above (0 °C, 10 mol% (8)-VANOL-83 catalyst) to afford crude 60I. Column chromatography with regular silica gel and an eluent mixture of 1:6 EtOAc:hexanes afforded pure em as a white foamy solid in 79% isolated yield (90 mg, 0.16 mmol). The optical purity of 60f was determined to be 81% ee by HPLC analysis (Chiralcel OD column, hexanes:2-propanol 97:3, 222 nm, flow 240 rate 1 mL min"). Retention times were 39 min (major enantiomer, (2R,3S)-6OI) and 54 min (minor enantiomer, (2S,3Ff)-6OI). Data for 60i: R; = 0.25 (1:5 EtOAc:hexanes); 1H NMR (DMSO-06, 500 MHz) 6 2.03 (s, 6H), 2.04 (s, 6H), 3.03 (d, 1H, J = 2.0 Hz), 3.49 (s, 3H), 3.52-3.53 (m, 4H), 5.09 (s, 1H), 7.02 (s, 2H), 7.05 (t, 1H, J = 7.4 Hz), 7.09 (s, 2H), 7.29 (t, 2H, J = 8.0 Hz), 7.47-7.52 (m, 5H), 7.87-7.92 (m, 4H), 10.30 (s, 1H); 13c NMR (DMSO-06, 125 MHz) 6 15.70, 15.87, 46.16, 47.36, 58.95, 59.03, 65.47, 119.22, 123.52, 123.86, 125.10, 125.73, 126.28, 127.33, 127.47, 127.55, 127.83, 127.98, 128.61, 129.64, 129.69, 132.34, 132.78, 136.43 ,138.59, 138.63, 138.88, 155.13, 155.24, 164.81; IR (thin film) 3313w, 2928w, 1666m, 16013, 15298, 14853, 1444s, 1221s cm"; HRMS calcd for C33H39N203 (M+H, ES+) m/z 571.2961, meas 571.2954; [01235 = +623 (0 = 1, EtOAc) on 80% ee (2R,35')-60i; white foamy solid: 98-1 08 oC. Me Me MeO O 0 OMG Me Me N /©: ‘coNHPh Br F 60i (2R, 3S)- 1-(bis(4-methoxy—3,5—dimethylphenyl)methyl)-3—(4-bromo-2— fluorophenyl)-N—phenylaziridine-2-carboxamide 60]. lmine 9] (97 mg, 0.2 mmol) and diazoacetamide 14a (45 mg, 0.28 mmol) were reacted according to the general procedure described above (0 °C, 5 mol% (8)-VANOL-B3 catalyst) to afford crude 60]. Column chromatography with regular silica gel and an eluent 241 mixture of 1:6 EtOAc:hexanes afforded 60] which was 95% pure. Subsequent column chromatography with regular silica gel and an eluent mixture of 1:40 EtOAc:benzene afforded pure 60] as a white foamy solid in 62% isolated yield (77 mg, 0.12 mmol). The optical purity of 60] was determined to be 92% ee by HPLC analysis (Chiralcel OD column, hexanes:2-propanol 97:3, 222 nm, flow rate 1 mL min“). Retention times were 16 min (major enantiomer, (2R,3S)-60j) and 52 min (minor enantiomer, (2S,3R)-60j). Data for 60]: Ft; = 0.22 (1:6 EtOAc:hexanes); R; = 0.26 (1:40 EtOAc:benzene); ‘H NMR (DMSO-06, 500 MHz) 5 2.01 (s, 6H), 2.10 (s, 6H), 2.97 (d, 1H, J = 2.6 Hz), 3.47 (m, 4H), 3.56 (s, 3H), 4.98 (s, 1H), 6.99 (s, 2H), 7.04-7.06 (m, 3H), 7.89 (t, 2H, J = 7.6 Hz), 7.35-7.39 (m, 1H), 7.45-7.51 (m, 4H), 10.31 (s, 1H); 13c NMR (DMSO-06, 125 MHz) (1 sp3 carbon missing) 5 15.67, 15.87, 46.83, 58.93, 59.07, 65.57, 118.39, 118.59, 119.27, 120.23 (d, 10, J: 9.0 HZ), 123.64, 125.34 (d, 1C, J = 13.0 Hz), 127.34, 127.67, 127.86 (d, 10, J = 3.0 Hz), 128.56 (d, 10, J: 4.5 Hz), 128.62, 129.69, 129.89, 138.24, 138.41, 138.48, 155.28, 160.44 (d, 10, J = 248.1 Hz), 164.13; 19f= NMR (DMSO-06, 283 MHz) 5 - 117.99; IR (thin film) 3340w, 2926w, 16603, 1603s, 1531m, 1467s, 14443, 12213 cm"; HRMS calcd for C34H35N203F79Br (M+H, ES+) m/z 617.1815, meas 617.1804; [61230 = +729 (0 = 1, EtOAc) on 94% ee (2R,3S)-60j; white foamy solid: mp. 90-98 °C. 242 II.“ Me Me M80 0 O 0M8 Me Me N O“ ‘CONHPh 60k (2R, 3S)- 1-(bis(4-methoxy-3, 5-dimethylphenyl)methyl)-3-cyclohexyl-N- phony/aziridine-2-carboxamide 60k. lmine 9k (79 mg, 0.2 mmol) and diazoacetamide 14a (45 mg, 0.28 mmol) were reacted according to the general procedure described above (0 °C, 10 mol% (5)-VANOL-B3 catalyst) to afford crude 60k. Column chromatography with regular silica gel and an eluent mixture of 1:5 EtOAc:hexanes afforded 60k which was 95% pure. Subsequent column chromatography with regular silica gel and an eluent mixture of (1:50 EtOAczCHZCIz followed by 1:20 EtOAczCHzClz) afforded analytically pure 60k as a white foamy solid in 50% isolated yield (53 mg, 0.1 mmol). The optical purity of 60k was determined to be 30% ee by HPLC analysis (Chiralcel OD-H column, hexanes:2-propanol 97:3, 222 nm, flow rate 0.7 mL min“). Retention times were 9 min (minor enantiomer, (2S,3F1’)-60k) and 13 min (major enantiomer, (2R,38)- 60k). Data for 60k: Fl; = 0.19 (1:5 EtOAc:hexanes); Fl; = 0.3 (1:50 EtOAc:CH2CI2); 1H NMR (DMSO-06, 500 MHz) 5 0.69-1.61 (m, 11H), 2.01 (s, 6H), 2.13 (dd, 1H, J = 2.9, 7.1 Hz), 2.18 (s, 6H), 2.67 (d, 1H, J = 2.9 Hz), 3.07 (s, 3H), 3.59 (3, 3H), 4.69 (s, 1H), 6.94 (s, 2H), 7.00 (t, 1H, J = 7.3 Hz), 7.05 (s, 2H), 7.20-7.25 (m, 2H), 7.41 (d, 2H, J = 7.6 Hz), 10.12 (s, 1H); ‘30 NMR (DMSO-d5, 125 MHZ) 6 15.72, 15.85, 25.08, 25.29, 25.81, 29.43, 29.87, 39.77, 41.41, 49.80, 243 _‘ 3.‘»V ‘1 58.90, 59.18, 65.68, 119.13, 123.20, 127.41, 127.96, 128.48, 129.35, 129.57, 138.76, 138.78, 139.26, 154.91, 155.31, 166.07; IR (thin film) 3316w, 29263, 2853m, 16643, 16013, 15333, 14853, 1444s, 12213 cm"; Mass spectrum: m/z(% rel intensity) 526 M+ (1), 443 (18), 350 (45), 322 (52), 284 (56), 283 (100); HRMS calcd for C34H43N203 (M+H, ES+) m/z 527.3274, meas 527.3264; white foamy solid: mp. 186-189 °C. Me Me M80 0 O 0M8 Me Me N :jw' ‘coNHPh 601 (2R, 3S)- 1 -(bis (4-methoxy-3, 5-dimethylphenyl)methyl)-3-tert—butyl-N- phenylaziridine-Z-carboxamlde 60!. Imine 9| (73 mg, 0.2 mmol) and diazoacetamide 14a (45 mg, 0.28 mmol) were reacted according to the general procedure described above (0 °C, 20 mol% (8)-VANOL-B3 catalyst) to afford crude 60l. Column chromatography with regular silica gel and an eluent mixture of 1:8 EtOAc:hexanes afforded pure 60l as a white foamy solid in 68% isolated yield (68 mg, 0.14 mmol). The optical purity of 60| was determined to be 88% ee by HPLC analysis (Chircalcel OD-H column, hexanes:2-propanol 98:2, 222 nm, flow rate 1 mL min"). Retention times were 10 min (minor enantiomer, (2S,3Fl)- 6OI) and 28 min (major enantiomer, (2R,3$)-60l). Data for 60!: R; = 0.17 (1 :8 EtOAc:hexanes); 1H NMR (CDCI3, 500 MHz) 6 0.73 (s, 9H), 2.09 (s, 6H), 2.23 (s, 6H), 2.38 (d, 1H, J = 2.7 Hz), 2.49 (d, 1H, J = 2.7 Hz), 3.55 (s, 3H), 3.64 (s, 3H), 4.50 (s, 1H), 7.03 (t, 1H, J = 7.5 Hz), 7.07 (s, 244 2H), 7.20 (s, 2H), 7.13-7.23 (m, 5H); 13c NMR (CDCI3, 125 MHz) 5 16.01, 16.11, 26.73, 30.42, 40.86, 54.60, 59.35, 59.57, 67.76, 119.86, 124.22, 127.56, 128.39, 128.69, 130.12, 130.20, 137.50, 139.17, 139.27, 155.48, 155.88, 166.15; IR (thin film) 3318m, 2953s, 2866w, 1658s, 1601s, 15413, 15003, 14443, 12213 cm"; HRMS calcd for C32H41N203 (M+H, ES+) m/z 501.3117, meas 501.3095; [(1]230 = -37.3 (c = 1, EtOAc) on 88% ee (2R,3S)-60l); white foamy solid: mp. 78-86 °C. tBu tBu MeO OMe O O N OWL—\CONHPh 61k (2R, 38)- 1-(bis(3,5-di-tert-butyI-4-methoxyphenyl)methyl)-3-cyclohexyl-N- phenylaziridine-Z-carboxamide 61k. Imine 58k (112 mg, 0.2 mmol) and diazoacetamide 14a (45 mg, 0.28 mmol) were reacted according to the general procedure described above (0 °C, 20 mol% (S-VANOL-Bg catalyst) to afford crude 61 k. Column chromatography with regular silica gel and an eluent mixture of 1:13 EtOAc:hexanes afforded 61k which was 95% pure. Subsequent column chromatography with regular silica gel and an eluent mixture of (1:1 CH2CI2zhexanes followed by CH2CI2 only) afforded analytically pure 61k as a white foamy solid in 62% isolated yield (86 mg, 0.12 mmol). The optical purity of 61k was determined to be 26% ee by HPLC analysis (Regis Pirkle Covalent (RF?) Whelk-O1 column, hexanes:2-propanol 98:2, 222 nm, flow rate 1 mL min' 245 1). Retention times were 15 min (major enantiomer, (2R,3S)-61k) and 22 min (minor enantiomer, (28,3R)-61 k). Data for 61k: R = 0.24 (1:13 EtOAc:hexanes); 1H NMR (DMSO-06, 500 MHz) 6 0.63-1.66 (m, 11H), 1.22 (s, 18H), 1.36 (s, 18H), 2.14 (dd, 1H, J = 2.2, 6.5 Hz), 2.72 (d, 1H, J = 2.7 Hz), 3.37 (s, 3H), 3.57 (s, 3H), 4.79 (s, 1H), 6.96 (t, 1H, J = 7.3 Hz), 7.19 (t, 2H, J: 8.0 Hz), 7.21 (s, 2H), 7.34 (s, 2H), 7.41 (d, 2H, J = 8.0 Hz), 10.06 (s, 1H); 130 NMR (DMSO-06, 125 MHz) 5 25.06, 25.25, 25.77, 29.27, 29.68, 31.74, 31.83, 31.92, 35.09, 35.27, 41.08, 50.00, 63.59, 64.03, 66.54, 118.91, 123.07, 125.26, 125.85, 128.35, 137.59, 138.11, 138.81, 141.85, 142.14, 157.17, 157.69, 166.25; IR (thin film) 3333w, 29813, 29263, 2853m, 1676s, 1603s, 1527s, 1444s, 1221s cm"; HRMS calcd for c.6H67N203 (M+H, ES+) m/z 695.5152, meas 695.5133; [5423D = +322 (0 = 1, EtOAc) on 73% ee (28,3H)-61 k; white foamy solid: mp. 192-198 °C. tBu tBu Meo OMe O O N EWLKCONHPh 6" (2R, 3S)- 1-(bis(3, 5 -di-tert-butyl-4-methoxyphen yl)meth yl)-3-tert-butyl—N- phenylaziridine-2-carboxamide 61I. lmine 58I (107 mg, 0.2 mmol) and diazoacetamide 14a (45 mg, 0.28 mmol) were reacted according to the general procedure described above (0 °C, 20 mol% (3)-VANOL-B3 catalyst) to afford crude 61l. Column chromatography with regular silica gel and an eluent mixture 246 of 1:15 EtOAc:hexanes afforded pure 61| as a white solid in 65% isolated yield (87 mg, 0.13 mmol). The optical purity of 61l was determined to be 80% ee by HPLC analysis (Regis Pirkle Covalent (RF?) Whelk-O1 column, hexanes:2- propanol 99:1, 222 nm, flow rate 1 mL min"). Retention times were 14 min (major enantiomer, (2R,35‘)-61 I) and 18 min (minor enantiomer, (2S,3F?)