EVOLVING TOWARDS A SUBSTRATE GENERAL ASYMMETRIC AZIRIDINATION REACTION AND ITS APPLICATION IN THE ENANTIOSELECTIVE SYNTHESIS OF SPHINGANINES AND PHYTOSPHINGOSINES By Munmun Mukherjee A DISSERTATION Submitted to Michigan State University in partial fulfillment of the requirements for the degree of Chemistry - Doctor of Philosophy 2013 ABSTRACT EVOLVING TOWARDS A SUBSTRATE GENERAL ASYMMETRIC AZIRIDINATION REACTION AND ITS APPLICATION IN THE ENANTIOSELECTIVE SYNTHESIS OF SPHINGANINES AND PHYTOSPHINGOSINES By Munmun Mukherjee The research in this dissertation involves methodology development and total synthesis of 'sphingoid bases'. In terms of methodology, a substrate general aziridination has been realized. This was done by the introducing MEDAM group as the most general N-protecting group for the aziridination reaction. This lead to the broadening of the substrate scope, which includes imines, prepared from electron rich and electron deficient aromatic aldehydes, and also from 1°, 2° and 3° aliphatic aldehydes. Thereafter, an unprecedented catalyst-controlled aziridination reaction of chiral aldehydes was developed and then subsequently applied towards the syntheses of natural and unnatural isomers of phytosphingosines. These natural products are involved in nearly all aspects of cell regulation including differentiation, proliferation, adhesion, signal transduction and neuronal repair. In addition, new strategies towards ring opening of aziridines were developed which were utilized in the enantioselective synthesis of threosphinganines. The enantioselective syntheses of the erythro-sphinganines were achieved via Lewis acid mediated ring expansion of the N-Boc protected cis-aziridines. Copyright by MUNMUN MUKHERJEE 2013 To, My Parents and Teachers iv ACKNOWLEDGEMENTS Life is full of experiences and challenges. So far, graduate school has been the most challenging period of my life, which started six years ago upon my arrival to a different country thousand miles away from my own land and loved ones. It is very difficult to pursue a career in an unfamiliar environment unless one gets support from people surrounding oneself. I consider myself lucky to be part of the MSU Chemistry graduate program as its friendly environment helped me to grow as a scientist. I feel very fortunate to have Professor W. D. Wulff as my Ph.D advisor. It’s very difficult for me to express my gratitude for him in few words. His intellect and tremendous knowledge in chemistry helped me in every stage of my graduate life. I must admit that, till date, I have not came across a person who has so much patience as he has. In last six years, I have never seen him angry or irritated irrespective of the situation. Apart from chemistry, I also learnt a lot about life from his calm and composed nature. He provided us the most conducive environment to grow as an independent researcher and always encouraged us to pursue our own ideas. Wine is another interesting addition to my life in Prof. Wulff’s group. I will always miss our group gathering or post-group meeting wine party. I am very thankful to Professor Babak Borhan, one of my committee members. Due to his kind nature and efforts, I was allowed to apply to the graduate school even after all the application deadlines were over. This provided me the wonderful opportunity to pursue my graduate studies in MSU chemistry. His kind and friendly nature made him easily approachable. In fact, most of the graduate students are very comfortable to discuss their problems to Dr. Borhan and as usual, he always had some solutions to our problems. Also, it is worth mentioning v that he is an exceptional teacher. I owe him all my knowledge regarding spectroscopy oand organic synthesis. I would like to thank him for his support through out my graduate studies. I, also, would like to thank Professor Robert Maleczka for his kind nature. I must say that he is also a great teacher and I learnt a lot from him. He was very generous to offer us a very informative course namely, Special Topics in Organic Chemistry. The particular coursework exposed us to the minute details and intricacies of the synthetic organic chemistry. I would also like to thank Professor Aaron Odom for giving his precious time and suggestions as my committee member. I owe special thanks to Dr Dan Homes for his assistance in NMR related problems pertaining to the concept or the instruments. He is undoubtedly one of the biggest assets of MSU chemistry department. I would like to thank all my teachers from my high school and my colleges for their continuous support As I mentioned earlier, it was a great experience to be the part of Prof. Wulff’s group. In addition to the focused approach towards chemistry, the presence of many fabulous Wulff group members makes it one of the best groups. I was very lucky to meet Dr. Zhenjie Lu who helped me in my initial days in the lab. I learnt a lot from her. Dr. Zhensheng Ding, an awesome person, was our entertainer in the group parties. Dr. Alex Predesus, Dr. Kostas Rampalakos and Dr. Aman Desai were really great group members with enormous knowledge. I was extremely fortunate to have Wynter Osminski, Dr. Dymtro Berbasov and Dr. Anil Gupta as my lab mates. Wynter Osminski has been like a younger sister to me whom I will miss a lot. She is a fun person to talk to and is always full of life. She helped me in many ways through out these years from taking me hospital to performing HRMS analysis for me. Dr. Dymtro Berbasov is a very talented person who is ready to help anyone at any moment. He is a great friend too. Another person, without whom this journey would not have been possible, is vi Dr. Anil Gupta. I would like to thank him for all his help and support throughout these years. He helped me in every possible way a person can be helped. His presence has been very helpful and inspiring during difficult times in my graduate life. He is an exceptional chemist and lab mate and I feel very fortunate to have him as my very close friend. I had great time with other group members like Victor Prutyanov, Dr. Mathew Vetticatt, Dr. Li Huang, Dr. Yong Guan, Dr. Nilanjana Majumdar, Hong Ren, Wenjun Zhao, Xin Zhang, Yubai Zhou and Xiaopeng Yin. I was fortunate to have these wonderful colleagues who were always ready for discussing chemistry and helping each other. Dr. Li Huang and Hong Ren were the among most hard working lab mates who always inspired others. I would like to thank my undergraduate student James Woods for his contribution to my research and for being a wonderful friend. Other group members from Prof. Borhan’s group and Prof. Maleczka’s group have always been very helpful. Specifically, I would like to thank Dr. Aman Kulshrestha for her help and efforts in my initial days. Also, I would like to thank my friend, Dr. Tejas Pathak for his help and support. Although I do not want to miss a single name, it is very difficult to mention all of them. I am really thankful to all my other friends from MSU and my college and school. I must say that they all have a significant contribution in my life or making my life happy and easy. Last but not the least, I would like to thank my parents. It would have been impossible for me to study so far without their constant support. My father, Rathindra Nath Mukherjee has been my inspiration and my teacher throughout my life. He is the best person I have in my life. My mother Rita Mukherjee is the kindest person I know. This journey would not have been possible for me without their sacrifice and I do not have enough words to express my gratitude to them. I dedicate my dissertation to my mother and father. vii TABLE OF CONTENTS LIST OF TABLES ......................................................................................................................... xi LIST OF FIGURES ..................................................................................................................... xiii LIST OF SCHEMES .....................................................................................................................xv CHAPTER 1 AZIRIDINE: AN IMPORTANT MOTIF IN ORGANIC SYNTHESIS   1.1   Biologically important alkaloids containing an aziridine core .............................................. 1   1.2   Aziridines as chiral ligands .................................................................................................... 4   1.3   Aziridines as chiral auxiliaries ............................................................................................... 7   1.4   Synthesis of natural products via aziridine intermediates...................................................... 8   1.5   Aziridines as the precursor for 1,2-amino alcohols ............................................................. 10   1.6   Catalytic asymmetric synthesis of aziridines ....................................................................... 12   1.7   Brønsted acid catalyzed asymmetric Aziridination reaction ............................................... 13   1.8   Conclusions .......................................................................................................................... 21   REFERENCES .................................................................................................................... 22 CHAPTER 2 EVOLUTION OF A SUBSTRATE GENERAL CATALYIC ASYMMETRIC AZIRIDINATION REACTION WITH N-MEDAM IMINES 2.1   Introduction .......................................................................................................................... 26   2.2   Study towards developing a universal N-protecting group .................................................. 28   2.3   MEDAM group: a universal protecting group ..................................................................... 32   2.4   Catalytic asymmetric aziridination with MEDAM imine 36 ............................................... 34   2.5   Simplification of the aziridination protocol ......................................................................... 38   2.6   Deprotection of MEDAM group.......................................................................................... 47   2.7   Conclusions .......................................................................................................................... 52   APPENDIX . ........................................................................................................................ 55   REFERENCES .................................................................................................................. 109   CHAPTER 3 APPLICATION OF THE CATALYIC ASYMMETRIC AZIRIDINATION REACTION: SYNTHESIS OF ALL FOUR ISOMERS OF SPHINGANINE 3.1   Biological properties of sphinganies .................................................................................. 111   viii 3.2   3.3   3.4   3.5   Previous approaches towards the synthesis of sphinganines ............................................. 113   Retro-synthetic analysis of sphinganines ........................................................................... 116   Synthesis of aziridine 37l via catalytic asymmetric cis-aziridination ................................ 116   Synthesis of aziridine starting material via multi-component catalytic asymmetric cisaziridination ....................................................................................................................... 119 3.6   Ring opening of cis-aziridine with oxygen nucleophile .................................................... 122   3.7   Synthesis of D and L-threo-sphinganines .......................................................................... 127   3.8   Synthesis of erythro-sphinganine ...................................................................................... 131   3.9   Study towards synthesis of mycestericin E........................................................................ 139   3.10    Retro-synthetic analysis of mycestericin E ........................................................................ 139   3.11    Synthesis of aziridine 123 via multi-component aziridination reaction ............................ 140   3.12    Conclusions ........................................................................................................................ 142   APPENDIX . ...................................................................................................................... 143 REFERENCES .................................................................................................................. 188 CHAPTER 4 THE EFFECT OF CHIRAL SUBSTRATES IN THE CATALYIC ASYMMETRIC AZIRIDINATION REACTION 4.1   Introduction ........................................................................................................................ 192   4.2   Proposed model and the predicted stereochemical outcome for the AZ reaction of α-chiral imines ................................................................................................................................. 194   4.3   Synthesis of Chiral aldehydes ............................................................................................ 197   4.4   Aziridination reaction with chiral imine (R)-129a: a substrate controlled reaction ......... 199   4.5   Aziridination reaction with chiral aldehyde (R)-130b: a catalyst controlled reaction ...... 206   4.6   Aziridination reaction with chiral aldehyde (S)-130c: a catalyst controlled reaction ....... 209   4.7   Aziridination reaction with the acetonide of glyceraldehyde (R)-140: a catalyst controlled reaction ............................................................................................................................... 