-61I). Data for 61l: R = 0.28 (1:15 EtOAc:hexanes); 1H NMR (CDCI3, 500 MHz) 6 0.68 (s, 9H), 1.30 (s, 18H), 1.39 (s, 18H), 2.37 (d, 1H, J: 2.7 Hz), 2.44 (d, 1H, J = 2.7 Hz), 3.45 (s, 3H), 3.60 (s, 3H), 4.52 (s, 1H), 6.89 (bs, 1H), 7.00 (t, 1H, J = 6.8 Hz), 7.17-7.22 (m, 4H), 7.38 (s, 2H), 7.39 (s, 2H); 13c NMR (CDCI3, 125 MHz) 6 26.49, 30.49, 32.05, 32.11, 35.57, 35.69, 41.00, 54.67, 63.86, 64.14, 68.87, 119.31, 124.16, 125.36, 126.47, 128.78, 137.55, 137.86, 138.14, 142.64, 142.69, 157.85, 158.39, 166.03; IR (thin film) 3294w, 29593, 2868w, 1662m, 1601m, 1541m, 1442m, 1414m, 1219m cm"; HRMS calcd for C44H55N203 (M+H, ES+) m/z 669.4995, meas 669.4973; [51230 = -15.2 (c = 1, EtOAc) on 80% ee (2R,3S)-61I; white solid: mp. 178-180 °C. tBu tBu M80 0 O 0M8 tBu tBu N \“" ‘CONHPh 61m (2R, 3S)- 1-(bis(3,5-di-tert-butyl-4-methoxyphenyl)methyl)-3-ethyl-N- phenylaziridine-Z-carboxamide 61m. lmine 58m (101 mg, 0.2 mmol) and diazoacetamide 14a (45 mg, 0.28 mmol) were reacted according to the general procedure described above (0 °C, 20 mol% (8)-VANOL-B3 catalyst) to afford 247 crude 61m. Column chromatography with regular silica gel and an eluent mixture of 1:8 EtOAc:hexanes to afford pure 61m as a white solid in 66% isolated yield (85 mg, 0.13 mmol). The optical purity of 61m was determined to be 88% ee by HPLC analysis (Regis Pirkle Covalent (Fl,Fl) Whelk-O1 column, hexanes:2- propanol 99:1, 222 nm, flow rate 1 mL min"). Retention times were 26 min (minor enantiomer, (28,3Fl)-61 m) and 49 min (major enantiomer, (2R,3S)-61m). Data for 61m: R; = 0.22 (1 :8 EtOAc:hexanes); 1H NMR (CDCI3, 500 MHz) 6 0.86 (t, 3H, J: 7.3 Hz), 1.33 (s, 18H), 1.42 (s, 18H), 1.63-1.73 (m, 2H), 2.20 (d, 1H, J: 2.2 Hz), 2.37 (bs, 1H), 3.61 (s, 3H), 3.66 (s, 3H), 4.28 (s, 1H), 7.06 (t, 1H, J = 7.3 Hz), 7.26 (s, 2H), 7.29 (t, 2H, J = 7.6 Hz), 7.34 (s, 2H), 7.48 (d, 2H, J = 7.8 Hz), 8.56 (s, 1H); 13C NMR (CDCI3, 125 MHz) 6 12.35, 19.81, 32.04, 32.13, 35.68, 35.76, 45.13, 49.04, 63.99, 64.16, 68.33, 119.17, 123.90, 125.20, 125.27, 128.92, 136.98, 137.12, 137.58, 143.24, 143.51, 158.34, 158.47, 168.81; IR (thin film) 3310w, 2983s, 2872w, 1676m, 1603m, 1529s, 14443, 14123, 12213 cm“; HRMS calcd for C42H61N203 (M+H, ES+) m/z 641.4682, meas 641.4667; [81230 = +610 (0 = 1, EtOAc) on 88% ee (2R,3S)-61m; white solid: mp. 186-192 °C. tBu tBu MeO OMe O O N WWLKCDNHPh 61h (2R, 3S)- 1 -(bis(3, 5 -di- tert-butyl-4-methoxyphen yl)meth yl)-3-isoprop yl-N- phony/aziridine-2-carboxamide 61n. Imine 58n (104 mg, 0.2 mmol) and diazoacetamide 14a (45 mg, 0.28 mmol) were reacted according to the general 248 procedure described above (0 °C, 20 mol% (S)-VANOL-B3 catalyst) to afford crude 61h. Column chromatography using regular silica gel and an eluent mixture of 1:9 EtOAc:hexanes afforded 61n which was 95% pure. Subsequent column chromatography with regular silica gel and an eluent mixture of 1:100 EtOAc:benzene afforded analytically pure 61n as a white solid in 60% isolated yield (78 mg, 0.12 mmol). The optical purity of 61 n was determined to be 58% ee by HPLC analysis (Regis Pirkle Covalent (R,Fl) Whelk-O1 column, hexanes:2- propanol 98:2, 222 nm, flow rate 1 mL min"). Retention times were 12 min (major enantiomer, (2R,3S)-61n) and 19 min (minor enantiomer, (28,3Fl)-61n). Data for GM: Fl; = 0.20 (1:9 EtOAc:hexanes); Fl; = 0.29 (1:100 EtOAc:benzene); 1H NMR (DMSO-06:CDCI3 3:1, referenced to DMSO-o5, 500 MHz) 5 0.60 (d, 3H, J = 6.6 Hz), 0.77 (d, 3H, J = 6.8 Hz), 1.21 (s, 18H), 1.35 (s, 18H), 1.39-1.48 (m, 1H), 2.13 (dd, 1H, J = 3.0, 6.6 Hz), 2.66 (d, 1H, J = 2.7 Hz), 3.35 (s, 3H), 3.56 (s, 3H), 4.77 (s, 1H), 6.93 (t, 1H, J = 7.4 Hz), 7.15 (t, 2H, J = 7.5 Hz), 7.19 (s, 2H), 7.32 (s, 2H), 7.41 (d, 2H, J = 7.8 Hz), 10.02 (s, 1H); “’0 NMR (DMSO-06:CDCI3 3:1, referenced to DMSO-05, 125 MHz) 6 18.86, 19.24, 29.65, 31.69, 31.81, 35.04, 35.23, 41.11, 51.22, 63.45, 63.86, 66.61, 118.84, 122.88, 125.25, 125.77, 128.15, 137.52, 138.05, 138.77, 141.77, 142.08, 157.12, 157.62, 166.18; IR (thin film) 3327w, 22613, 28703, 1670m, 1603m, 15293, 14443, 1414s, 1221s cm"; HRMS calcd for C43H53N203 (M+H, ES+) m/z 655.4839, meas 655.4827; [5:123D = -37.3 (c = 1, EtOAc) on 76% ee (2R,3S)-61 n; white solid: mp. 182-186 0C. 249 tBu tBu M80 0 O 0M8 tBu tBu N WAWCONHPh 610 (28, 3R)- 1-(bis(3,5-di-tert—butyl-4-methoxyphenyl)methyl)-3-(2-methylpent- 4-en-2-yl)-N-phenylaziridine-2—carboxamide 61o. lmine 580 (112 mg, 0.2 mmol) and diazoacetamide 14a (45 mg, 0.28 mmol) were reacted according to the general procedure described above (0 °C, 20 mol% (H)-VAPOL-B3 catalyst) to afford crude 61o. Column chromatography with regular silica gel and an eluent mixture of 1:15 EtOAc:hexanes afforded 610 which was 95% pure. Subsequent column chromatography with regular silica gel and an eluent mixture of 1:1 CHzclzzhexanes afforded analytically pure 610 as a white foamy solid in 53% isolated yield (74 mg, 0.11 mmol). The optical purity of 610 was determined to be 81% ee by HPLC analysis (Regis Pirkle Covalent (RH) Whelk-O1 column, hexanes:2-propanol 99:1, 222 nm, flow rate 1 mL min"). Retention times were 14 min (minor enantiomer, (2R,3S)-61o) and 21 min (major enantiomer, (23,319)— 610). Data for 610: Ft; = 0.24 (1:15 EtOAc:hexanes); R; = 0.3 (1:1 CH2CI2:hexanes); 1H NMR (CDCI3, 500 MHz) 6 0.62 (s, 3H), 0.74 (s, 3H), 1.29 (s, 18H), 1.40 (s, 18H), 1.68-1.84 (m, 2H), 2.45 (d, 1H, J: 2.7 Hz), 2.48 (d, 1H, J: 2.7 Hz), 3.45 (s, 3H), 3.61 (s, 3H), 4.53 (s, 1H), 4.74 (d, 1H, J: 16.9 Hz), 4.88 (d, 1H, J = 8.5 Hz), 5.57-5.65 (m, 1H), 6.88 (bs, 1H), 7.01 (t, 1H, J = 6.9 Hz), 7.17- 7.23 (m, 4H), 7.39 (s, 2H), 7.41 (s, 2H); 130 NMR (CDCI3, 125 MHz) 5 23.11, 250 24.10, 32.08, 32.12, 33.43, 35.60, 35.71, 41.02, 45.14, 53.73, 63.84, 64.14, 69.01, 117.07, 119.34, 124.18, 125.31, 126.45, 128.79, 134.86, 137.59, 137.98, 138.17, 142.73, 142.84, 157.89, 158.50, 165.90; IR (thin film) 3341w, 2983s, 1666m, 1601m, 1529m, 1442s, 14123, 12193 cm°1; HRMS calcd for C45H67N203 (M+H, ES+) m/z 695.5152, meas 695.5131; [0t]230 = +21.5 (c = 1, EtOAc) on 81% ee (2S,3Fl)-61o; white foamy solid: mp. 70-78 °C. Conversion of the trans-amide aziridine 60a to the trans-ester aziridine 73“1 1) (Boc)20, DMAP MEDAM DCM/ACN, 22 °C, 1 h MEDAM N 2) NaOEt, EtOH, 0 °c, 1 h N .. HPh = OEt Ph,. AW»! 96% Ph 4* O (2 runs) 0 603 73 (2R,3S)-ethyl 1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3- phenylaziridine-2-carboxylate 73. To a 25 mL round bottom flask fitted with a magnetic stir bar, previously flame dried and cooled under Argon, was added sequentially the trans-aziridine (2R,3S)-60a (120 mg, 0.23 mmol, 1 equiv, 90% ee), 9 mL dry CH3CN, and 1.5 mL dry CHZClz to get a clear solution. The flask was then fitted with a rubber septum and an Argon balloon. This was followed by the addition of DMAP (57 mg, 0.46 mmol, 2 equiv) and (Boc)20 (151 mg, 0.69 mmol, 3 equiv), and the reaction mixture was then stirred at room temperature for 1 h, at which time the reaction was judged complete by TLC. The reaction mixture was then subjected to rotary evaporation to afford a yellow oil, which was subjected to flash column chromatography with regular silica gel and an eluent mixture of 1:5 EtOAc:hexanes (R = 0.33). This afforded the intermediate product as a white foamy solid (147 mg). This was taken in a 25 mL round bottom flask 251 fitted with a magnetic stir bar, to which was then added 6 mL EtOH. The flask was fitted with a rubber septum and an Argon balloon and the solution was cooled to 0 °C in an ice bath, followed by the addition of NaOEt (21 wt% solution of NaOEt in EtOH, 132 uL, 0.35 mmol, 1.5 equiv). This reaction mixture was stirred at 0 °C for 1 h, at which time the reaction was complete by TLC. The reaction was then quenched with the addition of 9 mL sat. aq. NH4CI solution, and the reaction mixture was concentrated by rotary evaporation. This was followed by the addition of 30 mL water, which was extracted three times with CH2CI2. The organic layers were combined, dried over N82804, filtered through a pad of Celite, subjected to rotary evaporation till dryness and finally to high vacuum to afford the crude product 73. This was then subjected to column chromatography with regular silica gel and an eluent mixture of 1:9 EtOAc:hexanes to afford the pure product 73 as a white semi-solid in 96% isolated yield (average of two runs, 105 mg, 0.22 mmol). Data for 73: R = 0.23 (1 :9 EtOAc:hexanes); 1H NMR (CDCI3, 500 MHz) 5 1.03 (t, 3H, J = 7.1 Hz), 2.15 (s, 6H), 2.24 (s, 6H), 2.82 (d, 1H, J = 2.4 Hz), 3.39 (d, 1H, J = 2.4 Hz), 3.62 (s, 3H), 3.66 (s, 3H), 3.96-4.05 (m, 2H), 4.89 (s, 1H), 7.05 (s, 2H), 7.07 (s, 2H), 7.22-7.28 (m, 5H); 13c NMR (CDCI3, 125 MHz) 5 13.89, 16.14, 16.17, 45.09, 48.71, 59.50, 59.52, 60.90, 67.04, 126.47, 127.36, 127.77, 127.89, 128.21, 130.24, 130.34, 138.34, 138.50, 138.75, 155.73, 155.81, 168.66; IR (thin film) 2932m, 1724s, 1483s, 1221s, 1108s cm"; HRMS calcd for C30H36N04 (M+H, ES+) m/z 474.2644, meas 474.2656; [5:123D = -4.4 (c = 1, EtOAc) on 90% ee (2R,3S)-73; white semi-solid. 252 “51“.- a: 3.. ’_IAE .I‘ [Q i I TfOH catalyzed aziridination reactions ‘ For experimental details, see published work (Vetticatt, M. J.; Desai, A. A.; Wulff, W. D. 2010, submitted). Determination of absolute configuration in the trans-selective aziridination \ PhAN'MEDAM 9a 5 mol% + = + o ‘0'“?6‘1 £5052 M) Ph“"3 2‘coNHPh Ph’ 3 2‘CONHPh (“\th (2R,38)—60a (2R,3R)-65a H 100% conversion 71% yield 14% yield 5:1 trans:cis 33% ee 77% ee 14a . 