211   4.8   Aziridination reaction with Garner’s aldehyde (S)-147: a catalyst controlled reaction.... 214   4.9   Aziridination reaction with aziridine 2-carboxaldehyde (S, S)-148: a catalyst controlled reaction ............................................................................................................................... 216   4.10    Aziridination reaction with 2-phenylpropanal (S)-150: The problem of racemization of the corresponding intermediate imine (S)-152 and its solution ............................................... 218   4.11    Aziridination reaction of chiral aldehydes with a β-chiral center: catalyst controlled reaction ............................................................................................................................... 222   4.12    Conclusions ........................................................................................................................ 226   APPENDIX . ...................................................................................................................... 227   REFERENCES .................................................................................................................. 282 CHAPTER 5 STUDIES TOWARDS THE ASYMMETRIC SYNTHESIS OF PHYTOSPHINGOSINES   5.1   Introduction ........................................................................................................................ 285   5.2   Biological activity and previous syntheses of phytosphingosines ..................................... 285   5.3   Retro-synthetic analysis of phytosphingosines .................................................................. 292   5.4   Synthesis of chiral aldehyde (R)-192 via hydrolytic kinetic resolution of rac-epoxide .... 294   ix 5.5   Synthesis of aziridine precursor via multi-component catalytic asymmetric aziridination reaction of chiral aldehyde (R)-192. .................................................................................. 296   5.6   Studies towards the synthesis of phytosphingosines 75 .................................................... 301   5.7   Conclusions ........................................................................................................................ 309   APPENDIX . ...................................................................................................................... 310   REFERENCES .................................................................................................................. 335   x LIST OF TABLES Table 2.1 Catalytic asymmetric aziridination with alkyl imines 33, 38 and 55 ........................... 30   Table 2.2 Asymmetric aziridination with MEDAM imines 36 .................................................... 35   Table 2.3 Asymmetric aziridination with MEDAM imine 36 with Method B ........................... 40   Table 2.4 Catalytic asymmetric aziridination with MEDAM imine 36 with Method D ............. 44   Table 2.5 Deprotection of MEDAM aziridines 37 ...................................................................... 48   Table 3.1 Asymmetric aziridination with alkyl imine 36l ........................................................ 117   Table 3.2 Multi-component catalytic asymmetric aziridination with hexadecanal 77 ............. 120   Table 3.3 Ring opening of aziridine 37a with water in acidic medium .................................... 122   Table 3.4 Ring opening of aziridine 37a with water in acidic medium via deprotection of NMEDAM group ......................................................................................................... 124   Table 3.5 Synthesis of N-Boc-β-hydroxy-α-amino ester 96 from imine 36a without isolation of intermediates ............................................................................................................ 125   Table 3.6 Screening of Lewis acids for the ring expansion of aziridine 100 ............................ 132   Table 3.7 Multi-component catalytic asymmetric trans-aziridination with secondary diazoacetamide 106 ................................................................................................................. 135   Table 4.1 Aziridination reaction of chiral imine (R)-129a in presence of chiral catalyst ........ 200   Table 4.2 Multi-component aziridination reaction of chiral aldehyde (R)-130a in presence of a chiral boroxinate catalyst ......................................................................................... 203   xi Table 4.3 Multi-component aziridination of aldehyde (R)-130b in the presence of chiral catalyst ................................................................................................................................... 207   Table 4.4 Multi-component aziridination reaction of chiral aldehyde (S)-130c in the presence of chiral boroxinate catalyst: a catalyst controlled case .............................................. 210   Table 4.5 Multi-component aziridination reaction of the chiral aldehyde (R)-140 in the presence of a chiral boroxinate catalyst ................................................................................... 213   Table 4.6 Multi-component aziridination reaction of Garner’s aldehyde (S)-147 in the presence of a chiral boroxinate catalyst ................................................................................... 215   Table 4.7 Multi-component aziridination reaction of aziridine 2-carboxaldehyde (S,S)-148 in the presence of a chiral boroxinate catalyst .................................................................... 217   Table 4.8 Multi-component aziridination reaction of 2-phenylpropanal (S)-150 in the presence of a chiral boroxinate catalyst ....................................................................................... 219   Table 4.9 Multi-component aziridination reaction of 3-phenylbutanal (S)-155 in the presence of a chiral boroxinate catalyst: a catalyst controlled case ........................................... 224   Table 4.10 Multi-component aziridination reaction of aldehyde (R)-159 in the presence of a chiral boroxinate catalyst: a catalyst controlled case ........................................... 225   Table 5.1 Multi-component aziridination reaction of chiral aldehyde (R)-192 in the presence of a chiral boroxinate catalyst ......................................................................................... 296   xii LIST OF FIGURES Figure 1.1 Aziridines in natural products....................................................................................... 1   Figure 1.2 Biologically important aziridines ................................................................................. 3   Figure 1.3 Natural products via nucleophilic ring opening of aziridine intermediates.................. 9   Figure 1.4 Natural products via azomethine ylides derived from aziridines ............................... 10   Figure 1.5 Possible approach towards naturally occurring ‘Long chain bases’ from aziridine 2carboxylate ................................................................................................................ 11   Figure 1.6 Different reactions of aziridine-2-carboxylate ........................................................... 12   Figure 1.7 (S)-VAPOL boroxinate catalyst for the Wulff aziridination reaction ........................ 15   Figure 2.1 Distribution of the asymmetric inductions with the protecting group for the VANOL derived catalyst .......................................................................................................... 53   Figure 2.2 Distribution of the asymmetric inductions with the protecting group for the VAPOL derived catalyst .......................................................................................................... 54   Figure 3.1 Subunits of sphingolipids ......................................................................................... 112   Figure 3.2 A list of: (A) naturally occurring sphingoid bases. (B) Unnatural isomers of sphinganine 74 ....................................................................................................... 112   Figure 4.1 Different interactions in the active catalyst structure .............................................. 193   Figure 4.2 (A) Proposed catalytic asymmetric aziridination reaction with chiral imines 127. (B) Projected approach of the nucleophile to chiral imine 127 using Felkin-Anh model for Re-face attack of the nucleophile (favored). (C) Projected approach of the nucleophile to chiral imine 127 using Felkin-Anh model for Si-face attack of the nucleophile (unfavored). (C) the X-ray crystal structure of active catalyst consisting xiii of an iminium cation (from achiral imine 36a) and the boroxinate anion (from (S)VAPOL). The boroxinate anion is green in color and the iminimium cation is in traditional color. ..................................................................................................... 194   Figure 4.3 The X-ray crystal structure of 138b………………………………………………..209 Figure 5.1 Family of phytosphingosines 75 .............................................................................. 286 xiv LIST OF SCHEMES Scheme 1.1 C2-Symmetric bis-aziridine 8 as chiral ligands in different asymmetric transformations ...................................................................................................... 5 Scheme 1.2 Aziridino alcohol 17 as chiral ligand in asymmetric addition of diethyl zinc to the imine 16 ..................................................................................................................... 6 Scheme 1.3 Aziridino alcohol 19 as chiral ligand in asymmetric addition of diethyl zinc to the aldehyde 20 ................................................................................................................ 6   Scheme 1.4 Chiral ferrocenyl aziridino alcohol in the catalytic asymmetric alkylation of aldehydes .................................................................................................................. 7   Scheme 1.5 C2-Symmetric  aziridine as auxiliary for asymmetric alkylation ................................ 7   Scheme 1.6 C2-Symmetric  aziridine as auxiliary for asymmetric syn-aldol reaction ................... 8   Scheme 1.7 Approaches towards catalytic asymmetric aziridination .......................................... 13   Scheme 1.8 The Wulff-cis aziridination with benzhydryl imines ................................................ 14   Scheme 1.9 The Wulff-cis aziridination with N-MEDAM imines 36.......................................... 16   Scheme 1.10 The Wulff trans-aziridination reaction .................................................................. 16   Scheme 1.11 BINOL dicarboxylic acid catalyzed trans-aziridination with diazoacetamide ....... 18   Scheme 1.12 BINOL dicarboxylic acid catalyzed asymmetric alkylation of diazoester 46 ........ 19   Scheme 1.13 BINOL phosphoric acid catalyzed asymmetric alkylation with a diazoester 46 .... 19   Scheme 1.14 BINOL phosphoric acid catalyzed trans-aziridination with diazoacetamides 39 .. 20   xv Scheme 1.15 BINOL phosphoric acid catalyzed asymmetric cis-aziridination reaction ............. 20   Scheme 2.1 Asymmetric aziridination with benzhydryl imines 33. ............................................. 26   Scheme 2.2 Relative rates and asymmetric inductions for the aziridinations of Ndiarylmethylimines .............................................................................................. 29   Scheme 2.3 Catalytic asymmetric aziridination with N-BUDAM imines 38. ............................. 30   Scheme 2.4 Acid catalyzed deprotection of N-protected aziridines 56a and 58a ........................ 32   Scheme 2.5 Large scale synthesis of MEDAM amine 66 6 .......................................................... 33   Scheme 2.6 Formation of the boroxinate (B3) catalyst 35 ........................................................... 39   Scheme 2.7 Catalytic symmetric aziridination reaction with benzhydryl imine 33a with Method B ............................................................................................................................... 39   Scheme 2.8 Asymmetric aziridination with MEDAM imine 36e with Method B ....................... 41   Scheme 2.9 Asymmetric aziridination with MEDAM imine 36e with Method B' ...................... 42   Scheme 2.10 Catalytic asymmetric aziridination with MEDAM imine 36e with Method C....... 43   Scheme 2.11 Catalytic asymmetric aziridination with MEDAM imine 36e with Method D ...... 43   Scheme 2.12 Proposed Protocol for trapping of dianisyl cation 69 with acetonitrile .................. 49   Scheme 2.13 Deprotection of DAM aziridine 58a in acetonitrile ................................................ 50   Scheme 2.14 Equilibrium between cation 69 and 70 ................................................................... 50   Scheme 2.15 Deprotection of N-protected aziridines and trapping of dianisyl cation with water. (A) Deprotection of N-DAM aziridine 58a (B) Deprotection of N-MEDAM aziridine 37a ........................................................................................................... 52   xvi Scheme 3.1 L-threo-sphinganine 74b synthesis via asymmetric catalytic nitro aldol reaction . 114   Scheme 3.2 D-erythro-sphinganine 74a synthesis via asymmetric catalytic hydrogenation ..... 115   Scheme 3.3 D-erythro-sphinganine 74a synthesis via Sharpless asymmetric dihydroxylation and epoxidation............................................................................................................. 115   Scheme 3.4 Retro-synthetic analysis: erythro-sphinganine and threo-sphinganine ................. 116   Scheme 3.5 Self-condensation of imine 91 ................................................................................ 119   Scheme 3.6 Ring opening of N-H aziridine 59a with water in acidic medium .......................... 124   Scheme 3.7 Synthesis of N-Boc-β-hydroxy-α-amino ester 98 from aziridine 37l ..................... 127   Scheme 3.8 (A) Synthesis of L-threo-sphinganine 74b (B) Synthesis of D-threo-sphinganine 74c ................................................................................................................................ 128   Scheme 3.9 Ring opening of aziridine 37l with water ............................................................... 129   Scheme 3.10 (A) Synthesis of D-threo-sphinganine 74c (B) Synthesis of N-Boc-L-threosphinganine 105 ................................................................................................. 130   Scheme 3.11 (A) synthesis of D-erythro-sphinganine 74a (B) synthesis of L-erythro-sphinganine 74d ........................................................................................................................ 133   Scheme 3.12 (A) Ring opening of trans-aziridine 88c with water in acidic medium (B) Ring opening of trans-aziridine 88c with TFA ........................................................................... 137   Scheme 3.13 (A) Synthesis of trans-aziridine 110 (B) Ring opening of trans-aziridine 110 with TFA ..................................................................................................................................... 138   Scheme 3.14 Proposed solution for regioselective Ring opening of trans-aziridine ................ 139   Scheme 3.15 Retro-Synthetic analysis of mycestericin E ........................................................ 140   xvii Scheme 3.16 Synthesis of aldehyde 122 .................................................................................. 141   Scheme 3.17 Synthesis of aziridine 123 ................................................................................... 142   Scheme 4.1 Chiral imines (R)-129 for aziridination reaction..................................................... 198   Scheme 4.2 Synthesis of chiral aldehyde (R)-130a and (R)-130b ............................................. 198   Scheme 4.3 Synthesis of chiral aldehyde (S)-130c .................................................................... 199   Scheme 4.4 Multi-component asymmetric aziridination reaction ............................................. 202   Scheme 4.5 Aziridination reaction with (S)-129a' and the ORTEP diagram of the crystal structure of the major diastereomer ent-136b' ..................................................... 205   Scheme 4.6 Possible synthetic route for (–)-polyoxamic acid ................................................... 211   Scheme 4.7 Synthesis of (R)-140 via oxidative cleavage of the diacetonide of D-mannose 142 ................................................................................................................................ 212   Scheme 4.8 Possible synthetic route for Manzacidin B 146 ...................................................... 215   Scheme 4.9 Synthesis of aziridine 2-carboxaldehyde (S,S)-148 ................................................ 217   Scheme 4.10 Synthesis of 3-phenylbutanal (S)-155 ................................................................... 223   Scheme 4.11 Synthesis of 3-((tert-butyldimethylsilyl)oxy)butanal (R)-136 .............................. 223   Scheme 5.1 Synthesis of xylo-phytosphingosine derivative via Sharpless asymmetric dihydroxylation ................................................................................................. 287   Scheme 5.2 Synthesis of phytosphingosines ent-75d and its derivative 173 via (A) Sharpless asymmetric epoxidation (B) Sharpless kinetic resolution ..................................... 289   Scheme 5.3 Synthesis of phytosphingosines ent-75d and its derivative 177 and 178 via organocatalytic aldol reaction .............................................................................. 290   xviii Scheme 5.4 Synthesis of D-ribo-phytosphingosine 75a via Trost asymmetric alkynylation reaction and Sharpless asymmetric epoxidation .................................................. 291   Scheme 5.5 Synthesis of D-ribo-phytosphingosine 75a via palladium-catalyzed dynamic kinetic asymmetric transformation from the racemic epoxide 184 ................................... 292   Scheme 5.6 Retro-synthetic analysis: D-ribo-phytosphingosine 75a, D-xylo-phytosphingosine 75b, L-arabino-phytosphingosine 75c and L-lyxo-phytosphingosine75d............. 293   Scheme 5.7 Synthesis of optically pure 1,2- diol (R)-195 by hydrolytic kinetic resolution ...... 294   Scheme 5.8 Synthesis of optically pure aldehydes (R)-192a and (R)-192b ............................... 295   Scheme 5.9 Aziridination reaction with rac-168a in the presence of the (R)-VAPOL catalyst 300   Scheme 5.10 Proposed synthesis of Myriocin via aziridination of rac-202 in the presence of the (R)-VAPOL catalyst. ............................................................................................ 301   Scheme 5.11 Ring opening of aziridine ent-37l with TFA ........................................................ 301   Scheme 5.12 Deprotection of N-MEDAM group and subsequent protection with Boc2O. ....... 302   Scheme 5.13 Ring opening of N-Boc aziridines 101 and ent-101 with formic acid .................. 303   Scheme 5.14 Reaction of N-Boc aziridine 204 with formic acid ............................................... 304   Scheme 5.15 Cbz protection and subsequent ring opening ........................................................ 305   Scheme 5.16 Proposed synthesis of L-lyxo-phytosphingosine 75d from lactone 207 ............. 305   Scheme 5.17 (A) Ring expansion of N-Boc aziridine 204 to oxazolidinones 208 and 209. (B) possible rational for the formation of 208.......................................................... 306   Scheme 5.18 Possible solution to synthesize the required regio-isomer of oxazolidinone 211 by ring expansion of the N-Boc aziridine 210 ........................................................... 307   xix Scheme 5.19 Possible synthetic route to (A) D-ribo-phytosphingonine and (B) D-xylophytosphingonine from aziridine 199a.............................................................. 308   xx CHAPTER 1   AZIRIDINE: AN IMPORTANT MOTIF IN ORGANIC SYNTHESIS 1.1 Biologically important alkaloids containing an aziridine core Aziridines are highly valuable saturated three-membered heterocyclic compounds containing one nitrogen atom. The presence of the aziridine ring in natural and synthetic compounds is responsible for their anticancer, antimicrobial and antibacterial activity against selected cancer cell lines, microorganisms and pathogenic bacteria. The study to determine their mode of action has revealed that the electrophilic nature of the aziridine ring plays an important role in the mechanism at the molecular level. Figure 1.1 Aziridines in natural products. “ For interpretation of the references to color in this and all other figures, the reader is referred to the electronic version of this dissertation.” H2N O R H2N O O O OR1 H N R NR2 O O OR1 H N NMe O Mitomycin A, R = OMe, R1, R2 = H O Mitomycin B, R = OMe, R1 = H Mitomycin F, R = OMe, R1, R2 = Me Mitomycin J, R = OMe, R1 = Me Mitomycin C, R = NH2, R1= Me, R2 = H Mitomycin D, R = NH2, R1 = H Porfiromycin, R = NH2, R1, R2 = Me Mitomycin E, R = NH2, R1 = Me 1 Figure 1.1 (cont’d) OR2 X O O N NH2 OR1 O NR FR 073317 R = R1 = Ac, R2 = Me, X = CHO FR 70496 R = Ac, R1 = H, R2 = Me, X = CHO FR 66979 R = R1= R2 = H, X = CH2OH FR 900482 R = R1= R2 = H, X = CHO O MeO O O N H O O O R H N H2N N O O HO R= Azinomycin A O HN N H H2N O NH Ficellomycin Azinomycin B O HO OH N HO O O N H O H N N H O O H N OH O NH Miraziridine A HN NH2 A few of the natural products containing an aziridine core are outlined in Figure 1.1. Mitomycins are the first known natural products containing an aziridine ring. Synthetic organic 2 chemists have dedicated a substantial effort towards the synthesis of the Mitomycins, a class of 1 very potent antibacterial and anticancer compounds.     The natural products FR-900482 and FR66979 are structurally related to mitomycin C and exhibits similar antitumor and antibiotic activities. 2 These natural products were isolated from Streptomyces sandaensis 2b,3 and they show less toxicity than mitomycins in clinical cancer chemotherapeutics. In 1976 ficellomycin 4 was isolated from Streptomyces ficellus. It exhibits in vivo effectiveness against Staphylococcus aureus infections in mice and inhibits the growth of Gram-positive bacteria in vitro. The SS pharmaceutical company in Japan has reported the isolation of azinomycin A and 5 B from Streptomyces griseofuscus in 1986. These compounds display significant in vivo antitumor activity with potent in vitro cytotoxicities. 6 Miraziridine A was found to inhibit the 7 cysteine protease cathepsin B and was isolated from a marine sponge. In addition to the naturally occurring aziridines, synthetic aziridine containing compounds have been shown to be promising candidates for the development of new drugs for several diseases. Some biologically important synthetically prepared compounds containing the aziridine core are listed in Figure 1.2. 8 Figure 1.2 Biologically important aziridines 6 6 1 5 O H N O O OH OH 5 N 2 3 O N 3 N NH2 Figure 1.2 (cont’d) H N R N S 4 OH N H N 5 CO2Me 7 O O OH O 4 (R = H, CH2CH2OH, CONHEt, COPh, CH2Ph) H N H N 6 H N CO2Me 7 Synthetic monoglyceride 1 display antimicrobial activity against Gram-positive bacteria 9 and yeasts. Synthetically prepared 2-ethyl-1-oleoyl-aziridine 2 exhibits a wide spectrum of antimicrobial and antifungal activity. The immunosuppressant Imexon 3 selectively suppresses B-lymphocyte activation and can be used in the treatment of plasma cell or B-cell leukemias or neoplasias. The aziridine analogues 4 of epothiloneA show cytotoxicity against cancer cell lines. Bis-aziridines 5 (all diastereomers) and tris-aziridines 6 (all diastereomers) derived from linolenic acid exhibits cytotoxic and antimicrobial activity. Useful neuroprotective as well as antitumor-promoting effects are the other important properties of these aziridines. There are many more interesting examples of naturally occurring, synthetic or semi-synthetic compounds with aziridinyl scaffold with clinical utility, which have been well reviewed by Ismail et al. in 8 2009. 1.2 Aziridines as chiral ligands Tanner and Andersson demonstrated the use of C2-symmetric bis-aziridines 8 and its derivatives as chiral ligands in various asymmetric transformations (Scheme 1.1) with good to 4 moderate selectivity. 10 The transition metal mediated transformations involve both stoichiometric and catalytic use of these ligands. Scheme 1.1 C2-Symmetric bis-aziridine 8 as chiral ligands in different asymmetric transformations Ph Ph ligand 8 7 Cu(I), ligand 8 OH OsO4 Ph Ph Ph Ph Ph Ph Ph 13 MeO2C Ph ligand 8 NaCH(CO2Me)2 Cyclopropanation N Ph 8 Bis(aziridine) ligand Alkylation Pd(0) N Ph Ph 12 yield 82% trans:cis 3:1 60% ee EtO2C N2 11 Dihydroxylation OAc CO2Et 10 9 OH yield 90% 95% ee Aziridination CO2Me Ts N Cu(I), ligand 8 Ph Ph 10 14 yield 89% 99% ee The asymmetric addition of diethyl zinc to the imine 16 11 PhINTs Ph 15 yield 68% 33% ee 12 or the aldehyde 20 showcases another use of chiral aziridine ligands in asymmetric transformations (Scheme 1.2 and Scheme 1.3). 5 Scheme 1.2 Aziridino alcohol 17 as chiral ligand in asymmetric addition of diethyl zinc to the imine 16 Et2Zn, 17 (1 equiv) H N O PPh2 toluene, 0 ºC to rt Ar O Ph2P R1 N Ar Et 18 16 HO R NH R2 R 17 R1 = alkyl, R = H, alkyl, R2 = H, alkyl, Phenyl Scheme 1.3 Aziridino alcohol 19 as chiral ligand in asymmetric addition of diethyl zinc to the aldehyde 20 O R   OH Et2Zn, ligand 19 H toluene, –23 ºC 20 R Et 21 Ph Ph N HO Et Et Ph Ph N OH Et HO Ph Et 19a 3 mol% 6 examples 70-95% yield 10-94% ee Ph 19b 5 mol% 9 examples 48-91% yield 80-99% ee 6 Wang and coworkers reported the use of chiral ferrocenyl aziridino alcohol 22 in the catalytic asymmetric alkylation of aldehyde 23 (Scheme 1.4).  13 Scheme 1.4 Chiral ferrocenyl aziridino alcohol in the catalytic asymmetric alkylation of aldehydes Ar'B(OH)2 (1 equiv), Et2Zn (3 equiv), toluene O Ar OH H Ar 23 Ph Ph N Fe Ar' 24 28 examples 81-96% yield 81-98% ee HO 22 (10 mol%) 1.3 Aziridines as chiral auxiliaries The utility of C2-symmetric aziridines as auxiliaries for asymmetric alkylation (Scheme 1.5) and aldol reactions (Scheme 1.6) of amide enolates was demonstrated by Tanner and coworkers. 