1'2 “UN 26 h 25% Pd(OH)2/C 40 h , , rt, MeOH, (Boc)20 1 atm H S 2 Ph CONHPh NHBoc Ph/\R/CONHPh Ph/‘R/CONHPh Literature values for optical rotation: i i c = 1, MeOH, +229 (ref. 43) NHBoc NHBoc C = 2, CH2C12, -37 (ref. 44) 75 75 L 76% yield 66% yield Optical rotations obtained: Optical rotations obtained: c =1,CH2c12,+16.5 C: 1, CHZCIZ, +179 0 = 1, MeOH, -29.8 c = 0.5, MeOH, -14.7 10 mol% Pd(OH) /C MEDAM 2 I 1 atm H2, 22 °C, 6 h S CONHPh CONHPh N e Ph/Y + Ph Phfls 24%,,th MeOH. (800)20 NHBoc NHMEDAM (28,3R)—60a ent. 75 76 91 % ee 13% yield 62% yield Optical rotations obtained: 0 = 0.4, CH2CI2, -25.6 c = 0.4, MeOH, +26.1 As indicated in the Scheme above, the major and minor diastereomers in the trans-selective aziridination reaction, trans-60a and cis-65a, were isolated from the aziridination reaction performed according to the general procedure described above. These were then subjected to a reductive ring- 253 opening/deprotection/Boc-protection sequence, and transformed to the corresponding Boc-protected aminoamides 75. The optical rotations of these products were compared to literature values (indicated in the Scheme above), and the absolute configurations were assigned. Representative procedure for the reductive ring-opening/deprotection/Boc- protection sequence for conversion of 60a to 75: A 25 mL round bottom flask fitted with a magnetic stir bar was flame dried under vacuum and cooled under Argon. To this flask was then added, the trans-aziridine 60a (80 mg, 0.154 mmol), Pd(OH)2 (68 mg, 0.0385 mmol, Pd(OH)2 on carbon powder, 20% Pd, moisture ca. 60%), (Boc)20 (100 mg, 0.462 mmol) and MeOH (5 mL), and a black suspension was obtained. The flask was then equipped with a vacuum transfer adapter connected to vacuum and a balloon filled with hydrogen. The valve to vacuum (5-10 mm Hg) was opened for a few seconds, and then switched to the hydrogen balloon; this process was repeated 5 times. This entire process of vacuum/hydrogen was repeated for a total of three times (at time t = 0 h, 4 h, and 18 h). The reaction mixture was stirred at room temperature for 26 h. It was then filtered through a pad of Celite, subjected to rotary evaporation until dryness and put on high vacuum for 5 minutes to afford the crude product 75. Column chromatography with regular silica gel and an eluent mixture of 1:5 EtOAc:hexanes afforded pure 75 as a white solid in 76% isolated yield (40 mg, 0.118 mmol). Data for 75: 1H NMR (CDCI3, 500 MHz) 5 1.43 (s, 9H), 3.12-3.17 (m, 2H), 4.55 (bs, 1H), 5.36 (bs, 1H), 7.09 (t, 1H, J = 7.3 Hz), 7.24-7.32 (m, 7H), 7.38 (d, 254 2H, J = 7.8 Hz), 8.07 (bs, 1H); 13C NMR (CDCI3, 125 MHz) 6 28.25, 36.64, 39.49, 38.65, 120.07, 120.18, 124.42, 126.98, 128.72, 128.84, 129.29, 136.67, 137.32, 169.72. Optical rotations indicated in Scheme above. Deprotectlon to the NH aziridine MEDAM , H N 8 equ TfOH, CH3CN '1' y; 0°Ctort,3h 2 :1 /£::]: CONHPh '5 /£::]:' CONHPh Br F Br F 66 81 (2R,3S)-3-(4-bromo-2-fluorophenyl)-N-phenylaziridine-2-carboxamide 81. A 25 mL round bottom flask fitted with a magnetic stir bar was flame dried under vacuum and cooled under Argon. To this was added aziridine 60] (55 mg, 0.092 mmol), which was dissolved in 2 mL dry CHaCN. The flask was then fitted with a rubber septum and an Argon balloon, and cooled to 0 °C in an ice bath. TfOH (65 “L, 0.74 mmol, 8 equiv) was added to the reaction mixture, the ice bath was removed and the reaction mixture stirred for a total of 3 h. For the work-up, sat. aq. Na2C03 was added till pH > 9, the reaction mixture was diluted with water and ether, and the layers were separated. The aqueous layer was extracted with ether three times, the organic layers combined, washed with brine, dried over MgSOa, filtered through a pad of Celite, subjected to rotary evaporation till dryness and finally to high vacuum to afford the crude product 81. Column chromatography with regular silica gel and an eluent mixture of 1:3 EtOAc:hexanes afforded pure 81 as a white solid in 53% isolated yield (16 mg, 0.049 mmol). 255 Data for 81: R; = 0.24 (1:3 EtOAc:hexanes); 1H NMR (acetone-06, 500 MHz) (invertomers observed) 6 2.19 (t, 1H, J = 8.5 Hz), 2.63-2.65 (m, with invertomer, 1H), 2.79-2.82 (m, with invertomer, 1H), 3.31-3.33 (m, with invertomer, 1H), 7.09 (t, 1H, J = 7.3 Hz), 7.25-7.38 (m, 5H), 7.68 (d, 2H, J = 7.8 Hz); 13C NMR (acetone-06, 125 MHz) (invertomers observed) 6 33.49 (m, invertomers/F-splitting), 41.51 (m, invertomers/F-splitting), 119.20 (d, J = 24.9 Hz), 120.07, 120.15, 121.28 (d, J = 9.7 Hz), 124.73, 126.97 (d, J = 13.3 Hz), 128.52 (d, J = 3.7 Hz), 129.48 (d, J = 4.6 Hz), 129.69, 139.69 (m, invertomers), 161.27, 163.26, 168.35 (m, invertomers); 19F NMR (acetone-06, 283 MHz) 5 - 119.46; IR (thin film) 3283w, 1651s, 1603m, 1545m, 1487m, 1446m, 1404m cm' 1; HRMS calcd for C15H13N20FBr (M+H, ES+) m/z 335.0195, meas 335.0187; white solid. 256 Appendix D Experimental Information for Chapter Four 2-pentquuinoline 87 was kindly provided by Dr. Supriyo Majumder, from the research group of Prof. Aaron Odom.51 2-phenquuinoline 100 was used as purchased from Aldrich. The requisite Hantzsch esters 98 were prepared according to, or in a similar manner as, previously published procedures.56 Hantzsch ester 98a is commercially available. The boroxinate B3 catalysts were prepared according to the procedures detailed in the experimental information for Chapters 2 and 3. 10 mol% (R)-VAPOL-83 m cataIYSt W / 2 N N H benzene, 60 °C, 12 h 37 Hantzsch ester 983 88 (2.4 equiv) r W EtOzC coza II N H 98a L J (R)-2-pentyl-1,2,3,4-tetrahydroquinoline 88. A small vial (3.7 mL), fitted with a Teflon liner, was flame dried and cooled under Argon. 2-pentquuinoline 87 (10 mg, 0.05 mmol, 1 equiv) was added from a stock solution in CH2CI2. The vial was directly subjected to gradual high vacuum to remove the CH2CI2. Hantzsch ester 98a was then added (31 mg, 0.12 mmol, 2.4 equiv) to the vial. The vial was evacuated and back-filled with Argon. 10 mol% of the (R)-VAPOL-B3 catalyst was added from a stock solution in benzene (1 mL). The reaction mixture was flushed 257 with Argon above the solvent surface; the vial was capped and stirred at 60 °C for 12 h. The reaction was judged complete by TLC; the crude reaction mixture was subjected to rotary evaporation till dryness and finally to high vacuum to afford crude 88. This was then subjected to column chromatography with regular silica gel and an eluent mixture of 1:50 EtOAc:hexanes to afford pure 88 as a colorless oil in >99% isolated yield (10 mg, 0.05 mmol). The optical purity was determined to be 73% ee by HPLC analysis (Chiralcel OD-H column, hexanes:2- propanol 99.5:0.5, 222 nm, flow rate 0.5 mL min"). Retention times were 10 min (major enantiomer) and 12 min (minor enantiomer). Data for 88: R = 0.26 (1 :39 EtOAc:hexanes); 1H NMR (CDCI3, 500 MHz) 5 0.90 (t, 3H, J = 7.0 Hz), 1.24-1.42 (m, 6H), 1.45-1.50 (m, 2H), 1.54-1.62 (m, 1H), 1.92-1.97 (m, 1H), 2.69-2.83 (m, 2H), 3.19-3.24 (m, 1H), 3.75 (bs, 1H), 6.46 (d, 1H, J = 7.4 Hz), 6.58 (t, 1H, J: 7.5 Hz), 6.92-6.96 (m, 2H); 13c NMR (CDCI3, 125 MHz) 6 14.03, 22.62, 25.38, 26.42, 28.10, 31.94, 36.66, 51.57, 114.00, 116.85, 121.37, 126.66, 129.21, 144.71; IR (thin film) 3406m, 3053w, 3015w, 29283, 28533, 1608s, 1583s, 1487s, 1275s cm"; Mass spectrum: m/z (% rel intensity) 203 M+ (31), 133 (29), 132 (100); HRMS calcd for C14H22N (M+H, ES+) m/z 204.1752, meas 204.1743; [0L]230 = +370 (0 = 1, CHCI3) on 72% ee (FD-88, literature values: +607 (0 = 1.2, CHCI3, 92% ee)50b and +514 (0 = 1, CHCI3)5°a; : N Ph H 101 colorless oil. 258 (8)-2-phenyl-1,2,3,4-tetrahydroquinoline 101. The general procedure described above was followed for the reaction of 2-phenquuinoline 100 to afford crude 101. Column chromatography with regular silica gel and an eluent mixture of 1:50 EtOAc:hexanes afforded pure 101 as a colorless oil in >99% isolated yield (10 mg, 0.05 mmol). The optical purity was determined to be 67% ee by HPLC analysis (Chiralcel OD-H column, hexanes:2-propanol 95:5, 222 nm, flow rate 0.6 mL min"). Retention times were 9 min (major enantiomer) and 13 min (minor enantiomer). Data for 101: R = 0.49 (1 :9 EtOAc:hexanes); 1H NMR (CDCI3, 500 MHz) 5 1.95-2.03 (m, 1H), 2.09-2.14 (m, 1H), 2.74 (dt, 1H, J: 4.7, 16.3 Hz), 2.89-2.95 (m, 1H), 4.02 (s, 1H), 4.43 (dd, 1H, J: 3.2, 9.3 Hz), 6.53 (CI, 1H, J: 7.6 Hz), 6.65 (t, 1H, J = 7.3 Hz), 6.99-7.02 (m, 2H), 7.27-7.29 (m, 1H), 7.33-7.39 (m, 4H); 130 NMR (CDCI3, 125 MHz) 6 26.36, 30.96, 56.24, 113.94, 117.13, 120.85, 126.52, 126.87, 127.41, 128.55, 129.27, 144.70, 144.79; IR (thin film) 3404w, 3026w, 2922w, 2841w, 1606m, 1585m, 1483m, 1309m cm"; Mass spectrum: m/z (% rel intensity) 209 M“ (41), 208 (22), 132 (59), 117 (22), 103 (25), 91 (37), 77 (100); HRMS calcd for C15H16N (M+H, ES+) m/z 210.1283, meas 210.1281; [04230 = - 27.5 (c = 1, CHCI3) on 67% ee (8)-101, literature valueszsoa'b -37.7 (c = 1, CHCI3); colorless oil. 259 Appendix E Experimental Information for Chapter Five General considerations Both antipodes of VAPOL and VANOL are commercially available from Aldrich and Strem Chemicals, Inc. Alternately, they can be prepared according to a procedure described in literature.65 Phosphorus oxychloride was purchased from Aldrich, and pyridine from Jade Scientific, and both were used as obtained. Other reagents were used as purchased from commercial sources. Dichloromethane and triethylamine were dried from calcium hydride under nitrogen. Propionitrile and DMF were distilled appropriately before use. The VANOL monomer 116 can be prepared on a multi-gram scale according to a procedure described in literature.65 a) POCI3, pyridine, 6 h, 25 °c Ph "’OH '0) H20. 2 hi 25 °C 2 Ph "’Osp’ro ph,“ 5 Ph,,. 0’ \OH 92% (2.1 9 product) 5 93 (8)-VANOL (8)-VANOL phosphoric acid (8)-VANOL phosphoric acid 93. To a 50 mL round bottom flask, flame- dried and cooled under Argon, was added (5)-VANOL (2 g, 4.57 mmol, 1 equiv) and 8 mL pyridine to obtain a clear yellow solution. The round bottom flask was fitted with a rubber septum and an Argon balloon. Thereafter, POCI3 (0.85 mL, 9.13 mmol, 2 equiv) was added slowly via a syringe. The reaction mixture was 260 ' "..‘h"‘.i..'-’." stirred at room temperature then for 6 h, in which time salts started precipitating out. Thereafter, 8 mL water was added via a syringe, and the reaction mixture was stirred at room temperature for 2 h. For the workup then, the reaction mixture was taken in a separatory funnel and 350 mL CH2CI2 was added. This was then extracted with 4 X 350 mL 1 N HCI. The organic layer was collected, dried over Na2304, filtered through a pad of Celite, subjected to rotary evaporation and finally high vacuum to afford the crude product 93 as a white solid. The purification was a simple precipitation. The crude solid was dissolved in a minimum amount of CH2CI2 to obtain a clear yellow solution, which was followed by the addition of excess pentane to precipitate the product as a white solid in the solution. Filtration off a Buchner funnel then provided the pure (5')- VANOL phosphoric acid product 93, which was subjected to high vacuum to completely remove all organic volatiles. Thus, (3)-VANOL phosphoric acid 93 was obtained as a white solid (mp. decomposes >250 °C) in 92% yield (2.1 g, 4.2 mmol). It was found that (8)-VANOL phosphoric acid decomposed on regular silica gel column chromatography. Spectral data for 93: 1H NMR (THF-08, 500 MHz) 5 6.50 (d, 4H, J = 8.2 Hz), 6.92 (t, 4H, J = 7.7 Hz), 7.07 (t, 2H, J = 7.4 Hz), 7.53 (s, 2H), 7.54-7.61 (m, 4H), 7.86 (d, 2H, J = 7.6 Hz), 8.46 (d, 2H, J = 8.2 Hz); 130 NMR (THF-be, 125 MHz) 5 123.78, 123.84 (d, 1C, J = 2.0 Hz), 127.08 (d, 1C, J = 2.6 Hz), 127.13, 127.20, 127.38, 128.15, 128.43, 128.46, 129.84, 135.31, 141. 14, 141.27, 147.40 (d, 10, J = 9.8 Hz); 3‘13 NMR (CDCI3, 121 MHz) 5 7.03 (3); IR (thin film) 3435s, 261 3057w, 1634m, 1489m, 1026m cm"; Mass spectrum, m/z (% rel intensity) 500 M+ (13), 83 (14), 73 (20), 57 (22), 44 (100), 41 (25); HRMS calcd for C32H2004P (M-H, 531-) m/z 499.1099, meas 499.1118; [01235 = +430 (c 1.0, CHzClz) for (3)- VANOL phosphoric acid 93. CH2Cl2, NEt3 . POCI3 TfNH2, EtCN "0H 01025°C,2L 100 °c,12n ph OH Ph,,, O 76% (2.2 9 product) 0 (8)-VANOL (S)-N-triflyl VANOL phosphoramide (8)-N-triflyl VANOL phosphoramide 94. This was prepared in the same manner as the preparation of the (R)-N-triflyl VAPOL phosphoramide 92 described below. The entire process was similar, except that DMAP was not utilized in the synthesis of 94. Thus, (3)-VANOL (2 g, 4.57 mmol) was reacted accordingly to afford crude 94. This was also purified and precipitated accordingly to afford the pure product 94 as a white solid (mp. decomposes >250 °C) in 76% isolated yield (2.2 g, 3.49 mmol). Spectral data for 94: 1H NMR (DMSO-06, 500 MHz) 6 6.38-6.40 (m, 4H), 6.96 (dt, 4H, J = 2.6, 5.6 Hz), 7.12 (t, 2H, J = 7.4 Hz), 7.56 (d, 2H, J = 8.3 Hz), 7.60-7.70 (m, 4H), 7.95-7.99 (m, 2H), 8.27 (d, 1H, J = 8.3 Hz), 8.35-8.37 (m, 1H); "’0 NMR (CDCI3, 125 MHz) 5 120.10 (CF3(q), J = 318.2 Hz), 122.13, 122.51, 122.95, 123.20, 125.69, 125.73, 125.75, 126.29, 126.52, 126.57, 126.71, 126.86, 127.17, 127.35, 127.48, 127.60, 127.72, 127.65, 128.87, 128.96, 133.82, 134.22, 262 139.85, 139.90, 140.00, 140.16, 145.30 (d, 1C, J = 8.7 Hz), 146.34 (d, 1c, J: 9.7 Hz); 3‘P NMR (CDCI3, 121 MHz) 5 0.75 (s); ‘91: NMR (CDCI3, 283 MHz) 5 - 78.69 (3); IR (thin film) 34303, 3055w, 1284m, 1217s, 1084s, 760m cm"; Mass spectrum: m/z (% rel intensity) M+ 631 (11), 420 (14), 170 (17), 80 (81), 79 (48), 44 (100); HRMS calcd for 033H20N05F3PS (M-H, ESl-) n12 630.0752, meas 630.0785; [81230 = +1373 (01.0, CHZCIZ) for (S)-N-triflyl VANOL phosphoramide 94. a) POCI3, pyridine 0 °C - 25 °C, 6 h b) H20, 0 °C - 25 °C, 2 h 84-90% yield (~ 6 9 product) 91 (R)-VAPOL phosphoric acid (R)-VAPOL phosphoric acid 91. Procedure for the reaction A one-neck 100 mL round-bottom flask, fitted with a magnetic stirrer (2.50 X 1.30 X 1.10 cm), was flame-dried and cooled under Argon to room temperature. (FD-VAPOL (6.00 g, 11.15 mmol) was added to this flask followed by the addition of pyridine (24.50 g, 25.00 mL, 0.31 mol). The flask was then fitted with a rubber septum and an Argon balloon. The mixture was stirred to completely dissolve the (FD-VAPOL, and a clear intense yellow solution was obtained. The flask was then placed in an ice-bath and the solution stirred at 0 °C for 20 min. POCI3 (3.42 g, 2.08 mL, 22.30 mmol) was added slowly via a plastic 263 I 1 syringe over a period of 10 min at 0 °C. The ice-bath was removed and the flask was allowed to warm up to room temperature. The reaction mixture was then stirred at room temperature for another 6 h. Over this period, the color of the solution changed from intense clear yellow to a cloudy pale yellow, and solid salts started precipitating out. The flask was then placed in an ice-bath again, and stirred for 10 min at 0 °C. Water (25.00 mL, 1.39 mol) was added slowly via a plastic syringe into the flask over 5 min at 0 °C. The ice-bath was removed, the flask warmed up to room temperature and the reaction mixture was stirred at room temperature for 2 h. Procedure for work-up The reaction mixture was transferred to a 2 L separatory funnel. The round-bottom flask was rinsed twice with 15 mL dichloromethane and once with 15 mL water, and the rinse was transferred to the separatory funnel each time. 750 mL dichloromethane was added to the separatory funnel, followed by the addition of 1000 mL 1 N HCI. The mixture was vigorously shaken for 3 min, and the organic layer collected. This organic layer was washed again, vigorously each time, with 6 X 1000 mL 1 N HCI. Towards the end of this process, the organic layer changed from a clear pale yellow to a white cloudy composition. Thereafter, the organic layer was washed with 2 X 900 mL saturated NaCl solution (brine), towards the end of which the organic layer regained its clear pale yellow composition. This was then dried over 80 g anhydrous sodium sulfate, filtered through a sintered glass frit covered with a layer of Celite, washed with 150 mL dichloromethane and all volatiles were then removed via rotary 264 evaporation. The resulting light brown solid was subjected to high vacuum (0.1 mm Hg) overnight to afford the crude product in 94% yield (6.30 g, 10.50 mmol). Procedure for column chromatography A 3” diameter column was packed to a depth of 17” with 1700 mL silica gel, in the form of a slurry with 1:14 MeOHzCHCla (Note 1). The crude product was dissolved in 35 mL 1:1 MeOHzCHCla (Note 2) to obtain a cloudy yellow solution, and added to the top of the silica gel layer via a pipette. The round- bottom flask, which previously contained the crude product, was rinsed twice with 3 mL 1:1 MeOHzCHClg, and the rinse was added to the top of the silica gel layer each time. The top of the product solution layer was brought to the top of the silica gel layer, and then a layer of sand (0.5” X 3”) was added on the top of the silica gel layer. The top of the column was then rinsed twice with 10 mL 1:14 MeOH:CHCl3, and the solution let run into the sand layer each time. The column was run under gravity with a 1:14 mixture of MeOH:CHCl3 as eluent. During this time, two bands could be observed travelling down the column, visible under long wave UV (365 nm), and these bands appeared to be bright purple in color under the long wave UV. The first band, the smaller band, is a side-product formed during the reaction (Note 3), and the second band, a much broader band, is the product of the reaction. After the elution started, ca. 900 mL of a void volume was collected under gravity as the first fraction. Thereafter, a second fraction was collected under gravity, ca. 350 mL (1:14 MeOHzCHClg), which was the side- product. After the side-product completely eluted (confirmed by the disappearance of the purple band on the column under long wave UV), a void 265 ma--. mm. volume of ca. 200 mL (1 :14 MeOHzCHCla) was collected under gravity before the product began to elute. Once the product started eluting, the eluent system was changed to 1:3 MeOH:CHCl3, and N2 pressure was applied and the column was flushed. The product continued to elute for ca. 3600 mL of the eluent (1:3 MeOHzCHCla). At that point, the product stopped eluting, as observed by the disappearance of an intense purple spot on TLC, observed under short wave UV (254 nm) (Note 4). All product fractions were then collected, the volatiles removed by rotary evaporation and subjected to high vacuum (0.1 mm Hg) overnight, to afford the product as a light brown solid in 109% yield (7.30 g, 12.17 mmol). 