14 Scheme 1.5 C2-Symmetric  aziridine as auxiliary for asymmetric alkylation R1 R1 O 1) LiHMDS N BnO OBn 25 2) R2X R1 O R2 + N BnO R2 = alkyl OBn N BnO 26a R1 = Me, (CH2)7CH3 4 examples 40-88% yield 26a:26b 3:1 to > 99:1 7 O R2 OBn 26b Scheme 1.6 C2-Symmetric  aziridine as auxiliary for asymmetric syn-aldol reaction R O N n-Bu OH O 1) LiHMDS n-Bu R = aryl, alkenyl, alkyl 27 O + N 2) RCHO n-Bu R OH n-Bu N n-Bu 28a n-Bu 28b 12 examples 63-91% yield 28a:28b 3:1 to > 99:1 1.4 Synthesis of natural products via aziridine intermediates Aziridines have become important building blocks in synthetic chemistry, especially for nitrogen-containing bioactive natural compounds. The usefulness of these three membered heterocycle is greatly associated with its ability to undergo nucleophilic ring opening to release the ring strain. A wide array of nucleophiles can be used. In most of the cases the regio- and stereoselctivity of the ring opening is predictable, which plays an important role in designing a synthetic plan. Although the reaction condition and substrates play major role in stereochemical outcome, often the regioselectivity is governed by steric congestion. In general, the nucleophile attacks the less congested terminus and an anti attack (SN2) determines the stereoselectivity of the ring opening. Till date many authors have extensively reviewed the nucleophilic ring opening of the aziridine ring. 15 Along the same line, the synthetic potential of aziridine ring opening reactions has been well established in the synthesis of complex natural products. Some representative examples are 8 16 shown in Figure 1.3. Figure 1.3 Natural products via nucleophilic ring opening of aziridine intermediates OH O O Attack of 'O' Nucleophile R 1 N R3 R R2 NH2 O (–)-chloroamphenicol D-erythro-sphingosine ref 16c H N R4 OH OH OH CHCl2 C13H27 HN O O Ustiloxin D ref 16a, b Attack of 'N' Nucleophile OH N H HN H N HO HN COOH ref 16d Br NH2 N NHAc Me HO N O H2N Attack of 'C' Nucleophile R CO2H EtO2C N N H NH2 N H O Tetrahydrolathyrine tamiflue (–)- Agelastatin A synthetic drug candidate ref 16g, h ref 16e ref 16f Me Me NMe Me OO OMe Et MeO Ac H HN N S O O N H COOH N O Me NMe RO R2 (±)-Desoxyeseroline (R=H) (+)-PS-5 1 (±)-Physostigmine (R=OCONHMe) R ref 16k ref 16i 1=CN, R2=H, R= angeloyl ) (–)-Renieramycin M (R (–)-Renieramycin G (R1=R2=O, R= angeloyl ) (–)-Jorumycin (R1=CN, R2=H, R= Ac ) (–)-Jorinnamycin A (R1=CN, R2=H, R= H ) ref 16j 9 The ring strain of the aziridine ring makes it a potential substrate for [3+2] cycloaddition to obtain cyclic adducts. Aziridine esters are used as a precursor of azomethine ylides. Subsequently, they are reacted with olefin substrates. This serves as the key step in 17 many natural product syntheses. A few examples are listed in Figure 1.4. Figure 1.4 Natural products via azomethine ylides derived from aziridines R [3+2] cycloaddition R1 N R3 CO2R R2 MeO MeO HO2C CO2H H H HN O N H CO2H CO2H Acromelic acid A ref 17a 1.5 N H CO2H N O Me H (–)-Mesembrine (–)-Kainic acid ref 17b ref 17c Aziridines as the precursor for 1,2-amino alcohols The use of aziridines as an intermediate in natural product synthesis has attracted considerable attention over last two decades. cousins”, 18 Nonetheless, aziridines, “the epoxides’ ugly have received little interest compared to that for epoxides. The aziridine ring has been used as an efficient precursor of 1,2-amino alcohols and other polyfunctionalized scaffolds. The 1,2-amino alcohol functionality is present in a structurally related family of compounds known as sphingoid bases, where are often termed as ‘long-chain bases’. 19b alcohols is known to contain hundreds of different molecules. 10 19 This family of amino The synthesis of such sphingoid bases can be planned via regio- and stereo-selective ring opening of the aziridine 2carboxylates (Figure 1.5). Figure 1.5 Possible approach towards naturally occurring ‘Long chain bases’ from aziridine 2carboxylate NH2 OH 6 OH R O 3 6 OH O OH NH2 OH 12 NH2 Rhizochalinin D COOH OH OH NH2 D-erythro-sphinganine OH Myriocin R=H Sphingofungin E R = OH R" 12 N R' OH OH NH2 D- ribo- phytosphingosine CO2Et OH 1 R2 R O 3 11 6 COOH OH NH2 Mycestericin E R1 = H, R2 = OH Mycestericin D R1 = OH, R2 = H 12 NH2 OH OH 5 O 11 2 R1 R OH OH NH2 D-erythro-sphingosine Rhizochalinin C R1 = H, R2 = NH2 R1 = NH2, R2 = H oceanin In addition to ring opening reactions other multi-dimensional reactivity patterns of aziridine 2-carboxylates (Figure 1.6) makes them versatile synthetic intermediates in organic synthesis. 11 Figure 1.6 Different reactions of aziridine-2-carboxylate R2 N H Reaction at 'N' center R1 Deprotonation and electrophilic substitution CO2R Reaction at carboxylate group Nucleophilic ring opening at C-2 or C-3 center Formation of azomethine ylide 1.6 Catalytic asymmetric synthesis of aziridines As a result of their importance in synthesis, a lot of effort has been directed towards the preparation aziridines in last two decades. Most effort has been focused on synthesizing chiral 15c,20 aziridines from chiral substrates. Synthesis of aziridines via catalytic asymmetric reactions offer a more general method since it is not tied to the chiral pool and two general approaches 15c,21 have been taken (Scheme 1.7). One of them involves oxidation of alkenes i.e. the addition of a nitrene to the alkene precursor. carbenoid to an imine. 22 The other approach is the addition of a carbene or A summary of the extensive study in the field of asymmetric aziridination has been described in several excellent reviews over last few years. 12 15c,18,20-21,23 Scheme 1.7 Approaches towards catalytic asymmetric aziridination Carbene or cerbenoid addition to imine Oxidation of olefin with nitrene or 'N' source R2 R1 R3 C–N and C–C bond formed N M or H N N2 R3 R3 R1 + R2 R1 + X N R3 N 2 C–N bonds formed H R2 or M R2 The Wulff group has pioneered the second approach that involves catalytic asymmetric aziridination of imines with carbenoids (viz diazoacetaes or diazoacetamides) in the presence of a Brønsted acid catalyst and the contributions of the Wulff group are summarized below. 1.7 Brønsted acid catalyzed asymmetric Aziridination reaction In 2000, our group reported a very general catalytic asymmetric cis-aziridination reaction with high yields and enantioselectivities. 24 In this reaction enantiopure aziridines 34 were prepared by the reaction between the imines 33 and stabilized diazo compounds in presence of the catalyst prepared from the VAPOL 30 or VANOL 29 ligand and B(OPh)3 . In 2008 the aziridination reaction with benzhydryl imines 33 was reexamined under new 25 reaction conditions (Scheme 1.8). Improved yield and asymmetric induction was observed. 13 Scheme 1.8 The Wulff-cis aziridination with benzhydryl imines O Ph R Ph N + OEt N2 33 R = aryl and alkyl Ph Ph OH OH ligand-borate catalyst (5-10 mol%) Ph N toluene 25 ºC, 24 h R 11 1) B(OPh)3 (4 equiv) toluene, 80 ºC, 1 h 2) 0.1 mm Hg 80 ºC, 0.5 h Ph CO2Et 34 12 examples 43-89% yield 77-94% ee Ph Ph B2 32a (32b) B1 31a (31b) (S)-VANOL 29 [(S)-VAPOL 30] OPh O B O B O OPh Ph O B OPh + Ph O (ligand borate catalyst) 26 Based on the preliminary studies on catalyst structure, it was thought that the active catalyst in the aziridination reaction was a Lewis acid, specifically a mixture of meso-borate 31 (B1) and pyroborate 32 (B2). Interestingly, when VAPOL 30 and B(OPh)3 are mixed together at room temperature there is no reaction even after 24 h. 27 However, there is immediate formation 27 of a boroxinate catalyst 35 after addition of imine to the mixture of VAPOL and B(OPh)3. Gang Hu, a previous group member, was able to obtained a crystal structure of the active catalyst. 27 The catalyst 35 exists as an ion-pair consisting of a boroxinate anion and an iminium 14 cation resulting from protonation of the imine (Figure 1.7). So the actual catalyst is a chiral Brønsted acid in the Wulff aziridination reaction. Figure 1.7 (S)-VAPOL boroxinate catalyst for the Wulff aziridination reaction H[Imine]+ Ph Ph OPh –O B O B O O O B OPh 35 (S)-VAPOL-B3 catalyst The aziridination reaction with the N-benzhydryl imine 33 gives acceptable asymmetric induction with aromatic substrates (90-94% ee) but they fail to give satisfactory results with aliphatic imines (78-87% ee, Scheme 1.8). After an extensive search of N-protecting group, it was delightful to find that the MEDAM group gave high inductions with both classes of 28 substrates (Scheme 1.9). A considerable amount of the work in this thesis has been focused on the study of aziridination reaction of N-MEDAM imines 36 and is discussed in Chapter 2. 15 Scheme 1.9 The Wulff-cis aziridination with N-MEDAM imines 36 O Ar + Ar N R (S)-ligand borate catalyst (2-10 mol%) OEt N2 Ar OMe Ar N toluene 25 ºC, 24 h R 11 36 R = aryl and alkyl Ar CO2Et 37 10 examples 67-98% yield 90- >99% ee In 2010, another group member, Aman Desai, demonstrated a method for synthesizing trans-aziridines with high yields and enantioselectivities using the boroxinate catalyst (Scheme 1.10). 29 In this trans-aziridination reaction, diazo acetamides were used instead of diazo esters. The switch in the diastereoselectivity was explained as the outcome of an H-bonding interaction of the diazo acetamide with the boroxinate catalyst 30 . Scheme 1.10 The Wulff trans-aziridination reaction O Ar R N Ar NHPh + (S)-VANOL boroxinate catalyst Ar toluene R N2 36 (Ar2CH = MEDAM) 38 (Ar2CH = BUDAM) Ar OMe 39a MEDAM 10 examples (R = aryl) 66-90% yield 81-98% ee Ar N CONHPh 40 (Ar2CH = MEDAM) 41 (Ar2CH = BUDAM) Ar OMe t-Bu 16 t-Bu BUDAM 3 examples (R = alkyl) 67-90% yield 82-90% ee Scheme 1.10 (cont’d) * OPh B O O O B– B Ph O O O H Ar H O N Ar + N2 N Ph Ph H H H-bonding and charge stabilization Thus, the Wulff aziridination system is the only universal catalytic asymmetric aziridination method where the same imine substrate and same catalyst can be used to generate either cis or trans aziridines. Over the past few years an enormous amount of work has been carried out in the Wulff group towards addressing different aspects of the aziridination protocol. Not only has it been possible to increase the scope of the reaction methodology but also significant contributions towards mechanistic understanding and to applications of the reaction methodology towards total synthesis have been made in our group. In addition to the Wulff’s aziridination system, three other groups have reported Brønsted acid catalyzed asymmetric aziridination reactions. In 2008, Maruoka reported the first trans-selective chiral Brønsted acid catalyzed 31 aziridination which involved the N-Boc imines 42 with diazo acetamides 39 (Scheme 1.11). 17 Scheme 1.11 BINOL dicarboxylic acid catalyzed trans-aziridination with diazoacetamide CO2H CO2H N Ar 44 (5 mol%) O Boc NHAr1 + N2 42 Boc N toluene, 0 ºC 2-8 h 39 Ar CONHAr1 43 14 examples 20-70% yield 89-99% ee O R O H – O N H O N H O Ar1 + Ph H N2 45 favored The trans- selectivity was explained with the help of a proposed transition state 45 where hydrogen bonding between the Boc group of the imine and the diazoacetamide N-H bond plays a major role. Interestingly, they were able to perform an asymmetric alkylation reaction of diazo compounds with the same BINOL dicarboxylic acid catalyst 44 when they substituted the diazo acetamide with a diazo acetate (Scheme 1.12). 32 18 Scheme 1.12 BINOL dicarboxylic acid catalyzed asymmetric alkylation of diazoester 46 CO2H CO2H N O Boc OtBu + Ph N2 42a 44 (5 mol%) NHBoc CO2tBu Ph N2 CH2Cl2, MS 4Å, 0 ºC, 20 h 47a 81% yield, 95% ee 46 In 2005, Terada and coworkers reported alkylation of diazo acetates utilizing chiral BINOL phosphoric acid 48 (Scheme 1.13). 33 Later, Zhong and coworkers used the same chiral BINOL phosphoric acid 48 for trans-aziridinaton reaction with diazoacetamides (Scheme 1.14). 34 Scheme 1.13 BINOL phosphoric acid catalyzed asymmetric alkylation with a diazoester 46 O O P O OH NMe2 NMe2 O N Ar O 49 OtBu + N2 48 2-3 mol% HN Ar toluene, rt, 5-24 h 46 O CO2tBu N2 50 8 examples yield 62-89% 91-97% ee 19 Scheme 1.14 BINOL phosphoric acid catalyzed trans-aziridination with diazoacetamides 39 O O P O OH N Boc N NHR + Ar 48 5 mol% O Boc CH2Cl2, rt, 10 min N2 42 39 R = aryl Ar CONHR 43 14 examples yield 81-97% 88-98% ee cis:trans ! 19:1 In 2009 Akiyama reported a Brønsted acid catalyzed asymmetric cis-aziridination reaction between in-situ formed activated imines 51 and ethyl diazoacetate 11 in the presence of the 35 chiral BINOL phosphoric acid 53 (Scheme 1.15). The scope of the reaction is limited to the activated imine substrates made only from aryl glyoxal derivatives. Scheme 1.15 BINOL phosphoric acid catalyzed asymmetric cis-aziridination reaction Si(4-tBu-C6H4)3 O O P O OH OMe Ar N O 51 O OEt + N2 OMe Si(4-tBu-C6H4)3 53 2.5 mol% toluene, –30 ºC, 23 h N Ar O 11 CO2Et 52 10 examples yield 84-100% 92-95% ee cis:trans ! 50:1 in-situ generated 20 1.8 Conclusions The ability of aziridines to undergo various regio- and stereo-selective reactions, makes these strained three-membered heterocycle an invaluable motif in organic synthesis. The synthetic potential of aziridines has attracted considerable attention of the scientific community towards the preparation of stereo- and enantioselective aziridinyl core. In past few years our group has made significant progress in different aspects of catalytic asymmetric aziridination methodology. 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(34) Zeng, X.; Zeng, X.; Xu, Z.; Lu, M.; Zhong, G. Org. Lett. 2009, 11. (35) Akiyama, T.; Suzuki, T.; Mori, K. Org. Lett. 2009, 11, 2445. 25 CHAPTER 2   EVOLUTION OF A SUBSTRATE GENERAL CATALYIC ASYMMETRIC AZIRIDINATION REACTION WITH N-MEDAM IMINES 2.1 Introduction Over the last decade, the Wulff group has developed a very efficient catalytic asymmetric 1 aziridination reaction that is based on the reaction of imines with stabilized diazo compounds. A catalyst prepared from either the VAPOL 30 or VANOL 29 ligand and B(OPh)3 mediates the reaction. In early studies, it was determined that N-benzhydryl group in imine 33 was the optimal ‘N’ protecting group in the Wulff’s cis-aziridination reaction. 2 Scheme 2.1 Asymmetric aziridination with benzhydryl imines 33.   (S)-ligand borate catalyst (5-10 mol%)   O Ph R   N Ph + 33 R = aryl and alkyl   OEt N2 Ph solvent, 25 ºC, 24 h R 11 Ph N CO2Et 34 R = aryl 43-87% yield, 90 - 95 % ee Method A (solvent = toluene) R = alkyl 54-89% yield, 78 - 87 % ee Method A' R = aryl 67-88% yield, 83-93 % ee (solvent = CH2Cl2) R = alkyl 74-83% yield, 78- 83 % ee 26 Scheme 2.1 (cont’d) Method A 1) B(OPh)3 (4 equiv) H2O (1 equiv) toluene, 80 ºC, 1 h (S)-ligand 2) 0.1 mm Hg 80 ºC, 0.5 h Ph Ph OH OH (S)-VANOL 29 [(S)-VAPOL 30] Method A' (S)-ligand borate catalyst (mixture of B1 and B2) Ph Ph O B OPh O B1 31a for VANOL (31b for VAPOL) 1) B(OPh)3 (3 equiv) CH2Cl2, 55 ºC, 1 h (S)-ligand 2) 0.1 mm Hg 55 ºC, 0.5 h Ph Ph OPh O B O B O OPh B2 32a for VANOL (32b for VAPOL) The aziridination reaction is highly diastereoselective furnishing cis-2, 3-disubstituted 2 aziridines 34 with high yields and good to moderate enantioselectivity (Scheme 2.1).   