1H NMR analysis of this product revealed substantial amounts of residual methanol and chloroform solvents, which explained the >100% yield. Procedure for removal of residual solvents The product, in a one-neck 500 mL round-bottom flask, was dissolved in a minimum amount of CH2Cl2 to get a clear yellow solution (Note 5). Then the 500 mL RBF was filled almost completely with pentanes while swirling by hand, during which time the product VAPOL hydrogenphosphate started precipitating out. The resulting solution was swirled by hand for a few minutes. This was then filtered with a Biichner funnel, the solid product dried under a stream of N2 on the BI'JIchner funnel, collected and subjected to high vacuum (0.1 mm Hg) for at least 3-4 h. This precipitation cycle was repeated (usually 6-7 times) until 1H NMR analysis of the product showed complete (or almost complete) removal of the residual solvent peaks. Procedure for drying of the product (Note 6) 266 The VAPOL hydrogenphosphate obtained from the above procedure was placed on an aluminum foil boat into an Abderhalden drying gun. It was then dried under high vacuum (0.1 mm Hg) over refluxing benzene for 48 h. The above procedure affords the product (R)-VAPOL hydrogenphosphate as a white solid (mp >300 °C) in 84-90% isolated yield (for 87% yield — 5.83 g, 9.72 mmol). Spectral data for VAPOL phosphoric acid 91: 1H NMR (DMSO-06, 500 MHz) 6 6.44 (d, 4H, J: 8.2 Hz), 6.96 (t, 4H, J = 7.6 Hz), 7.11 (t, 2H, J = 7.4 Hz), 7.64 (s, 2H), 7.70-7.76 (m, 4H), 7.89 (d, 2H, J = 8.8 Hz), 7.94 (d, 2H, J = 8.8 Hz), 8.05 (d, 2H, J: 7.8 Hz), 9.75 (d, 2H, J: 8.1 Hz); "’0 NMR (DMSO-06, 125 MHz) (1 carbon not located) 6 121.23, 125.98, 126.46, 126.58, 126.79, 126.92, 127.51, 128.03, 128.48, 128.58, 128.88, 129.13, 132.81, 133.91, 139.34, 140.55, 149.2 (d, 10, J = 9.3 Hz); 3‘P NMR (DMSO-06, 121 MHz) 5 1.05 (s); IR (thin film) 38543, 16533, 15583; Mass spectrum (% rel intensity) M1 600 (43), 520 (21), 221 (64), 44 (100); HRMS calcd for C40H24O4P (M-H, ESl-) m/z 599.1412, meas 599.1434; [012% : -146.5 (c 1.0, CHgClz) for (R)-VAPOL phosphoric acid 91. Notes 1. Commercial chloroform stabilized with amylene was used; and NOT the chloroform stabilized with ethanol. It was found that if the latter is used, it becomes extremely difficult to remove the residual ethanol from the product. 2. Sometimes it is difficult to dissolve the crude product in 35 mL of 1:1 MeOH2CHCl3. In such cases, a little pure MeOH could be added to help the 267 dissolution. Alternately, the mixture could be heated at ca. 30 °C to aid the dissolution. . The side-product was collected, subjected by rotary evaporation to dryness and high vacuum (0.1 mm Hg) for 2 hours. Its weight was 21 mg, and 1H NMR analysis showed a mixture of unidentified products. . The product, when spotted on a TLC and observed under short wave UV (254 nm), is an intense purple spot. . Sometimes, the VAPOL hydrogenphosphate obtained after column chromatography did not dissolve in CHZCIZ to give a clear solution. In such cases, the crude product should be left on high vacuum (0.1 mm Hg) overnight again, which might solve the problem. If not, then the precipitation should be carried out with the emulsion obtained on the addition of CH2CI2 to the crude product — it was found that it proceeded just fine even if a clear solution was not obtained. . It has been observed in some reactions72 that lower asymmetric inductions are obtained if the VAPOL hydrogenphosphate is not properly dried. CH2Cl2, NEt3 POClg, DMAP TfNHz, EtCN 010 25 °C,2hk 100 °C, 12": 70% (1.9 9 product) (R)-VAPOL (R)-N-trifly| VAPOL phosphoramide (R)-N-triflyl VAPOL phosphoramide 92. To a 100 mL RBF, flame-dried and cooled under Argon, was added (R)-VAPOL (2 g, 3.72 mmol) and dry CH2Cl2 (20 268 mL) to obtain a clear solution. The RBF was fitted with a rubber septum and an Argon balloon. It was then cooled to 0 °C in an ice-bath. Thereafter, dry NEt3 (3.62 mL, 26 mmol) and POCI3 (0.42 mL, 4.46 mmol) were added sequentially via a syringe, which was followed by the addition of DMAP (0.91 g, 7.44 mmol), all at 0 °C. The reaction flask was then warmed up to room temperature, and stirred for 2 h. Thereafter, TfNH2 (1.11 g, 7.44 mmol) and distilled EtCN (20 mL) were added, and a water condenser (flame-dried and cooled under Argon separately) was attached. The reaction mixture was then heated at 100 °C for 12 h and cooled down to room temperature thereafter. For the work-up, 100 mL water and 150 mL diethyl ether were then added, and the mixture extracted. The aqueous layer was extracted with 2 X 100 mL ether, the organic layers combined and washed with 300 mL sat. NaHCOa solution, 2 X 300 mL 4N HCI, dried over Na2S04, filtered through a pad of Celite and subjected to rotary evaporation and high vacuum (0.1 mm Hg) to afford the crude product 92 as a light brown solid. Crude TLC (EtOAc) showed a long product streak in the middle of the TLC plate and a baseline impurity spot. For purification thus, the crude product was dissolved in EtOAc, flushed through a glass frit packed with 1:1 Celitezsilica gel and rinsed with EtOAc. Different fractions were collected and analyzed by TLC. All product fractions showed absence of the baseline impurity. This process was repeated if the fractions were not pure and contained the baseline impurity. All fractions were collected, subjected to rotary evaporation and high vacuum. The pure product was then subjected to precipitation. It was dissolved in a minimum amount of CHzclz and an excess of pentane was added to precipitate 269 the product. It was then filtered off a Buchner funnel; the solid product was collected and subjected to high vacuum. This precipitation cycle was repeated until 1H NMR analysis indicated complete (or almost complete) removal of all residual solvent peaks. This process thus afforded the pure product 92 as a white solid (mp. decomposes >250 °C) in 70% isolated yield (1.9 g, 2.60 mmol). Spectral data for 92. 1H NMR (DMSO-~06, 500 MHz) 5 6.43 (t, 4H, J : 7.8 Hz), 6.96 (t, 4H, J = 7.6 Hz), 7.11 (t, 2H, J = 7.5 Hz), 7.62-7.73 (m, 6H), 7.88- 7.96 (m, 4H), 8.03-8.06 (m, 2H), 9.67-9.69 (m, 1H), 9.91 (d, 1H, J = 8.5 Hz); ”C NMR (DMSO-06, 125 MHz) 6 120.24 (CF3 (q), J = 323.6 Hz), 121.40, 121.17, 121.42, 121.44, 125.98, 125.99, 126.43, 126.49, 126.57, 126.58, 126.64, 126.68, 126.73, 126.77, 126.91, 126.92, 126.94, 127.52, 127.53, 128.28, 128.36, 128.48, 128.68, 128.73, 128.85, 128.92, 128.95, 132.77, 133.96, 134.00, 139.18, 139.33, 140.54, 140.59, 147.91 (d, 10, J = 8.7 Hz), 148.96 (d, 1c, J : 11 Hz); 3‘P NMR (CDCI3, 121 MHz) 5 1.07 (s); 19F NMR (CDCI3, 283 MHz) 5 -79.69 (3); IR (thin film) 3424s, 1653m, 1635m, 1213w cm"; Mass spectrum: m/z (% rel intensity) (MI) 730 (100), 630 (3); HRMS calcd for C41H24N05F3PS (M-H, ESl-) m/z 730.1065, meas 730.1080; [51230 : 4761 (c 1.0, CH2CI2) for (R)-N-triflyl VAPOL phosphoramide 92. 270 iPr HZNOZS‘QiPr CH2Cl2, N513 iPr POCI3, DMAP EtCN 0to25°c,2h__ 100°C,12h _ 73% 1 1 2 N-TRIP-benzene sulfonyl VAPOL phosphoramide (8)-N-(2, 4, 6-triisopropylbenzene sulfonyl) VA POL phosphoramide 1 12. This was prepared in the same manner as the preparation of the (R)-N-triflyl VAPOL phosphoramide 92 described above. The reaction and work-up was identical, but the purification was different. Thus, (8)-VAPOL (0.30 g, 0.56 mmol) was reacted and worked-up accordingly to afford crude 112. After work-up, crude TLC showed presence of 2,4,6-triisopropylbenzene sulfonamide. Thus, the crude solid product 112 was subjected to column chromatography with an eluent system of 1:3 EtOAc:hexanes to elute the sulfonamide first (R; = 0.3). Once the sulfonamide was completely eluted from the column (as judged by TLC), the column was flushed with EtOAc to elute the product 112. This afforded the pure product 112 as a light brown solid (mp. decomposes >250 °C) in 73% isolated yield (0.35 g, 0.41 mmol). Spectral data for 112: 1H NMR (DMSO-06, 500 MHz) 5 0.91 (t, 12H, J : 7.1 Hz), 1.20 (t, 6H, J = 6.8 Hz), 2.81-2.87 (m, 1H), 4.42-4.50 (m, 2H), 6.37 (d, 2H, J = 7.1 Hz), 6.44 (d, 2H, J = 7.1 Hz), 7.52 (t, 1H, J = 7.1 Hz), 7.56 (d, 2H, J = 3.4 Hz), 7.64-7.68 (m, 2H), 6.93 (t, 4H, J = 7.3 Hz), 6.97-7.02 (m, 3H), 7.06-7.10 271 .4!) ‘2‘"... IF fl'..-"- (m, 2H), 7.81-7.87 (m, 3H), 7.89-7.94 (m, 2H), 8.00-8.02 (m, 1H), 9.55 (d, 1H, J : 8.8 Hz), 9.90-9.92 (m, 1H); ”C NMR (DMSO-06, 125 MHz) (1 sp2 carbon missing) 5 23.72, 23.75, 24.52, 24.81, 28.02, 33.37, 121.48, 121.50, 121.62, 121.65, 122.20, 125.68, 125.90, 126.03, 126.16, 126.48, 126.60,126.65, 126.86, 126.95, 127.01, 127.02, 127.34, 127.41, 127.97, 128.15, 128.38, 128.87, 128.91, 129.04, 129.35, 132.52, 132.73, 133.72, 133.79, 139.51, 139.67, 140.51, 140.54, 142.17, 142.20, 147.64, 148.33, 148.91, 148.98, 148.94 (d, 1c, J = 9.2 Hz), 150.02 (d, 10, J : 10.9 Hz); 3‘P NMR (CDCI3, 121 MHz) 5 0.78 (3); IR (thin film) 5 3414s, 3057w, 2961m, 1626s, 15993, 12263, 11263 cm"; Mass spectrum: m/z (% rel intensity) (M+1)+ 866 (100), 301 (60); HRMS calcd for 055H47N05PS (M-H, ESI- -) m/z 864. 2913, meas 864.2951; [(1]230= +270. 