2c aromatic aziridines could be crystallized to afford optically pure (≥ 99% ee) aziridines, The the aliphatic imines afforded corresponding aziridines with moderate ee (78-87% ee). The optical purity of the aziridines, which are not solid, cannot be enhanced by crystallization. A considerable amount of effort has been made towards extending the substrate generality of our aziridination protocol. There are several factors that were identified that could potentially contribute to the asymmetric induction, and these include the method for catalyst preparation, the nature of the ligand and the nature of the N-substituent on the imines. During mechanistic 27 studies, it was found that the catalyst preparation (Method A', Scheme 2.1) lead to the formation of a mixture of mesoborate B1 (31) and pyroborate B2 (32). Also, a new procedure was developed (Method A in Scheme 2.1) for catalyst preparation that gave a higher ratio of B2 (32) to B1 (31). It was found that the catalyst enriched in B2 gave higher asymmetric induction and the results were reproducible, which was not the case for Method A' (Scheme 2.1). Employing different N- protecting groups on the imine provides a convenient handle for reaction optimization. A comprehensive study regarding variation of the N-protecting group is discussed below. 2.2 Study towards developing a universal N-protecting group 3 In a study designed for mapping the active site of the chemzyme in the aziridination reaction, a clearer picture concerning the correlation between the shape, size and electronic nature of the N-substituent on the imine substrate and the rates and enantioselectivities of the reaction was revealed. The extensive study of the effect of changing the conformation, electronics, and sterics of the two-phenyl groups on the benzhydryl group lead to the identification of the tetra-tert-butyldianisylmethyl (BUDAM) group (imine 38a) as the optimal N-substituent for a high yielding aziridination reaction with near-perfect asymmetric induction 3 (Scheme 2.2). 28 Scheme 2.2 Relative rates and asymmetric inductions for the aziridinations of Ndiarylmethylimines   Ph N VAPOL borate catalyst O Ar Ar + Ar N OEt N2 Ph 11 CF3 Ar CO2Et CH3 H t-Bu = Ar OCH3 CF3 54a Imine CH3 H t-Bu 55a 33a 38a rel rate 50 500 800 % ee r e 1 37 89 92 99 With the VAPOL derived catalyst, the reactions of BUDAM imines 38 from aromatic aldehydes resulted in 90-99% ee for most substrates whereas their benzhydryl analogues gave only 90-95% ee. However, there was no significant difference in the asymmetric induction between BUDAM or benzhydryl imines derived from aliphatic aldehydes. The asymmetric induction with N-BUDAM protecting group was in the range of 78-93% (Scheme 2.3) giving greater than 90% ee (93% ee) with only the ethyl imine. 29 Scheme 2.3 Catalytic asymmetric aziridination with N-BUDAM imines 38.   O Ar R + Ar N (S)-ligand borate catalyst (2-10 mol%) OEt toluene 25 ºC, 24 h N2 11 38 R = aryl and alkyl Ar2CH = BUDAM Ar Ar Ar OMe N R t-Bu t-Bu CO2Et 56 R = aryl 83-99% yield, 90 - 99 % ee R = alkyl 62-89% yield, 78 - 93 % ee At this point, the goal was to find a universal N-protecting group, which would provide high asymmetric induction in the aziridination reaction irrespective of the substrate. During the studies directed toward the mapping of the active site of the catalyst, the tetra3 methyldiphenylmethyl (MEDPM) group was examined as one of the N-protecting group. In the subsequent studies, Zhenjie Lu a former group member, found that the aliphatic imine 55i derived from cyclohexane carboxaldehyde and imine 55j derived from pivaldehyde underwent asymmetric aziridination with significantly enhanced inductions as compared to the 2c benzhydryl 3 and BUDAM imines (Table 2.1). Table 2.1 Catalytic asymmetric aziridination with alkyl imines 33, 38 and 55 Ar R N Ar (S)-Ligand borate catalyst (4-10 mol %) O + OEt N2 toluene, 25 °C, 24 h 11 30 Ar Ar N R CO2Et Table 2.1 (cont’d) R (S)-VAPOL (5) 34i 73 81 33i (R)-VANOL (5) 34i 79 –82 33j (S)-VAPOL (5) 34j 72 87 33j (R)-VANOL (5) 34j 89 –85 Imine Ligand (mol%) aziridine % Yield % ee Cy 38i (S)-VAPOL (4) 56i 89 89 Cy 38i (S)-VANOL (4) 56i 87 84 t-Bu 38j (S)-VAPOL (10) 56j 60 78 t-Bu 38j (S)-VANOL (10) 56j 76 80 R Imine Ligand (mol%) aziridine % Yield % ee Cy 55i (S)-VAPOL (4) 57i 87 91 Cy 55i (S)-VANOL (4) 57i 93 92 t-Bu 55j (S)-VAPOL (10) 57j 94 96 t-Bu Ar 33i R OMe % ee t-Bu t-Bu % Yield t-Bu t-Bu aziridine Cy Ar Ligand (mol%) Cy Ar Imine 55j (S)-VANOL (10) 57j 94 96 Although, the MEDPM imines 55i and 55j exhibit higher asymmetric induction in the aziridination reaction with aliphatic imines, the applicability of N-MEDPM aziridines 57 was found to be limited due to unsatisfactory results form the acid cleavage of the N-protecting group 31 4 from aziridines. In previous studies, it was established that the benzhydryl protecting groups 5 with p-methoxy groups such as BUDAM and DAM could be readily cleaved from aziridines by acid without ring opening (Scheme 2.4). Hence, it was thought to install the methoxy group at the pare position of the N-MEDPM protecting group. This led us to target the tetra-methyl dianisylmethyl (MEDAM) group as a N-protecting group in the aziridination reaction. Scheme 2.4 Acid catalyzed deprotection of N-protected aziridines 56a and 58a         Ar Ar N Ph CO2Et anisole, 25 ºC, 2 h t-Bu Ph CO2Et 59a 97% yield (from 56a) 99% yield (from 58a) 56a, Ar2CH = BUDAM 58a, Ar2CH = DAM MeO t-Bu OMe t-Bu t-Bu MeO BUDAM 2.3 H N CF3SO3H OMe DAM MEDAM group: a universal protecting group The tetra-methyldianisylmethyl (MEDAM) amine 66 (Scheme 2.5) was prepared and the aziridination reaction with imines 36 derived from 66 was then evaluated. Imine 36a prepared from MEDAM amine 66 and benzaldehyde had been previously evaluated in the aziridination reaction but not with imines from aliphatic aldehydes and other aromatic aldehydes. 3 The synthesis of tetra-methyldianisylmethyl (MEDAM) amine 66 shown in Scheme 2.5 follows that 6 previously reported and was scaled up to 100 g on the commercially available phenol 61. 32 The large scale preparation begins with the synthesis of the the bromide 62 from the inexpensive 4bromo-2,6-dimethylphenol 61. The nitrile 63 can be obtained from the bromide 62 by the Shechter modification of the Rosenmund-Van Braun reaction. 7 The key step in the synthesis of amine 66 involves the reaction of the nitrile 63 with the in-situ generated Grignard reagent 64. Scheme 2.5 Large scale synthesis of MEDAM amine 66 OH OMe NaH, MeI DMSO Br 61   6 (100 g scale) OMe CuCN Br 62 99% yield DMF reflux, 8 h (45 g scale) CN 63 90% yield MgBr (31 g scale) MeO 64 THF reflux, 12 h MeO OMe NH2 LiAlH4 THF reflux, 20 h 66 88% yield MeO OMe N MgBr 65 The subsequent in-situ reduction of the resulting imine intermediate 65 provides the amine 66 in 88% yield from the nitrile 63. Yu Zhang, a former group member, developed the small-scale synthesis of the MEDAM amine 66. The synthesis was then scaled up from original small-scale synthesis by Yu Zhang and the concentration of the reaction in each step was increased to 33 minimize the solvent waste and to simply the overall process. The entire process of preparation of MEDAM amine 66 was carried out efficiently without the use of any column chromatography purification. At this point, the project was taken over by another group member, Anil Gupta. The modifications that he made in the reaction sequence are as follows: a) commercially available bromide 62 was used, b) the nitrile 63 was made from 56 mmol of bromide 62, c) the nitrle 63 was used in the Grignard reaction without any purification and d) MEDAM amine• HCl salt was made using dry HCl gas instead of a 12M HCl solution during the purification of final product 66. 2.4 Catalytic asymmetric aziridination with MEDAM imine 36 During the investigation of the scope of the aziridination reactions with MEDAM imines 6 36 (Table 2.2) the catalyst was formed following method A. The catalyst, was prepared by heating the mixture of ligand with 4 equiv of B(OPh)3 and 1 equiv water at 80 ºC for an hour. Further, it was exposed to the high vacuum to remove the volatiles. Catalyst formation was then followed by the addition of imine 36 and ethyl diazoacetate 11 and toluene. Later, it was found that the addition of water is not necessary during the catalyst preparation, as commercial B(OPh)3 has enough water to form the catalyst. 6 The aziridination reaction with the MEDAM imines prepared from aryl aldehydes afforded cis-aziridines 37 with high asymmetric induction (98% ee to ≥ 99% ee) with the VAPOL catalyst. The VANOL catalyst produced slightly lower inductions (~ 97% ee) for the same imines. The MEDAM imine 36b made from o-tolualdehyde resulted in aziridine 37b with a 2c higher cis-selectivity (Table 2.2, entry 4 and 5) than the corresponding benzhydryl imine. 34 To our delight, the MEDAM imines 36 prepared from aliphatic aldehydes shows essentially the same levels of asymmetric induction as those observed for the corresponding MEDPM imines (Table 2.2, entries 23-28 vs. Table 2.1, entries 9-12). a Table 2.2 Asymmetric aziridination with MEDAM imines 36 . O Ar R N (S)-ligand borate catalyst (2-10 mol%) Ar + OEt N2 11 36 toluene 25 ºC, 24 h Ar OMe Ar Ar Ar Ar + N R NH CO2Et (R)H CO2Et R(H) 67 (68) 37 Method A 1) B(OPh)3 (4 equiv) H2O (1 equiv) (S)-ligand toluene, 80 ºC, 1 h 2) 0.1 mm Hg 80 ºC, 0.5 h entry imi R ligand (S)-ligand borate catalyst (mixture of B1 and B2) %yield %ee cis/trans %yield (mol%) b ne catalyst cis-37 e c cis- 67(68) f d 37 1 36a Ph (S)-VAPOL 5 98 99.8 >50:1 2.0(1.9) 2 36a Ph (R)-VANOL 5 94 –97 >50:1 2.1(1.8) 3 36a Ph (R)-BINOL 5 72 –38 17:1 14(10) 4 36b 2-MeC6H4 (S)-VAPOL 3 91 98 33:1 4.5(2.7) 5 36b 2-MeC6H4 (R)-VANOL 5 90 –97 50:1 2.7(2.7) 35 Table 2.2 (cont’d) 6 36c 4-MeC6H4 (S)-VAPOL 5 95 99.5 >50:1 3.8(0.9) 7 36c 4-MeC6H4 (R)-VANOL 5 94 –97 >50:1 3.6(2.7) 8 36d 4-MeOC6H4 (S)-VAPOL 3 85 98 50:1 1.0(1.0) 9 36d 4-MeOC6H4 (R)-VANOL 5 83 –96 33:1 3.3(4.0) 10 36e 4-BrC6H4 (S)-VAPOL 2 89 99.5 >50:1 1.0(1.0) 11 36e 4-BrC6H4 (S)-VAPOL 3 95 99.6 >50:1 2.0(1.9) 12 36e 4-BrC6H4 (S)-VAPOL 5 97 99.5 >50:1 1.0(1.0) 13 36e 4-BrC6H4 (R)-VANOL 5 95 –97 >50:1 1.2(1.4) 14 36f 4-NO2C6H4 (S)-VAPOL 5 96 99.7 >50:1 1.2(2.0) 15 36f 4-NO2C6H4 (R)-VANOL 5 95 –97 >50:1 1.0(1.9) 16 36k n-hexyl (S)-VAPOL 3 67 90 nd nd 17 36h n-propyl (S)-VAPOL 10 64 93 nd 5.3(8.0) 18 36h n-propyl (S)-VAPOL 10 72 97 nd 3.0(1.5) 19 36h n-propyl (R)-VANOL 10 73 –94 nd 1.0(1.5) 36h n-propyl (R)-VANOL 10 75 –95 nd 1.0(1.0) g h h 20 36 Table 2.2 (cont’d) h,i 21 38h n-propyl (S)-VAPOL 10 69 95 nd 10.3(4.4) h,i 22 38h n-propyl (R)-VANOL 10 75 –93 nd nd(5.3) 23 36i cyclohexyl (S)-VAPOL 3 98 91 >50:1 nd 24 36i cyclohexyl (S)-VAPOL 3 94 91 nd 1.0(3.0) 25 36i cyclohexyl (R)-VANOL 3 95 –91 >50:1 nd 26 36j tert-butyl (S)-VAPOL 3 95 94 >50:1 nd 27 36j tert-butyl (R)-VANOL 3 97 –96 >50:1 nd 36j tert-butyl (R)-VANOL 10 95 –96 nd 1.0(3.0) h h 28 a For all reactions with 5 and 10 mol% catalyst, the catalyst was prepared by Method A. For all reactions with 2 and 3 mol% catalyst, the catalyst was prepared by Method A without water. Unless otherwise specified, all reactions were carried out with 1.0 mmol of 36 at 0.5 M in toluene with 1.2 equiv of 11 at 25 °C and went to completion in 24 h. b All imines were purified by crystallization except 36h, 36k and 38h which were oils and were used without purification. Imine 36k was prepared by method 1 and 36h and 38h were prepared by method 2 given in the experimental section for chapter 2. d c Isolated yield of cis-37 after chromatography on silica gel. Determined on purified cis-37 by HPLC on a CHIRAL CEL OD-H column. 37 e Ratio Table 2.2 (cont’d) 1 determined by integration of the methine protons of the cis- and trans-aziridines in the H NMR spectrum of the crude reaction mixture. nd = not determined. f Determined by integration of the 1 NH signals of 67 and 68 relative to the methine proton of cis-37 in the H NMR spectrum of the crude reaction mixture. 24 h. i g Reaction went to 97% completion. h Reaction performed at 0 °C for Imine prepared from BUDAM amine (see experimental section for chapter 2) and the product was aziridine 56h. There was no improvement in asymmetric induction as a result of lowering the temperature to 0 ºC for either the cyclohexyl or tert-butyl substrates (entries 24 and 28). Most importantly, the asymmetric aziridination of imines from primary aliphatic aldehydes (entries 1622) with the MEDAM protecting group occurred with good yields and excellent asymmetric inductions. In this case, the asymmetric induction could be improved by lowering the temperature to 0 ºC (entries 17 vs. 18 and 19 vs. 20). A slightly lower induction was observed for the BUDAM imine 38h at this temperature (entries 20 vs. 22 and 21 vs. 18). 2.5 Simplification of the aziridination protocol In the continuing effort to gain a mechanistic rationale for the asymmetric induction observed for catalysts generated from VANOL 29 and VAPOL 30, a major breakthrough was the 8 identification of the active boron-ligand complex B3 35. A previous group member, Gang Hu, was able to obtain a crystal structure of the active catalyst 35 which is a complex consisting of a 8b protonated imine and a chiral counteranion in the form of a VAPOL boroxinate. 38 Evidence was also obtained which shows that the actual catalyst 35 was formed upon the addition of an imine to a mixture of pyroborate B2 32 and mesoborate B1 31. Scheme 2.6 Formation of the boroxinate (B3) catalyst 35               H[Imine]+ Ph Ph OPh O B O B O OPh Ph O B OPh + Ph O B1 31a Imine OPh –O B O B O O O B OPh Ph Ph 35 (S)-VAPOL-B3 catalyst B2 32a Therefore, it was thus envisioned that the active catalyst B3 35 could be generated in situ directly from VAPOL rather than making it via B2 32 and B1 31. Consequently, a simplified procedure (Method B, Scheme 2.7) was found. 8b Scheme 2.7 Catalytic asymmetric aziridination reaction with benzhydryl imine 33a with Method B   Ph (S)-VAPOL (5 mol%) + B(OPh)3 (20 mol%) Ph N Ph Ph 33a EDA 11 toluene, 25 ºC, 10min open to air rt, 24h Ph N Ph CO2Et 34a 92% yield 94% ee One of the aims of the current work was to simply the protocol of the catalytic AZ reaction. Hence, the MEDAM imines 36 were subjected to method B with 5 mol% catalyst loading. All imines but one (imine 36e, Table 2.3, entry 6) went to completion. All the imines went to completion when the reaction was done under argon atmosphere (Table 2.3, entries 2, 4, 39 8). Imine 36e went almost to the completion (95 % conversion, Table 2.3, entry 6). Unfortunately, the result with 36e was not reproducible (Table 2.3, entry 6). Table 2.3 Asymmetric aziridination with MEDAM imine 36 with Method B a Ar (S)-VAPOL (5 mol%) + B(OPh)3 (20 mol%) entry Imine b R Ar N Ar 36 EDA 11 toluene, 25 ºC, 10min conditions R N rt, 24h R 37 conditions Ar OMe Ar CO2Et conversion(%) c % yield cis-37 % ee d cis-37 1 Ph Open to air 100 92 98 2 36a Ph Under argon 100 93 98 3 36d 4-MeOC6H4 Open to air 100 78 82 4 36d 4-MeOC6H4 Under argon 100 82 84 5 36e 4-BrC6H4 Open to air 89 97 6 36e 4-BrC6H4 Under argon 58-95 51—87 97 7 36f 4-NO2C6H4 Open to air 100 53 96 8 a 36a 36f 4-NO2C6H4 Under argon 100 95 e 96 100 Unless otherwise specified, all reactions were carried out with 1.0 mmol of 36 at 0.5 M in toluene with 1.2 equiv of 11 at 25 °C following Method B with 5 mol % catalyst. 40 b All imines Table 2.3 (cont’d) were purified by crystallization. c Conversion was determined by integration of the methine 1 protons of the cis-aziridines relative to the Sp2 CH proton of unreacted imine in the H NMR spectrum of the crude reaction mixture. d Isolated yield of cis-37 after chromatography on silica e gel. Determined on purified cis-37 by HPLC on a CHIRAL CEL OD-H column. In order to observe the effect of lowering the catalyst loading on the conversion of imine to aziridine, imine 36e was subjected to method B (under argon) using 2 mol% of VAPOL derived catalyst. As expected, based on the results in table 2.3, only a 35 % conversion was observed (Scheme 2.9). Up until now, the catalyst was allowed to form for 10 min. It was then thought to increase this time period up 1 h. However, an even lower conversion (6%) was observed for imine 36e (Scheme 2.8). This may have happened due to the decomposition of the catalyst during the extended time. Scheme 2.8 Asymmetric aziridination with MEDAM imine 36e with Method B   Ar (S)-VAPOL (2 mol%) + B(OPh)3 (8 mol%) R N Ar 36e toluene, 25 ºC, t min under argon Ar EDA 11 rt, 24h 41 Ar N R CO2Et 37e R = 4-BrC6H4 t = 10 min, conv = 35% t = 60 min, conv = 06% Ar OMe Previously, Gang Hu observed that the benzyl imine 69 forms the boroxinate catalyst 9 readily with VAPOL and B(OPh)3. Thus, we thought to use the same imine in a catalytic amount to generate the B3 catalyst 35 for use in the turnover of the MEDAM imine 36e. Unfortunately, this resulted in a low conversion to aziridine 37e (15%, Scheme 2.9). The presence of aziridine derived from imine 69 could not be confirmed from the messy crude NMR. Scheme 2.9 Asymmetric aziridination with MEDAM imine 36e with Method B'   1)Ph (S)-VAPOL (2 mol%) + B(OPh)3 (8 mol%) N Bn 69 (2 mol%) toluene, 25 ºC, 10min under argon 2) R EDA 11 rt, 24h Ar N Ar Ar 36e Ar Ar OMe N R CO2Et 37e R = 4-BrC6H4 conv = 15% Given the less than satisfactory results with the in situ catalyst formation for imine 36e outlined in Scheme 2.8 (Method B), a variation of this method (Method C) which involved heating the ligand with B(OPh)3 before adding the imine was examined (Scheme 2.10). The only difference between Method C and Method A (Table 2.2) is that the volatiles were not removed under reduced pressure after the heating procedure. Very low conversion (18%) to 37e was observed. However, when water was excluded, an improved conversion of 64% was observed. This increase in conversion suggested that it is necessary to employ the high temperature and the exclusion of water for the generation of an effective catalyst system. As we know that the generation of the active catalyst occurs only after the addition of imine, the next 42 protocol involved heating the ligand, B(OPh)3 and imine altogether (Method D, Scheme 2.11). As with Method C the removal of volatiles after catalyst formation was not employed. The reaction of imine 36e with Method D with 2 mol% catalyst loading gave an 86 % conversion. Finally, an increase in the catalyst loading to 3 mol% (Method D) gave 100 % conversion affording aziridine 36e in 94% yield and 99 % ee (Scheme 2.11). Scheme 2.10 Catalytic asymmetric aziridination with MEDAM imine 36e with Method C   Ar R toluene, 80 ºC 1 h, N2 (S)-VAPOL (2 mol%) + B(OPh)3 H2O (8 mol%) (x mol%) N Ar 36e Ar imine 36e EDA 11 10 min, rt rt, 24h Ar OMe Ar N R CO2Et 37e R = 4-BrC6H4 H2O = 2 mol%, conv = 18% H2O = 0 mol%, conv = 64% Scheme 2.11 Catalytic asymmetric aziridination with MEDAM imine 36e with Method D   Ar (S)-VAPOL (x mol%) + B(OPh)3 (4x mol%) R N Ar 36e toluene, 80 ºC 1 h, N2 Ar EDA 11 rt, 24h x 2 3 43 Ar OMe Ar N R CO2Et 37e R = 4-BrC6H4 conv (%) 86 100 %y % ee – 94 – 99 Henceforth, Method D became the protocol of choice to re-evaluate the aziridination reaction with MEDAM imines 36 with a simplified catalyst preparation procedure. The catalyst was generated by heating VAPOL with B(OPh)3 and the imine 36 in toluene at 80 °C for 1 h. The procedure is experimentally far easier to perform and the results for several aryl imines are (Table 2.4) comparable with that shown in Table 2.2 (Method A). It is to be noted that the asymmetric inductions for the MEDAM imines of aliphatic aldehydes dropped off slightly (2-4% ee) with Method D (Table 2.4) compared to Method A (Table 2.2). The minimum reaction times for the aziridination reaction were determined for all nine MEDAM imine substrates (Table 2.5) with 3 mol% of the catalyst. Table 2.4 Catalytic asymmetric aziridination with MEDAM imine 36 with Method D O Ar (S)-VAPOL (3 mol%) + B(OPh) 3 (12 mol%) entry OEt Ar N R N2 36 b Ar Ar 11 25 °C toluene, 80 °C, 1 h imine Ar N R + time (h) g 4 R(H) 67(68) %yield c %ee cis/trans d cis-37 e %yield 67(68) f 36a Ph 3 94 99 >50:1 3.8(1.9) 36a Ph 0.25 93 98.5 >50:1 2.5(2.0) h 36a Ph 24 94 95.5 50:1 2.8(2.8) i 36a Ph 24 ≤15 nd 2 3 CO2Et (R)H 37 R Ar OMe NH CO2Et cis-37 1 Ar a 44 nd nd Table 2.4 (cont’d) j 36b 2-MeC6H4 24 87 96 33:1 5.0(3.2) 36c 4-MeC6H4 0.5 94 99 >50:1 3.0(1.2) 36d 4-MeOC6H4 24 83 97 50:1 1.2(2.1) 8 36e 4-BrC6H4 2 94 99 >50:1 1.5(1.9) 9 36f 4-NO2C6H4 0.75 95 99 >50:1 1.2(2.0) 36k n-hexyl 24 64 86 nd 10(0) 36i cyclohexyl 3 96 89 50:1 nd 36j tert-butyl 24 93 92 50:1 nd 5 6 7 k 10 l 11 12 a m Unless otherwise specified, all reactions went to completion and were performed with 3 mol% catalyst prepared (Method D) by heating 3 mol% of (S)-VAPOL with 12 mol% B(OPh)3 and 1 mmol of imine 36 as a 0.5 M solution in toluene at 80 °C for 1 h. The flask was cooled to room temperature and then 1.2 equiv of EDA (11) was added and the mixture stirred for the indicated time. nd = not determined. b All imines were purified by crystallization except 36k which was an oil and was used without purification. Imine 36k was prepared by method 1 described in the experimental section for chapter 2. c Isolated yield after column chromatography on silica gel. Determined on purified cis-37 by HPLC on a CHIRAL CEL OD-H column. e d Ratio determined by integration of the methine protons of the cis- and trans-aziridines in the 1H NMR spectrum of 45 Table 2.4 (cont’d) f the crude reaction mixture. nd = not determined. Determined by integration of the NH signals of 67 and 68 relative to the methine proton of cis-37 in the 1H NMR spectrum of the crude reaction mixture. g A separate reaction with 1 mol% catalyst and 5 mmol of 36a and went to 67% completion in 0.5 h. h 100 mol% PhOH was added just prior to EDA (11); this reaction was allowed to run for 24 h, and no attempt was made to determine the minimum reaction time but the reaction did go to completion in 24 h. i 100 mol% H2O was added just prior to EDA (11). Reaction only went to 15% completion in 24 h. No further purification was carried out. 94% conversion after 12 h. completion. m k Reaction went to 97% completion. l j Reaction only went to 87% 20% conversion after 2 h, 44% conversion after 8 h, and 98% conversion after 24 h. With the exception of the p-methoxyphenyl imine 36d and o-methylphenyl imine 36b, which required 24 h to go to 97% and 94% completion respectively (entries 5 and 7, Table 2.4), the reactions of the aryl imines were all complete within 15-120 min. The secondary and tertiary alkyl imines 36i and 36j required 3 – 24 h to reach to completion in the aziridination reaction. The n-hexyl-substituted imine 36k was slower than the cyclohexyl imine 36i and this may be due to the fact that the imine 36k was an oil and was not purified by crystallization. The effects of the added phenol and water on the aziridination reaction of the MEDAM imine 36a were examined. The addition of 100 mol% phenol just prior to the addition of ethyl diazoacetate does not effect the yield of the reaction and only a slight drop in asymmetric induction was observed 46 (entry 3, Table 2.4). This suggests that the removal of phenol during catalyst preparation in Method A does not have a significant benefit on the aziridination reaction. The reaction went to only 15% completion after 24 h when 100 mol% water was added to the reaction mixture which suggests that the catalyst may have been effected (entry 4, Table 2.4). 2.6 Deprotection of MEDAM group The nucleophilic opening of the aziridines usually requires an electron-withdrawing group on the nitrogen. Hence, the ability to remove the MEDAM protecting group from the nitrogen in the aziridines 37 would be important for their applications in organic synthesis. The protocol for the deprotection of MEDAM group involves treatment with 5 equiv of triflic acid in anisole. 5 This deprotection protocol was previously developed for the cleavage of DAM aziridines 58. To our delight, the deprotection of the phenyl-substituted MEDAM aziridine 37a proceeded smoothly under this standard procedure to give the N-H aziridine 59a in 95% yield. The attempted deprotection of electron rich p-methoxyphenyl aziridine 37d and p-methylphenyl aziridine 37c resulted in complex mixtures of various products. Interestingly, the cleavage of 2methyl substituted aryl aziridine 37b proceeded smoothly to give a 97% yield of the N-H aziridine 59b. The aziridines 37e and 37f with electron poor phenyl substituents gave 96% and 97% yields of the corresponding N-H aziridines upon deprotection of the MEDAM group (entry 5 and 6 in Table 2.5). The alkyl substituted aziridines required heating to 65 ºC to liberate the NH aziridines (entry 7–9 Table 2.5) and gave good to excellent yields. 47 Table 2.5 Deprotection of MEDAM aziridines 37 MEDAM N R a H N TfOH (5 equiv) CO2Et anisole 37 R CO2Et 59 b entry R time (h) temp (ºC) % yield 59 1 37a Ph 2 25 95 2 37b 2-MeC6H4 1 25 97 3 37c 4-MeC6H4 1 25 – 4 37d 4-MeOC6H4 1 25 – 5 37e 4-BrC6H4 1 25 96 6 37f 4-NO2C6H4 1 25 97 7 37h n-propyl 1 65 73 8 37i cyclohexyl 0.5 65 90 9 a aziridine 37j tert-butyl 0.7 65 88 c c d Unless otherwise specified, all reactions went to completion and were performed with 5 equivalent of triflic acid 60 and 0.5 mmol of aziridine 37 as a 0.15 M solution in anisole at the indicated temperature for the indicated time. The reactions were quenched with saturated aq. Na2CO3 solution. b Isolated yield after chromatography on silica gel. observed including ring-opened products. d c Mixtures of products The NMR yield was 76% with Ph3CH as internal standard. 48 In the deprotection of the dianysylmethyl group from aziridines, the solvent anisole acts as a nucleophile to trap the dianisylmethyl cation generated during the course of the reaction. Hence, it might be possible to intercept the reaction with another nucleophile to trap the dianisylmethyl cations. The aim of the present work is to trap the substituted dianisylmethylcation 69 with a nucleophile so that the resulting product could be transformed to substituteddianysylmethyl amine. In this way, it would be possible to recover the MEDAM amine 66. It was then thought to perform the reaction using acetonitrile as solvent following the Ritter reaction protocol. 