5 (c1 .0, CH2CI2) for (3)-112. WQM. 00 CH2CI2, NEt3 POCI3 DMAP EtCN O 0to25°c 2h: 100°C 12h _ Ph \ '30 V N’ 37% N02 4 113 (8)-VAPOL N-nitrobenzene sulfonyl VAPOL phosphoramide (S)-N-(4-nitrobenene sulfonyl) VAPOL phosphoramide 1 13. This was prepared in the same manner as the preparation of the (R)-N-triflyl VAPOL phosphoramide 92 described above. The entire process was similar, except that the precipitation was not done. Thus, (8)-VAPOL (0.30 g, 0.56 mmol) was reacted and purified accordingly to afford the pure product 113 as a yellow solid (mp. decomposes >250 °C) in 37% isolated yield (0.16 g, 0.21 mmol). 272 Spectral data for 113: 1H NMR (DMSO-06, 500 MHz) 5 6.29 (d, 2H, J : 7.3 Hz), 6.36 (d, 2H, J: 7.3 Hz), 6.91 (q, 4H, J = 7.9 Hz), 7.06-7.09 (m, 2H), 7.48 (d, 2H, J : 8.8 Hz), 7.54 (s, 1H), 7.58 (s, 1H), 7.61-7.72 (m, 4H), 7.84-7.94 (m, 6H), 8.02-8.06 (m, 2H), 9.67 (d, 1H, J = 8.1 Hz), 10.05 (d, 1H, J : 8.5 Hz); 13c NMR (DMSO-06, 125 MHz)6 121.20, 121.46, 122.95, 124.42, 126.01, 126.09, 126.17, 126.35, 126.50, 126.56, 126.60, 126.66,126.73, 126.76, 126.81, 127.03, 127.19, 127.35, 127.45, 128.17, 128.44, 128.53, 128.57, 128.82, 128.87, 128.98, 129.06, 129.35, 132.66, 132.72, 133.79, 133.83, 139.18, 139.24, 140.41, 140.48, 147.33, 148.30 (d, 10, J : 9.9 Hz), 149.10 (d, 10, J: 10.8 Hz), 153.18; 31P NMR (CDCI3, 121 MHz) 6 -0.11 (3); Mass spectrum: m/z (% rel intensity) (M-1)' 783 (100), 771 (7); HRMS calcd for C46H23N207PS (M-H, ESl-) m/z 783.1355, meas 783.1342; [61230: +257.4(c1 .0 MeOH) for (S) 1.13 l a) Pd(OAc)2( (2 5 mol%) Ph OAc CS2CO3, DMF, 110 °C, 24 h b) A020, pyridine 00 Ph 25 °C, overnight Ph 117 118 1. 2 equiv 75% (over 2 steps, 6 9 product) average of 3 runs 3,8-diphenylnaphthalen-1-yl acetate 118; A 250 mL round bottom flask, equipped with a magnetic stir bar and a water condenser, was flame dried and cooled under Argon. To the flask was added 032C03 (14.81 g, 45.45 mmol, 2 equiv), and the assembly was then heated at 150 °C for 2 h under high vacuum (0.1 mm Hg). This was subsequently cooled to room temperature, and the VANOL monomer (5.00 g, 22.73 mmol, 1 equiv) was added, which was followed by the addition of Pd(OAc)2 (127.5 mg, 0.57 mmol, 0.025 equiv), DMF (120 mL) 273 and iodobenzene (3.04 mL, 27.28 mmol, 1.2 equiv). The assembly was then fitted with a rubber septum and an Argon balloon, and stirred in an oil bath at 110 °C for 24 h. The reaction mixture was subsequently cooled to room temperature, and added to a separatory funnel. Also added to the funnel were 200 mL EtOAc, 200 mL water and 50 mL brine solution. The layers were separated, the aqueous layer extracted with 4 x 200 mL EtOAc, the organic layers were combined, and washed with 2 x 500 mL water, 2 x 500 mL 0.5 N HCI, and brine. The organic layer was dried over Na2804, filtered through a pad of Celite, subjected to rotary evaporation till dryness and finally to high vacuum (0.1 mm Hg) overnight to afford the crude intermediate product. To the flask containing the crude product was then added pyridine (120 mL) to dissolve the crude product. The flask was equipped with a rubber septum and an Argon balloon. AC2O (11.00 mL, 113.65 mmol, 5 equiv) was then added slowly via a syringe and the reaction mixture stirred at room temperature for 12 h. The reaction mixture was added to a separatory funnel, with 700 mL dichloromethane. This was then extracted with 4 x 700 mL 1 N HCI, the organic layers combined, washed with brine, dried over Na2804, filtered through a pad of Celite, subjected to rotary evaporation till dryness and finally to high vacuum to afford crude product 118. Column chromatography with regular silica gel and an eluent system of 1:19 EtOAc:hexanes afforded pure 118 as a light yellow solid in 76% isolated yield (5.86 g, 17.34 mmol). Data for 118: R = 0.24 (1 :19 EtOAc:hexanes); 1H NMR (CDCI3, 500 MHz) 5 1.38 (s, 3H), 7.25 (dd, 1H, J: 1.2, 7.1 Hz), 7.34-7.51 (m, 10H), 7.68-7.70 (m, 274 2H), 7.93 (d, 1H, J : 8.3 Hz), 8.02 (d, 1H, J = 1.8 Hz); 13c NMR (CDCI3, 125 MHz) 5 19.72, 119.83, 123.85, 124.67, 125.86, 126.60, 127.28, 127.62, 127.73, 128.60,128.89,129.47, 130.19, 136.02, 137.30.138.45, 139.75, 143.40, 147.17, 169.86; lR (thin film) 3055w, 3028w, 17853, 1367m, 12033 cm"; Mass spectrum: m/z (% rel intensity) M“ 338 (10), 297 (28), 296 (100); HRMS calcd for C24H1902 (M+H, ESl+) m/z 339.1385, meas 339.1393; light yellow solid, mp. 117-119 °C. K2003 Ph OAC CH2Cl22HZO:MeOH Ph OH ‘ . 25°C, overnight_ ‘I i C E Ph Ph 118 119 92% (5 9 product) average of 3 runs 3,8-diphenylnaphthalen-1-ol 119. To a 500 mL round bottom flask, fitted with a magnetic stir bar, was added compound 118 (5.76 g, 17.04 mmol, 1 equiv) and dry dichloromethane (25 mL) to obtain a clear yellow solution. To this was added slowly a clear solution of K2C03 (4.71 g, 34.08 mmol, 2 equiv) in water (18 mL). To the reaction flask was then added MeOH (110 mL), and the reaction mixture was stirred at room temperature for 15 h. During the course of the reaction, the color of the solution changed from yellow to an intense green and finally to light brown/orange, and salts precipitated out. For the work-up, the reaction mixture was added to a separatory funnel, and 150 mL of water and 150 mL dichloromethane were also added. The layers were separated, and the aqueous layer was washed with 3 x 150 mL dichloromethane and 2 x 150 mL diethylether. The organic layers were combined, washed with brine solution, dried over Na2804, filtered through a pad of Celite, subjected to rotary 275 evaporation till dryness and finally to high vacuum to afford crude product 119. Column chromatography with regular silica gel and an eluent mixture of 1:19 EtOAc:hexanes afforded pure 119 as a colorless oil in 94% isolated yield (4.80 g, 16.22 mmol). Data for 119: R = 0.22 (1:19 EtOAc:hexanes); 1H NMR (CDCI3, 500 MHz) 5 5.47 (s, 1H), 7.18-7.20 (m, 2H), 7.36 (ft, 1H, J = 1.2, 7.4 Hz), 7.44-7.48 (m, 3H), 7.50-7.54 (m, 5H), 7.70-7.72 (m, 3H), 7.90 (dd, 1H, J : 1.0, 8.3 Hz); “’0 NMR (CDCI3, 125 MHz) 6 111.19, 118.86, 120.46, 125.30, 127.24, 127.53, 128.45, 128.66, 128.80, 129.02, 129.04, 129.46, 135.95, 136.11, 139.58, 140.45, 141.12, 153.34; IR (thin film) 34903, 3055w, 1628m, 1496m, 1373m cm"; Mass spectrum: m/z (% rel intensity) M+ 296 (100); HRMS calcd for 022H170 (M+H, 0‘ Ph Ph OH neat, air 200 °C, 60 h _ P“ 0” P“ 0 Ph 119 0 120 53% (2.5 9 product) average of 3 runs ESl+) m/z 297.1279, meas 297.1274; colorless oil. 3,3',8,8'-tetraphenyl-2,2'-binaphthyl—1,1'-diol (racemic 8,8’-Ph2 VANOL) 120. The monomer 119 (4.65 g, 15.71 mmol) was dissolved in diethylether and divided equally into 5 glass test tubes (18 d x 150 h mm). The diethylether in all test tubes was then evaporated by heating slightly on a water bath in a fume hood. All test tubes were fitted with magnetic stir bars, and subsequently heated 276 ' ‘2 rtxb. in an oil bath at 200 °C with rapid stirring for 60 h. The test tubes were then allowed to cool down to room temperature, the crude product in the test tubes dissolved in dichloromethane, combined, and subjected to rotary evaporation till dryness and finally to high vacuum to afford crude product 120. Careful column chromatography with regular silica gel and an eluent mixture of 1:19 EtOAc:hexanes afforded pure 120 as a light yellow solid in 54% isolated yield (2.50 g, 4.24 mmol). Data for 120: R: 0.15 (1 :19 EtOAc:hexanes); 1H NMR (CDCI3, 500 MHz) 6 5.46 (s, 2H), 6.98 (d, 2H, J = 7.2 Hz), 7.00-7.02 (m, 4H), 7.11 (t, 4H, J = 7.5 Hz), 7.14-7.17 (m, 4H), 7.30-7.45 (m, 12H), 7.74 (d, 2H, J = 8.4 Hz); 13c NMR (DMSO-06, 125 MHz) 6 117.46, 120.64, 121.17, 125.16, 125.84, 126.30, 126.88, 127.06, 127.58, 128.57, 128.63, 129.39, 135.05, 138.49, 140.89, 141.23, 144.18, 152.20; IR (thin film) 3524s, 3053w, 1568m, 1493m, 13483 cm"; Mass spectrum: m/z (% rel intensity) M“ 590 (100), 295 (44); HRMS calcd for C44H3102 (M+H, ESl+) m/z 591.2324, meas 591.2309; light yellow solid, mp. 222-226 °C. 0 ph CuCl(1.7 equiv) (—)-sparteine (3.5 equiv) F’h OH MeOH, CH2Cl2, 25 °C _ Ph OH ' CO M. 120 121 (S)-8,8'-Ph2VANOL 62% (3 9 product), >99.9% ee average of 2 runs 277 sin z'-‘W l (8)-3,3',8,8'-tetraphenyl-2,2'-binaphthyl—1,1'-diol 121. A 250 mL round bottom flask was flame dried and cooled under Argon. After the flask had cooled to room temperature, it was opened to air. To the flask were then added CuCI (1.38 g, 13.9 mmol, 1.7 equiv), MeOH (125 mL), and (-)-sparteine (6.64 mL, 28.88 mmol, 3.5 equiv), and this mixture was sonicated open to air in an ultrasound water bath at room temperature for 1 h. A dark green solution was obtained at this stage; the flask was then fitted with a rubber septum, and the solution was deoxygenated by bubbling in Argon via a metallic needle (1 h inside the solution and 0.5 h above the solution). A different 1 L round bottom flask fitted with a magnetic stir bar was flame dried and cooled under Argon. To this flask was added the racemic ligand 120 (4.9 g, 8.3 mmol, 1 equiv), which was dissolved in 400 mL dry dichloromethane to obtain a clear yellow solution. The flask was then fitted with a rubber septum, and the solution was deoxygenated with Argon in a similar way as above. The copper-sparteine complex prepared above was added to this 1 L reaction flask via a cannula under Argon pressure. The cannula was replaced with an Argon balloon; the flask was sonicated in an ultrasound water bath for 15 min, covered with aluminum foil, and subsequently stirred at room temperature with a magnetic stirrer for 3 h. The reaction mixture was then quenched with 70 mL aq. sat. NaHCOa solution, stirred for 10 min and then added to a separatory funnel, which was followed by the addition of 200 mL water. The layers were separated, the aqueous layer extracted with 3 x 200 mL dichloromethane, the organic layers combined, dried over NaZSOa, filtered through a pad of Celite, subjected to rotary 278 evaporation till dryness and finally to high vacuum to afford a dark green crude product. This was dissolved in a minimum amount of dichloromethane, and subjected to flash column chromatography with regular silica gel and dichloromethane as the eluent, to separate the copper salts and other baseline impurities. This afforded again the crude product 121, which was subjected to careful column chromatography with regular silica gel and an eluent mixture of 1:9 EtOAc:hexanes to afford pure 121 as a light yellow solid (mp. 130-134 °C) in 60% isolated yield (2.92 g, 4.95 mmol). The optical purity of the product, (5)-121, was determined to be >99.9% ee by chiral HPLC analysis (Chiralcel OD-H column, hexanes:2-propanol 99:1, flow rate 0.5 mUmin, 222 nm). Retention times were 12.15 min (major enantiomer) and 19.37 min (minor enantiomer). Optical rotation: [0:12:39 = -43.2 (c 1.0, CH2CI2) for >99.9% ee (8)-121. POCI3, pyridine 25 °C, 24 h _ (S)-8,8’-Ph2 VANOL phosphorus oxychloride 122. A 10 mL round bottom flask, fitted with a magnetic stir bar, was flame dried and cooled under Argon. To this flask was then added the ligand 121 (100 mg, 0.17 mmol), which was followed by the addition of pyridine (1 mL) and POCla (32 uL, 0.34 mmol). The 279 flask was fitted with a rubber septum and an Argon balloon, and stirred at room temperature for 24 h, at which the reaction was judged complete by TLC. The reaction mixture was then diluted with dichloromethane, filtered through a pad of Celite, subjected to rotary evaporation till dryness and finally to high vacuum overnight. Dichloromethane was added to the thus obtained solid crude product to get a slurry, which was again filtered through a pad of Celite. The resulting solution was subjected to rotary evaporation till dryness and finally to high vacuum to afford the crude product 122. This was then subjected to column chromatography with regular silica gel and an eluent mixture of 1:9 EtOAc:hexanes to afford pure product 122 as a white foamy solid in 56% isolated yield (64 mg, 0.095 mmol). Data for 122- R : 0.17 (1 :9 EtOAc:hexanes); 1H NMR (CDCI3, 500 MHz) 5 6.54 (dd, 4H, J = 7.3, 11.4 Hz), 7.02 (q, 4H, J = 7.6 Hz), 7.17 (q, 2H, J = 7.5 Hz), 7.27-7.39 (m, 6H), 7.47-7.54 (m, 5H), 7.57-7.65 (m, 5H), 7.84 (t, 2H, J = 7.7 Hz); ”C NMR (CDCI3, 75 MHz) (2 sp2 carbons missing) 5 122.62 (d, 1c, J = 3.4 Hz), 123.40 (d, 1c, J = 2.9 Hz), 124.49 ((1, 10, J = 2.9 Hz), 124.58 (d, 1c, J : 3.4 Hz), 126.37, 126.64, 126.82, 126.91, 127.23, 127.77, 127.84, 127.94, 127.98, 128.18, 128.21, 128.50, 128.55, 128.58, 129.02, 129.15, 129.37, 129.96, 130.69, 130.97, 131.23, 135.55, 135.57, 135.62, 135.65, 138.16, 138.20, 138.35, 138.37, 139.25, 139.92, 139.95, 140.14, 140.17, 142.06, 142.58, 144.67 (d, 1C, J = 11.5 Hz), 144.91 (d, 10, J = 13.2 Hz); 31P NMR (CDCI3, 121 MHz) 6 7.30 (3); IR (thin film) 3057w, 1314s, 7603 cm"; Mass spectrum: m/z (% rel intensity) M“ 673 (15, 37Cl), 672 (40, 37CI), W 671 (42, 35CI), 670 (100, 35CI); HRMS calcd for C44H2903PCI 280 (M+H, ESl+) m/z 671.1543, meas 671.1572; [01230 = +3137 (c 1.0, CH2CI2) for (8)-122; white foamy solid, mp. decomposes 180-200 °C. a) POCI3, pyridine 25 °C, 24 h b) H20, 25 °C, 24 h (S)-8,8’-Ph2VANOL phosphoric acid 123. A 50 mL round bottom flask, fitted with a magnetic stir bar, was flame dried and cooled under Argon. To this flask was added the ligand 121 (442 mg, 0.75 mmol) and pyridine (3 mL) to obtain a clear solution. The flask was then fitted with a rubber septum and an Argon balloon. POCI3 (140 IIL, 1.5 mmol) was then added dropwise via a syringe, and the resulting reaction mixture was stirred at room temperature for 24 h. Water (3 mL) was then added dropwise via a syringe, and the reaction mixture stirred at room temperature for an additional 24 h. The reaction mixture was then added to a separatory funnel, along with 75 mL dichloromethane. This was washed seven times with 75 mL 1 N HCI, once with brine solution, dried over Na2SO4, filtered through a pad of Celite, subjected to rotary evaporation till dryness and finally to high vacuum to afford crude 123. The crude product was subjected to column chromatography with regular silica gel and an eluent mixture of 1:9 MeOH:CH20I2. The product fractions were collected, subjected to rotary evaporation till dryness and finally to high vacuum 281 to afford product 123. This was dissolved in a minimum amount of dichloromethane, and precipitated with the addition of excess pentane. Filtration off a Bi'Ichner funnel afforded product 123 again. This was again dissolved in dichloromethane, washed four times with 100 mL 1 N HCI, dried over Na2804, filtered through a pad of Celite, subjected to rotary evaporation till dryness and finally to high vacuum. The solid 123 thus obtained was again dissolved in a minimum amount of dichloromethane, and precipitated with the addition of excess pentane. Filtration once again off a Bilchner funnel afforded the final pure product 123 as a white solid in 69% isolated yield (335 mg, 0.51 mmol). Data for 123: R : 0.3 (streak, 1:9 MeOH:CH20l2); 1H NMR (CDCI3, 500 MHz) 6 6.50 (d, 4H, J = 7.2 Hz), 6.96 (t, 4H, J = 7.8 Hz), 7.11 (t, 2H, J = 7.4 Hz), 7.19 (t, 2H, J = 7.2 Hz), 7.25-7.30 (m, 6H), 7.36-7.37 (m, 4H), 7.43-7.47 (m, 4H), 7.73 (d, 2H, J = 7.6 Hz); 1“‘c NMR (DMSO-d6, 125 MHz) 5 123.26, 124.58, 125.72, 125.99, 126.17, 126.57, 127.59, 127.72, 128.11, 128.69, 130.06, 130.23, 135.06, 138.36, 139.46, 139.52, 142.99, 146.58; 31P NMR (DMSO-06, 121 MHz) 6 0.91 (3); IR (thin film) 3446s, 3055w, 1495m, 13343, 12633 cm'1 ; Mass spectrum: m/z (% rel intensity) M“ 652 (100); HRMS calcd for C44H3004P (M+H, ESl+) m/z 653.1882, meas 653.1863; [61230 : +3624 (c 1.0, CH2Cl2) for (3)-123; white solid, mp. decomposes >230 0C. 282 a) NEt3, DMAP CH2Cl2, POCI3 0 - 25 °C, 1 h b) TfNH2, EtCN reflux, 24 h 121 (S)-8,8’-Ph2VAN0L N-triflyl phosphoramide 124. A 25 mL round bottom flask, fitted with a magnetic stir bar, was flame dried and cooled under Argon. To the flask was added the ligand 121 (100 mg, 0.17 mmol, 1 equiv) and 2 mL dry dichloromethane to obtain a clear yellow solution. The flask was fitted with a rubber septum and an Argon balloon, and cooled to 0 °C in an ice bath. Triethylamine (165 ML, 1.19 mmol, 7 equiv) and POCI3 (19 IIL, 0.20 mmol, 1.2 equiv) were added via a syringe, followed by the addition of DMAP (42 mg, 0.34 mmol, 2 equiv). The reaction was then allowed to warm up to room temperature, and stirred at room temperature for 1 h; TLC at this stage indicated complete consumption of 121. EtCN (2 mL) was added to the reaction flask, followed by the addition of TfNH2 (50 mg, 0.34 mmol, 2 equiv). A water condenser, separately flame dried and cooled under Argon, was then attached to the reaction flask, and the mixture heated at 100 °C in an oil bath for 24 h. The reaction mixture was allowed to cool to room temperature, and stirred at room temperature for an additional 12 h. For the work up, the reaction mixture was diluted with water and dichloromethane, and the layers were separated. The aqueous layer was 283 WW} 1.4.; .. ‘ . 'l extracted with dichloromethane, the organic layers were combined, washed with sat. NaHCOa once, 4 N HCI twice, dried over Na2804, filtered through a pad of Celite, subjected to rotary evaporation till dryness and finally to high vacuum to afford crude product 124. This crude product was subjected to column chromatography with regular silica gel and an eluent mixture of 1:9 MeOH:CH20l2. The product fractions were collected, subjected to rotary evaporation till dryness and finally to high vacuum to afford 124 again, which was subsequently subjected to yet another round of column chromatography with regular silica gel and an eluent mixture of 5:1 EtOAc:hexanes to afford product 124. The solid product obtained was dissolved in dichloromethane, washed twice with 4 N HCI, dried over Na2804, filtered through a pad of Celite, subjected to rotary evaporation till dryness and finally to high vacuum to afford solid product 124. This was finally dissolved in a minimum amount of dichloromethane, and precipitated with excess pentane, which upon filtration off a BI'Jchner funnel afforded the final pure product 124 as a white solid in 55% isolated yield (72 mg, 0.092 mmol). I Data for 124: R; = 0.3 (streak, 1:9 MeOHzCH2Cl2 as well as 5:1 EtOAc:hexanes); 1H NMR (CDCI3, 500 MHz) 6 5.46 (bs, 1H), 5.71 (bs, 1H), 6.47 (d, 2H, J = 7.3 Hz), 6.62 (d, 2H, J = 7.3 Hz), 6.84 (bs, 1H), 6.96 (t, 2H, J = 7.9 Hz), 7.02 (t, 3H, J = 7.9 Hz), 7.10-7.16 (m, 2H), 7.19 (d, 1H, J = 6.9 Hz), 7.31- 7.53 (m, 