10 It was expected that acetonitrile would serve as a nucleophilic trap for the cation 69 to produce corresponding acetamide 71 upon hydrolysis (scheme 2.12). Scheme 2.12 Proposed Protocol for trapping of dianisyl cation 69 with acetonitrile   Ar Ar acid catalyzed deprotection N R H N R CO2Et Ar hydrolysis NH2 Ar Ar H CO2Et 59 37, Ar2CH = MEDAM 58, Ar2CH = DAM Ar + 69 CH3CN Ar Ar HN H2O Ar Ar N O 66, Ar2CH = MEDAM 72, Ar2CH = DAM 71 70 The N-DAM aziridine 58a was used as a model system for the optimization of this proposed deprotection protocol. It was envisioned that these conditions with little variations 49 would be general to all of the N-MEDAM aziridines 37. A series of experiments were carried out to study the effects of the concentration of reaction, equivalents of triflic acid 60, the temperature and the reaction time on the yield of aziridine 59. The optimized reaction conditions were found to be the use of 2.5 equivalents of triflic acid, 2 h reaction time and room temperature with 0.2 M concentration of 58a (Scheme 2.13). Although the N-H aziridine 59a was obtained with 92% yield, no N-DAM acetamide 71 was observed. This result could be explained to be the result of an equilibrium between dianisylmethyl cation 69 and 70 (Scheme 2.14) and the selective reaction of 69 with water during the reaction quench. Scheme 2.13 Deprotection of DAM aziridine 58a in acetonitrile   MeO OMe 1) TfOH (2.5 equiv) CH3CN, rt, 2 h N Ph CO2Et 2) sat. aq Na2CO3 H N Ph CO2Et 59a 92% yield 58a (0.2 M) Although the carbonium ion 69 is relatively stable, the electrophilic reactivity of the 11 carbocation might not be high. Additionally, it is possible that the dianisyl cation 69 could decompose via self-polymerization. Scheme 2.14 Equilibrium between cation 69 and 70   MeO OMe MeO OMe H N 70 69 50 If in fact the cations 69 and 70 are not being intercepted, it may perhaps be necessary to use a more nucleophilic solvent. Mayr and coworkers studied the rate of decomposition of different substituted benzhydryl cations in different solvent medium, 11 According to their study, 20% water (v/v) in acetonitrile could be the optimum solvent combination. A series of experiments were performed in acetonitrile water (4:2 v/v) medium to study the effects of the concentration of triflic acid, the temperature and the reaction time on the formation of the desired products. In all the experiments performed, a slow decomposition of initially formed N-H aziridine was observed with time. However, 4,4′-dimethoxybenzhydrol 73a was obtained as one of the major product of the reaction. These observations suggested that acid promoted ring opening of the aziridine was occurring in presence of water. Dry acetonitrile was then used as the solvent to avoid the ring opening of aziridine. After several attempts, the optimum reaction condition was found to be the use of 10 equiv of triflic acid 60 at room temperature at 0.1M concentration of 58a, which gave the aziridine 59a and benzhydrol 73a was 86% and 62% isolated yields respectively (Scheme 2.15). The alcohol 73a was possibly formed due to the trapping of cation 69 with water during the reaction quench. However, when the deprotection of N-MEDAM aziridine 37a was carried out using the same reaction conditions, the reaction was incomplete even after 2 h. However, at elevated temperature (65 ºC) the reaction went to completion after 15 min and afforded the N-H aziridine 59a and benzhydrol 73b in 88% and 40% NMR yields respectively (Scheme 2.15). It must be noted that water was acting as a nucleophile to trap the 4,4′-dimethoxybenzhydryl cation 69 in all of the above deprotection experiments during the work up procedure. In order to attain the dianisyl amine directly, nucleophilic amines could possibly be employed instead of oxygen nucleophile and this should be the subject of future experiments. 51 Scheme 2.15 Deprotection of N-protected aziridines and trapping of dianisyl cation with water. (A) Deprotection of N-DAM aziridine 58a (B) Deprotection of N-MEDAM aziridine 37a A. Ar Ar N   Ph 58a CO2Et 1) TfOH (10 equiv) CH3CN, 25 ºC, 50 min 2) sat. aq Na2CO3 Ar H N Ph Ar + Ar OH CO2Et 59a 86% yield 73a 62% yield OMe B. Ar Ar N Ph CO2Et 2) sat. aq Na2CO3 H N Ph + CO2Et 59a 86% NMR yield 37a 2.7 Ar 1) TfOH (10 equiv) CH3CN, 65 ºC, 15 min Ar Ar OH 73b 40% NMR yield OMe Conclusions A summary of the results of the asymmetric inductions for the catalytic asymmetric aziridination with the VANOL-derived catalyst are plotted in Figure 2.1 for nine different imine substrates against four different N-substituents on the imine. A similar plot with VAPOLderived catalyst is presented in Figure 2.2. The data in Figures 2.1 and 2.2 are taken from the present work (MEDAM) and from previous work (Bh, DAM and BUDAM). The AZ reactions were carried out in toluene at room temperature except for the imines derived from n-butanal which were done at 0 ºC. Also, the reactions of DAM imines with VANOL-derived catalyst were performed in carbon tetrachloride. 5 Similar trends are observed for both the VANOL and VAPOL ligands. The six aromatic substrates with benzhydryl 2c 5 and DAM protecting group gave an average induction of 89% ee and 94% ee, respectively. The aromatic substrates with 52 6 3 MEDAM and BUDAM protecting groups gave the highest inductions with an average of 99% ee and 98% ee, respectively. It is clear from both figures that the MEDAM substituent is the most effective protecting group for the aliphatic imines. The average induction for the 1º, 2º and 3º aliphatic imines with the MEDAM protecting group is 94% ee with both the VAPOL and VANOL-derived catalysts. In contrast, the aliphatic imines gave an average induction of 85% ee for benzhydryl, 79% ee for DAM and 87% ee for the BUDAM protecting group, which is clearly not as effective as the N-MEDAM substituent. Figure 2.1 Distribution of the asymmetric inductions with the protecting group for the VANOL derived catalyst O Br 53 NO 2 Figure 2.2 Distribution of the asymmetric inductions with the protecting group for the VAPOL derived catalyst O Br NO 2 The results from the above comparisons clearly indicate that for the catalytic asymmetric aziridination reaction of imines with ethyl diazoacetate, the best N-substituent is the MEDAM substituent. Later, another group member Anil Gupta developed a multi-component cis12 aziridination protocol utilizing MEDAM amine as one of the components. Further, the MEDAM substituent also proved to be the protecting group of choice for the trans-aziridination 13 reaction as well. 54 APPENDIX 55 2.8 2.8.1 Experimental procedure General information All reactions were carried out in flame-dried glassware under an atmosphere of argon or nitrogen unless otherwise indicated. Triethylamine, dichloromethane and acetonitrile were distilled over calcium hydride under nitrogen. Tetrahydrofuran, dioxane and ether were distilled from sodium and benzophenone. Toluene was distilled from sodium under nitrogen. Hexanes and ethyl acetate were ACS grade and used as purchased. Melting points were recorded on a Thomas Hoover capillary melting point apparatus and are uncorrected. IR spectra were recorded in KBr matrix (for solids) and on NaCl disc (for 1 liquids) on a Nicolet IR/42 spectrometer. H NMR and 13 C NMR were recorded on a Varian 300 MHz or VXR-500 MHz spectrometer using CDCl3 as solvent (unless otherwise noted) with the 1 residual solvent peak as the internal standard ( HNMR: 7.24 ppm, 13 CNMR: 77 ppm). Chemical shifts were reported in parts per million. Low-resolution Mass Spectrometry and High Resolution Mass Spectrometry were performed in the Department of Chemistry at Michigan State University. Analytical thin-layer chromatography (TLC) was performed on Silicycle silica gel plates with F-254 indicator. Visualization was by short wave (254 nm) and long wave (365 nm) ultraviolet light, or by staining with phosphomolybdic acid in ethanol or with potassium permanganate. Column chromatography was performed with silica gel 60 (230 – 450 mesh). HPLC analyses were peformed using a Varian Prostar 210 Solvent Delivery Module with a Prostar 330 PDA Detector and a Prostar Workstation. Chiral HPLC data for the aziridines were 56 obtained using a CHIRALCEL OD-H column, CHIRALPAK AD column and PIRKLE COVALENT (R, R) WHELK-O 1 column. Optical rotations were obtained on a Perkin-Elmer 341 polarimeter at a wavelength of 589 nm (sodium D line) using a 1.0 decimeter cell with a total volume of 1.0 mL. Specific rotations are reported in degrees per decimeter at 20 °C and the concentrations are given in gram per 100 mL in ethyl acetate unless otherwise noted. All reagents were purified by simple distillation or crystallization with simple solvents unless otherwise indicated. Ethyl diazoacetate 11, triphenylborate, p-toluenesulfonic acid, triflic acid and benzhydrylamine (distilled prior to use) obtained from Aldrich Chemical Co., Inc. and used as received. 4-Bromo-2,6-dimethylphenol (99%) was obtained from Alfa Aesar and used as 14 received. VAPOL and VANOL were made according to published procedure. These ligands are also commercially available from Aldrich Chemical Co., Inc and Strem Chemicals. Bis-(3,53 di-tert-butyl-4-methoxyphenyl)methanamine (BUDAM amine 60) was made according to the published procedure. Acronyms used for N-protecting groups. MeO t-Bu OMe t-Bu t-Bu t-Bu OMe MeO BUDAM MEDAM OMe MeO DAM Bh 57 Figure 2.3. Homemade Schlenk flask: The Schlenk flask was prepared from a single-necked 25 mL pear-shaped flask that had its 14/20 glass joint replaced with a high vacuum threaded Teflon valve. 2.8.2 Synthesis of MEDAM Amine 66 HO Br NaH, MeI DMSO 61 MeO DMF Br reflux, 8 h MeO Br 62 99% yield CuCN 62 MeO OMe MeO MeO CN MgBr 63 90% yield LAH 64 MeO OMe NH2 N 66 88% yield 65 58 MgBr 15,16 5-bromo-2-methoxy-1, 3-dimethylbenzene 62 : A 2-L three-necked round-bottomed flask, equipped with an overhead mechanical stirrer and sealed with rubber septum at the other two necks, was flame-dried and cooled under nitrogen. DMSO (1.2 L, stored over 4Å MS) was added through one of the necks using a glass funnel. Thereafter, sodium hydride (47.4 g, 1200 mmol, 60% dispersion in mineral oil) was added using a powder funnel. During addition, a continuous flow of nitrogen was maintained at the other neck using a needle attached directly to the nitrogen source. The source of nitrogen was then changed to a nitrogen-filled balloon. The flask was then transferred to an ice bath and stirred vigorously at 120 rpm. The stirring must be turned on before the flask was submerged into the 0 ºC bath (vigorous stirring is required in order to avoid DMSO freezing at 0 ºC). This was followed by the slow addition of 4-bromo-2, 6- dimethylphenol 61 (100 g, 497 mmol) in portions (~ 10 g each time) using a powder funnel, over a period of 40 min. The resulting suspension was stirred at 0 °C for 15 min. One of the rubber septums was then replaced by 250-mL pressure-equalizing addition funnel fitted with a nitrogen balloon through the rubber septum at the top of the funnel. Iodomethane (126.9 mL, 289.3 g, 2038 mmol) was then added via addition funnel over a period of 25 min. The mixture was stirred at 0 ºC (ice-bath) for 15 min. The reaction mixture was then allowed to gradually warm up to room temperature (~ 2 h), and stirred at room temperature for an additional 3 h. The reaction mixture was cooled to 0 °C, and diluted with hexanes (345 mL). The mixture was then poured into a 4 L Erlenmeyer flask containing hexanes (425 mL) at 0 ºC, the mixture was stirred with a mechanical stirrer at 100 rpm while slowly adding water (425 mL) over a period of 30 min and the mixture was then stirred until two layers appeared. The organic layer was separated using a 6 L separatory funnel, and the aqueous layer was extracted with hexanes (170 mL × 3). 59 The combined organic layer was then washed with water (300 mL × 3), dried over MgSO4 and concentrated by rotary evaporation to give the crude product 62 as a light yellow liquid. The crude product was purified by simple short-path distillation. The crude product was transferred to a 250-mL, round-bottomed flask equipped with a magnetic stir bar. The product is distilled under vacuum through a straight 12-cm air condenser, which is topped with a short-path distillation assembly. The product bumps during distillation. The desired product 62 was collected in the 8083 °C fraction (1 mm Hg, oil bath temp ~ 120 °C) and obtained as a colorless liquid in 99% yield (105.7 g, 492 mmol). 1 Spectral Data for 62: Colorless liquid; H-NMR (300 MHz, CDCl3) δ 2.15 (s, 6H), 3.83 (s, 3H), 7.08 (s, 2H); 13 C-NMR (75 MHz, CDCl3) δ 15.06, 60.72, 126.61, 131.80, 113.22, 155.51. These spectral data match those previously reported for this compound. 17 7 4-methoxy-3,5-dimethylbenzonitrile 63 : A 2-L three-necked round-bottomed flask, equipped with a stir bar and an air condenser (25 mm × 350 mm) followed by a water condenser (17 mm × 220 mm) and sealed with rubber septums at all three necks including the reflux condenser, was flame-dried and cooled under nitrogen. To this flask was added 5-bromo-2-methoxy-1, 3dimethylbenzene 62 (33.4 mL, 45 g, 209 mmol) and anhydrous DMF (450 mL, freshly distilled and stored over 4Å MS) using a 60 mL syringe. This was followed by the addition of CuCN (22.5 g, 251 mmol) through one of the necks utilizing a powder funnel. During addition, a continuous flow of nitrogen was maintained at the other neck using a needle attached directly to nitrogen source. The same nitrogen source was then used to purge the reaction mixture with nitrogen under the surface of the solution for 15 min. The source of nitrogen was then changed 60 to a nitrogen-filled balloon on the top of the condenser attached via needle through a rubber septum stopper. Thereafter, the rubber septums at the other two necks were replaced by Teflon stoppers. The mixture was then heated to reflux in an oil bath (180 ºC) for 8 h. During the refluxing, the solid CuCN dissolved after approximately 2 h and a light green precipitate of CuBr was observed which further dissolves to give a brown colored solution over the course of time. The reaction mixture was then cooled gradually to room temperature and after cooling down, it was a dark green solution with a small amount of a light green precipitate of a copper salt at the bottom of the flask. The reaction mixture was then slowly poured into a 4 L Erlenmeyer flask containing an aqueous solution of ethylene diamine (90 mL ethylene diamine in 2240 mL water) at 0 ºC (ice-bath). The resulting reaction mixture was then allowed to warm gradually to room temperature. Benzene (680 mL) was added and the resulting mixture was stirred at room temperature for 20 min and then transferred directly into a 6 L separatory funnel. The top organic layer was separated. The aqueous layer was then extracted with benzene (250 mL × 4). The combined organic layer was washed with an aqueous 1.2 M NaCN solution (350 mL), and then with water (400 mL × 2). After drying over MgSO4 the volatiles were removed by rotary evaporation to afford the crude product as an off-white solid (32 g). The crude product was purified by crystallization (using hot hexanes, ~ 40 mL) to afford the final product 63 as white solid (mp 48-49 °C) in 90 % yield (30.3 g, 188 mmol, a combine yield of two crops). 