8H), 7.61 (s, 1H), 7.65-7.70 (m, 2H), 7.77 (d, 1H, J : 8.4 Hz), 7.87 (d, 1H, J = 7.4 Hz); 13C NMR (CDCI3, 125 MHz) (4 sp2 carbons and CF3 missing) 6 117.92, 118.03, 120.46, 120.57, 123.00, 124.32, 124.34, 124.75, 125.27, 126.23, 284 126.59, 126.80, 126.89, 126.97, 127.27, 127.75, 127.81, 127.87, 127.97,128.08, 128.36, 128.86, 129.42, 129.69, 130.52.131.58, 132.73, 135.59, 135.65, 136.42, 138.64, 139.34, 139.67, 140.14, 142.84, 145.19, 145.33, 145.41, 145.60, 145.68; 3‘13 NMR (CDCI3, 121 MHz) 5 2.82 (s); 191: NMR (CDCI3, 283 MHz) 5 -79.18 (s); IR (thin film) 34353, 3055w, 12153 cm"; Mass spectrum: m/z (% rel intensity) M+ 783 (<1), 572 (90), 246 (33), 39 (100); HRMS calcd for C45H28NOSF3PS (M-H, ESl-) m/z 782.1378, meas 782.1374; [(1]230 : +3095 (01.0, CH2Cl2) for (3)-124; white solid, mp. decomposes >255 °C. 285 Appendix F Experimental Information for Chapter Six 6.1 Asymmetric catalysis vla chiral dirhodium catalysts BINOL phosphoric acid 132 was prepared using an Organic Synthesis procedure.84 The Rh2(P02BlNOL)4 complex 133 was prepared using a procedure developed by Pirrung.85 Nosyliminoiodinane (NsN=lPh) was prepared according to a report by Muller.81 The preparation of VANOL phosphoric acid 93 has been detailed in Chapter 5. Rh2OAC4 CBH5CI, reflux, 36 h 81% 93 139 (8)-VANOL phosphoric acid The Rh2(P02VANOL)4 complex 139. A Soxhlet extractor (25 mL), flame dried and cooled under argon, was set up with a 1:1 mixture of sand:Na2C03 (1.59 g, 15 mmol, Na2C03) in the thlmble. Under an Argon flow, 93 (1.5 g, 3 mmol), RthA04 (92 mg, 0.21 mmol) and freshly distilled chlorobenzene (15 mL) were then added. The resulting green slurry was stirred at reflux (165 °C) for 36 h. It was then cooled to room temperature. Rotary evaporation of the solvent followed by applying high vacuum (0.1 mm Hg) afforded crude 139 as a green non-homogenous solid. Purification by column chromatography on regular silica 286 gel with an eluent mixture of ethyl acetate:hexanes (1:2) gave pure 139 as a green solid in 81 % isolated yield (370 mg, 0.17 mmol). It was found that these dirhodium complexes decompose slowly with regular silica gel chromatography. They were also found to decompose slowly (green to red color) under exposure to light and excessive heat. The assignment of the structure of 139 is tentative at best. Spectral data for 139: R; = 0.3 (streak, 1:2 ethyl acetate:hexanes); 1H NMR (CDCI3, 500 MHz) 6 6.49 (d, 4H, J = 7.0 Hz), 6.88 (t, 4H, J = 8.0 Hz), 7.04 (q, 4H, J = 7.5 Hz), 7.30 (t, 2H, J = 8.0 Hz), 7.48 (s, 2H), 7.70 (d, 2H, J = 8.5 Hz), 8.56 (d, 2H, J = 8.5 Hz); 13c NMR (CDCI3, 125 MHz) 5 122.27, 123.89, 125.92, 126.33, 126.59, 126.81, 127.03, 127.44, 127.71, 129.05, 133.96, 139.92, 140.29, 146.39 (t, 1c, J: 4.6 Hz). 2 mol% NS Rh (PO VANOL) 139 ' NsN=lPh + ph/\ 2 2 4 = N CH2CI2. 4 A MS Pl‘l’l—S 136 137 25 °C, 6 h 138 40%, 20% ee 1-(4-nitrophenylsulfonyl)-2-phenylazin'dine 138. To a 100 mL round bottom flask, flame dried and cooled under argon, was added sequentially: (S)- Rh2(P02VANOL)4 139 (44 mg, 0.02 mmol), dry CH2CI2 (10 mL), 4 A molecular sieves (6 g, activated previously at 190 °C under 0.1 mm Hg high vacuum for 4 h), styrene 137 (2.3 mL, 20 mmol) and 136 (404 mg, 1 mmol). The resulting green slurry was stirred at room temperature for 6 h. It was then filtered through a pad of Celite and washed exhaustively with CH2Cl2. Rotary evaporation of the solvent following by applying high vacuum (0.1 mm Hg) afforded crude aziridine 287 138 as an off-white solid. Purification by column chromatography on silica gel with an eluent mixture of diethyletherzhexanes (1:2) afforded the pure aziridine 138 as an off-white solid in 40% isolated yield (121 mg, 0.4 mmol). The optical purity of 138 was determined to be 20% ee by chiral HPLC analysis (Pirkle Covalent (R,R) Whelk-O1 column, 99:1 hexanes:2-propanol, 222 nm, flow rate 0.7 mL min"). Retention times: R; = 63 min (major enantiomer) and R; = 78 min (minor enantiomer). Spectral data for 138: R : 0.27 (1:2 diethyletherzhexanes); 1H NMR (CDCI3, 300 MHz) 6 2.54 (d, 1H, J = 4.5 Hz), 3.15 (d, 1H, J = 7.2 Hz), 3.94 (dd, 1H, J = 7.2, 4.5 Hz), 7.24-7.36 (m, 5H), 8.22 (d, 2H, J = 9.0 Hz), 8.41 (d, 2H, J = 8.7 Hz); "’0 NMR (CDCI3, 125 MHz) 5 36.51, 41.86, 124.31, 126.42, 128.71, 128.72, 129.14, 134.13, 143.96, 150.65; Mass spectrum: m/z (% rel intensity) 304 M” (<1), 167(4), 118 (100), 89 (15). 6.2 Organocatalytic asymmetric aziridination mediated by chiral Bronsted acid catalysts lmine 143 is a commonly known compound, and was prepared in a similar manner as the preparation of the benzhydryl imines 1 described in Chapter 2. ’Butyl diazoacetate 19 is commercially available from Aldrich, and can also be prepared according to previously reported procedures?"32 OMe O 20 mol% catalyst PMP toluene ' \ O * H991 = AN /\ o EtOZC N N2 -40 C (24 2) to rt (24 h) EtOZC COztBu 143 19 0 °C (24 h) to rt (24 h) 144 1.3 equiv 288 an" (2R,38)-2-tert-butyl 3-ethyl 1 -(4-methoxyphenyl)aziridine-2,3-dicarboxylate 144. A 5 mL round bottom flask, fitted with a magnetic stir bar, was flame dried and cooled under Argon. To this flask was sequentially added: the imine 143 (52 mg, 0.25 mmol), the catalyst 113 (39 mg, 0.05 mmol, 20 mol%), and dry toluene (1 mL). The flask was then fitted with a rubber septum and an Argon balloon, and was cooled to 0 °C with the help of a chiller. Diazoacetate 19 (46 mg, 0.325 mmol) was then added to the reaction flask, and the reaction mixture stirred at 0 °C for 24 h. The flask was allowed to warm up to room temperature, and the reaction mixture stirred at room temperature for an additional 24 h. Dilution with dichloromethane and hexanes, and subsequent rotary evaporation of the crude solution led to crude product 144. Column chromatography with regular silica gel and an eluent mixture of 1:5 EtOAc:hexanes afforded pure 144 as a light yellow oil in 60% isolated yield (48 mg, 0.15 mmol). The enantiomer for 144 has been assumed. The optical purity of 144 was determined to be 15% ee by chiral HPLC analysis (Chiralcel OD-H column, hexanes:2-propanol 95:5, flow rate 0.7 mL min' 1, 222 nm). Retention times were 9 min (minor enantiomer) and 10 min (major enantiomer). Data for 144: R; = 0.26 (1 :4 EtOAc:hexanes); 1H NMR (CDCI3, 500 MHz) 6 1.30 (t, 3H, J = 7.1 Hz), 1.47 (s, 9H), 2.88 (d, 1H, J: 6.9 Hz), 2.93 (d, 1H, J = 6.9 Hz), 3.72 (s, 3H), 4.21-4.28 (m, 2H), 6.75 (d, 2H, J = 8.8 Hz), 6.92 (d, 2H, J = 9.1 Hz); 13c NMR (CDCI3, 125 MHz) 5 14.11, 27.91, 43.18, 44.05, 55.41, 61.57, 82.43, 114.26, 120.88, 144.48, 156.08, 165.92, 167.11; IR (thin film) 29828, 289 2936m, 2837w, 1751vs, 1510s, 1369s, 1244s cm"; HRMS calcd for 017H24N05 (M+H, ESl+) m/z 322.1654, meas 322.1666; light yellow oil. 6.3 Asymmetric catalytic Darzens reaction The preparation of N-phenyldiazoacetamide 14a has been described in the experimental information for Chapter 3. The B3 catalysts were also prepared as described in the experimental information for Chapter 3. o 10 mol% (S)-VANOL-B3 catalyst 0 PhAO + (“\NHPI‘ = Ph“"A"’c0NHPh N2 toluene (0.1 M) 145 14a 0C(19h)t022 C(2h) 146 1.2 equiv 0.2 mmol (1 equiv) (2S,3S)-N,3-diphenyloxirane-2—carboxaml'de 146. A 5 mL round bottom flask, fitted with a magnetic stir bar, was flame dried and cooled under Argon. To this flask was then added benzaldehyde 145 (25 (IL, 0.24 mmol, 1.2 equiv) and 2 mL from a stock solution of the (3)-VANOL-B3 catalyst in toluene (corresponding to 10 mol% catalyst loading). The flask was fitted with a rubber septum and an Argon balloon, and was then cooled to 0 °C with a chiller. Diazoacetamide 14a (0.2 mmol, 32 mg) was then added in one portion, and the reaction mixture stirred at 0 °C for 19 h. This was allowed to warm up to room temperature, and stirred at room temperature for an additional 2 h. Dilution with hexanes and dichloromethane, followed by rotary evaporation of the crude reaction mixture afforded crude product 146. Column chromatography with regular silica gel and an eluent mixture of 1:3 EtOAczpetroIeum ether afforded approximately 97% pure product 146 as a white solid in 60% yield (29 mg, 0.12 mmol). The optical purity of 146 was determined to be 32% ee by chiral HPLC analysis (Chiralcel OD-H 290 column, hexanes:2-propanol 90:10, flow rate 1 mL min", 222 nm). Retention times were 9 min (major enantiomer) and 11 min (minor enantiomer). Data for 146:41 R; = 0.32 (1:3 EtOAczpetroleum ether); 1H NMR (CDCI3, 500 MHz) 5 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); 13C NMR (CDCI3, 125 MHz) 6 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, 2922w, 1672s, 1599m, 1529s, 14443 cm"; HRMS calcd for C15H14N02 (M+H, ESl+) m/z 240.1025, meas 240.1034; [qu30 = +3.7 (c 1.0, CH2CI2) on 32% ee (2S,3S)-146. Literature value:41 [0:123D = +191 (0 0.9, CHQClg) on 99% ee (23,33)-146; white solid, mp. 100-104 °C. 291 REFERENCES Ismail, F. M. D.; Levitsky, D. 0.; Dembitsky, V. M. Eur. J. Med. Chem. 2009, 44, 3373-3387. (a) Yudin, A. K. Aziridines and epoxides in organic synthesis, Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, 2006. (b) Tanner, D. Angew. Chem. Int. Ed. 1994, 33, 599-619. (c) Sweeney, J. B. Chem. Soc. Rev. 2002, 31, 247-258. (d) Watson, I. 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