1 Spectral Data for 63: H-NMR (CDCl3, 300 MHz) δ 2.26 (s, 6H), 3.72 (s, 3H), 7.29 (s, 2H); 13 C-NMR (CDCl3, 75 MHz) δ 15.93, 59,73, 107.25, 118.99, 132.46, 132.70, 160.75; IR (thin film) 2960vs, 2225vs, 1014s cm-1; Mass spectrum: m/z (% rel intensity) 161 M+ (80), 145 (100), 116 (24); Anal calcd for C10H11NO: C, 74.51; H, 6.88; N, 8.69. Found: C, 74.67; H, 6.87; N, 61 8.58. These spectral data match those previously reported for this compound. 3 18 Bis-(2,6-di-methyl-4-methoxyphenyl)methineamine 66 : A 1-L three necked round-bottomed flask, equipped with a stir bar and a reflux condenser (33 mm × 470 mm) and sealed with rubber septum at all three necks including reflux condenser, was flame-dried and cooled under nitrogen. To this flask was added magnesium (13.0 g, 534.7 mmol, 2.8 equiv, 20 mesh) through one of the necks utilizing a powder funnel. Next, anhydrous THF (450 mL, freshly distilled) and a few crystals of iodine were added. During addition, a continuous flow of nitrogen was maintained at the other neck using a needle attached directly to a nitrogen source. The source of nitrogen was then changed to a nitrogen-filled balloon on the top of the condenser via a needle through a rubber septum stopper. Then 5-bromo-2-methoxy-1,3-dimethylbenzene 62 (33.4 mL, 45 g, 209 mmol, 1.1 equiv) was added using a 60 mL syringe. Thereafter, the rubber septums at the other two necks were replaced by Teflon stoppers. The mixture was then heated to reflux in an oil bath (78 ºC) for 4 h. The resulting clear grey solution was allowed to cool down to room temperature. One of the Teflon stoppers was then replaced by a rubber septum. The mixture was then transferred via cannula to a flame-dried 2-L three-necked round-bottomed flask equipped with a refluxing condenser under nitrogen. Meanwhile, to a flame-dried 1L roundbottomed flask, filled with nitrogen, was added 4-methoxy-3, 5-dimethylbenzonitrile 63 (30.6 g, 190 mmol, 1.0 equiv) and THF (400 mL, freshly distilled). This solution was then transferred via cannula to the 2-L three-necked round-bottomed flask containing the freshly prepared Grignard reagent over a period of 20 min at room temperature. The resulting mixture was heated to reflux in an oil bath (78 ºC) for 7 h under nitrogen, then allowed to cool down to room temperature, and then to 0 ºC (ice-bath). Meanwhile, a suspension of LiAlH4 (8 g, 210 mmol) in 62 THF (200 mL, freshly distilled) was prepared in a flame-dried 500 mL flask filled with nitrogen and pre-cooled at 0 ºC. Next, the LAH suspension was transferred to 2-L three-necked roundbottomed flask containing in-situ generated imine 65 via cannula at 0 ºC. The ice bath was then removed, and the resulting greenish yellow reaction mixture was heated to reflux in an oil bath (78 ºC) for 20 h under nitrogen. The reaction flask was cooled down to room temperature, and carefully quenched by the slow addition of water (8 mL), then 3.75 M NaOH solution (8 mL), and water (24 mL) over a period of 10 min. The resulting suspension was filtered through a Celite (503) pad into a 2 L round bottom flask and washed with ether until no amine was left (monitored by TLC analysis on silica gel, appearance of red spot upon visualization with phosomolybidic acid indicates the presence of amine). The total volume of the ether mixture was reduced to around 500 mL using rotatory evaporation and then it was transferred to 2 L Erlenmeyer flask. Conc. HCl (~ 50 mL, 12 M, precooled to 0 ºC) was added portion-wise (~ 5 mL each time) till the pH ~ 2 (determined by pH paper) resulting in the appearance of a yellowish white precipitate. During the addition, continuous stirring is recommended. The yellow colored organic layer was discarded by decanting. The white solid was washed with ether (200 mL × 2) and organic layer was discarded by decanting. It was then followed by the addition of the ether (400 mL). To this mixture was added 6 M NaOH (~ 100 mL) in portions (~ 10 mL each time) till the pH~12. During addition, the mixture was stirred for approximately 20 min until the entire solid dissolved. The reaction mixture was then transferred to 2 L separatory funnel. The organic layer was separated and aqueous layer was washed with ether (200 mL × 3). The combined organic layer was dried over MgSO4, filtered, and concentrated by rotary evaporation to afford a pale-yellow solid (52 g). The crude amine 66 was crystallized from hot hexanes (~ 60 mL) to afford white crystalline solid (mp 59-61 °C) in 88% yield (50 g, 167.2 63 mmol, a combined yield of several crops). 1 Spectral Data for 66: H-NMR (CDCl3, 300 MHz) δ 1.73 (s, 2H), 2.26 (s, 12H), 3.69 (s, 6H), 5.00 (s, 1H), 7.01 (s, 4H); 13 C-NMR (CDCl3, 75 MHz) δ 16.10, 58.77, 59.50, 126.96, 130.56, -1 140.88, 155.65; IR (thin film) 3376m, 3306m, 2943vs, 1493s cm ; Mass spectrum: m/z (% rel + intensity) 299 M (35), 298 (54), 283 (47), 268 (94), 163 (100); Anal calcd for C19H25NO2: C, 76.22; H, 8.42; N, 4.68. Found: C, 75.89; H, 8.54; N, 4.62. These spectral data match those previously reported for this compound. 2.8.3 3 General Procedure for the synthesis of MEDAM aldimines 36 and BUDAM imine 38h – Illustrated for the synthesis of N-phenylmethylidene-bis(4-methoxy-3,5dimethylphenyl)methylamine 36a. All liquid aldehydes were distilled before use and the solid aldehydes were used as purchased from Aldrich. All imines 36a-j could be purified by crystallization except 36h, 36k and 38h. O + MEDAM NH2 MgSO4 MEDAM N CH2Cl2, 25 °C, 24 h 36a 66 3 N-phenylmethylidene-bis(4-methoxy-3,5-dimethylphenyl)methylamine 36a : To a 50 mL flame-dried round bottom flask filled with argon was added bis(2,6-di-methyl-4- 64 methoxyphenyl)methylamine 66 (1.49 g, 5.00 mmol), MgSO4 (1.0 g, 8.4 mmol, freshly flamedried) and dry CH2Cl2 (15 mL). After stirring for 10 min, benzaldehyde (0.54 g, 5.05 mmol, 1.01 equiv) was added. The reaction mixture was stirred at room temperature for 24 h. The reaction mixture was filtered through Celite and the Celite bed was washed with CH2Cl2 (10 mL × 3) and then the filtrate was concentrated by rotary evaporation to give the crude imine as an off-white solid. Crystallization (1: 9 CH2Cl2/hexanes) and collection of the first crop afforded 36a as a white solid (mp 144-146 °C) in 90% isolated yield (1.74 g, 4.5 mmol). 1 Spectral data for 36a: H-NMR (CDCl3, 500 MHz) δ 2.24 (s, 12H), 3.66 (s, 6H), 5.35 (s, 1H), 6.99 (s, 4H), 7.39-7.41 (m, 3H), 7.80-7.82 (m, 2H), 8.35 (s, 1H); 13 C-NMR (CDCl3, 125 MHz) δ 16.22, 59.59, 77.41, 127.86, 128.46, 128.49, 130.61, 130.63, 136.45, 139.22, 155.84, 160.28; -1 IR (thin film) 2944w, 1643vs, 1483vs cm ; Mass spectrum: m/z (% rel intensity) 387 M+ (3), 283 (100), 40 (17); Anal calcd for C26H29NO2: C, 80.59; H, 7.54; N, 3.61. Found: C, 80.42; H, 7.24; N, 3.55. These spectral data match those previously reported for this compound. O + MEDAM NH2 MgSO4 3 MEDAM N CH2Cl2, 25 °C, 24 h 36b 66 N-(o-tolylbenzylidene)-bis(4-methoxy-3, 5-dimethylphenyl)methylamine 36b: Imine 36b was prepared from o-tolualdehyde according to the procedure described above for imine 36a. 65 Crystallization (1:10 CH2Cl2/hexanes) and collection of the first crop afforded 36b as white solid crystals (mp 75-76 ºC) in 75% isolated yield (1.50 g, 3.75 mmol). 1 Spectral data for 36b: H-NMR (CDCl3, 500 MHz) δ 2.24 (s, 12H), 2.51 (s, 3H), 3.67 (s, 6H), 5.33 (s, 1H), 7.01 (s, 4H), 7.15 (d, 1H, J = 7.3 Hz), 7.22-7.24 (m, 1H), 7.26 (dd, 1H, J = 1.7, 7.3 Hz), 7.98 (dd, 1H, J = 1.7, 7.6 Hz), 8.65 (s, 1H); 13 C-NMR (CDCl3, 125 MHz) δ 16.22, 19.58, 59.59, 78.26, 126.03, 127.78, 128.34, 130.15, 130.62, 130.78, 134.34, 137.81, 139.48, 155.81, -1 158.99. IR (thin film): 2942vs, 1483vs, 1220vs cm ; HRMS (ESI-TOF) m/z 402.2434 [(M+H+); calcd. for C27H32NO2 : 402.2433]. O + MgSO 4 MEDAM NH 2 CH2Cl2, 25 °C, 24 h N MEDAM 36c 66 N-(p-tolylbenzylidene)-bis(4-methoxy-3,5-dimethylphenyl)methylamine 36c: Imine 36c was prepared from p-tolualdehyde according to the procedure described above for imine 36a. Crystallization (1:10 CH2Cl2/hexanes) and collection of the first crop afforded 36c as white solid crystals (mp 138.5-139 ºC) in 92% isolated yield (1.85 g, 4.60 mmol). 1 Spectral data for 36c: H-NMR (CDCl3, 500 MHz) δ 2.24 (s, 12H), 2.37 (s, 3H), 3.67 (s, 6H), 5.34 (s, 1H), 6.99 (s, 4H), 7.19 (d, 2H, J = 8.1 Hz), 7.71 (d, 2H, J = 8.4 Hz), 8.32 (s, 1H); 13 C- NMR (CDCl3, 125 MHz) δ 16.22, 21.51, 59.59, 77.36, 127.87, 128.46, 129.18, 130.59, 134.10, 66 -1 139.33, 140.88, 155.78, 160.21; IR (thin film) 2943vs, 1483vs, 1219vs cm ; HRMS (ESI-TOF) m/z 402.2425 [(M+H+); calcd. for C27H32NO2 : 402.2433]. O + NH2 MeO MEDAM MgSO4 MEDAM N CH2Cl2, 25 °C, 24 h MeO 66 36d N-(4-methoxybenzylidene)-bis(4-methoxy-3,5-dimethylphenyl)methylamine 36d: Imine 36d was prepared from p-methoxybenzaldehyde according to the procedure described above for imine 36a. Crystallization (1:10 CH2Cl2/hexanes) and collection of the first crop afforded 36d as white solid crystals (mp 119-120 ºC) in 85% isolated yield (1.40 g, 3.40 mmol). 1 Spectral data for 36d: H-NMR (CDCl3, 500 MHz) δ 2.24 (s, 12H), 3.67 (s, 6H), 3.82 (s, 3H), 5.32 (s, 1H), 6.91 (d, 2H, J = 8.5 Hz), 6.99 (s, 4H), 7.76 (d, 2H, J = 9.0 Hz), 8.29 (s, 1H); 13 C- NMR (CDCl3, 125 MHz) δ 16.21, 55.34, 59.59, 77.30, 113.85, 127.87, 129.47, 130.03, 130.57, -1 139.45, 155.78, 159.57, 161.63; IR (thin film) 2936vs, 1606vs, 1483vs, 1251vs cm ; HRMS + (ESI-TOF) m/z 418.2382 [(M+H ); calcd. for C27H32NO3 : 418.2382]. O Br + MEDAM NH2 MEDAM MgSO4 N CH2Cl2, 25 °C, 24 h Br 66 67 36e N-(4-Bromobenzylidene)-bis(4-methoxy-3,5-dimethylphenyl)methylamine 36e: Imine 36e was prepared from p-bromobenzaldehyde according to the procedure described above for imine 36a. Crystallization (1:10 CH2Cl2/hexanes) and collection of the first crop afforded 36e as white solid crystals (mp 156-157 ºC) in 93% isolated yield (2.20 g, 4.65 mmol). 1 Spectral data for 36e: H-NMR (CDCl3, 500 MHz) δ 2.25 (s, 12H), 3.68 (s, 6H), 5.35 (s, 1H), 6.99 (s, 4H), 7.53 (d, 2H, J = 8.0 Hz), 7.69 (d, 2H, J = 8.5 Hz), 8.29 (s, 1H); 13 C-NMR (CDCl3, 125 MHz) δ 16.23, 59.59, 77.39, 125.03, 127.79, 129.89, 130.72, 131.71, 135.30, 138.97, -1 155.91, 159.05; IR (thin film) 2941vs, 1483vs, 1221vs, 1011vs cm ; HRMS (ESI-TOF) m/z + 79 466.1374 [(M+H ); calcd. for C26H29NO2 Br : 466.1382]. O + O2N MEDAM NH2 MEDAM MgSO4 N CH2Cl2, 25 °C, 24 h O2N 66 36f N-(4-Nitrobenzylidene)-bis(4-methoxy-3,5-dimethylphenyl)methylamine 36f: Imine 36f was prepared from p-nitrobenzaldehyde according to the procedure described above for imine 36a. Crystallization (1:3 CH2Cl2/hexanes) and collection of the first crop afforded 36f as pale yellow solid crystals (mp 139-140 ºC) in 92% isolated yield (2.00 g, 4.62 mmol). 1 Spectral data for 26f: H-NMR (CDCl3, 500 MHz) δ 2.25 (s, 12H), 3.68 (s, 6H), 5.41 (s, 1H), 6.99 (s, 4H), 7.98 (d, 2H, J = 9.0 Hz), 8.25 (d, 2H, J = 8.7 Hz), 8.42 (s, 1H); 68 13 C-NMR (CDCl3, 125 MHz) δ 16.24, 59.61, 77.64, 123.78, 127.75, 129.13, 130.9, 138.51, 141.83, 149.07, 156.08, -1 158.03; IR (thin film) 2943vs, 1522s, 1344s, 1221s cm ; HRMS (ESI-TOF) m/z 433.2127 + [(M+H ); calcd. for C26H29N2O4 : 433.2127]. O + MEDAM NH2 MEDAM MgSO4 N CH2Cl2, 25 °C, 24 h 36i 66 N-Cyclohexylmethylidene-bis(3,5-dimethyl-4-methoxyphenyl)methylamine 36i: Imine 36i was prepared from cyclohexanecarbaldehyde according to the procedure described above for imine 36a. Crystallization (1: 60 EtOAc/hexanes) and collection of the first crop afforded 36i as white solid crystals (mp 108-109 ºC) in 71% isolated yield (1.40 g, 3.55 mmol). 1 Spectral data for 36i: H-NMR (CDCl3, 300 MHz) δ 1.17-1.34 (m, 5H), 1.64-1.84 (m, 5H), 2.19-2.35 (m, 1H), 2.23 (s, 12H), 3.67 (s, 6H), 5.05 (s, 1H), 6.91 (s, 4H), 7.59 (d, 1H, J = 5.1 Hz); 13 C-NMR (CDCl3, 75 MHz) δ 16.19, 25.42, 26.01, 29.79, 43.51, 59.59, 77.44, 127.74, -1 130.49, 139.39, 155.69, 168.59; IR (thin film): 2926s, 1665m, 1483s 1221s, 1142m, 1017s cm ; Mass spectrum m/z (% rel intensity) 393 M+ (0.22), 283 (100), 268 (15), 163 (54), 142 (24), 134 (15), 77 (11), 44 (10) O + MEDAM NH2 MgSO4 MEDAM N CH2Cl2, 25 °C, 24 h 36j 66 69 N-(1,1′-dimethylethylidene)-bis(4-methoxy-3,5-dimethylphenyl)methylamine 36j: Imine 36j was prepared according to the procedure described above for imine 36a. Crystallization (1: 100 CH2Cl2/hexanes) and collection of the first crop afforded 36j as white solid crystals (mp 90-91 ºC) in 85% isolated yield (1.56 g, 4.25 mmol). 1 Spectral data for 36j: H-NMR (CDCl3, 300 MHz) δ 1.09 (s, 9H), 2.23 (s, 12H), 3.68 (s, 6H), 5.08 (s, 1H), 6.91 (s, 4H), 7.61 (s, 1H); 13 C-NMR (CDCl3, 75 MHz) δ 16.22, 27.04, 36.33, 59.59, 76.75, 127.71, 130.41, 139.63, 155.62, 171.11; IR (thin film): 2955vs, 1663m, 1483s, -1 1221s, 1017s cm ; Mass spectrum m/z (% rel intensity) 367 M+ (0.8), 283 (100), 268 (22), 253 (12), 210 (11), 195 (14), 178 (8), 141 (34), 133 (11), 118 (19), 41 (10) See page 18, 21 and 26 for synthesis of Imines 36h, 38h and 36k respectively. 2.8.4 General Procedure for the synthesis of MEDAM aziridines 37 and BUDAM aziridine 56h (via Method A) - Illustrated for the synthesis of (2R,3R)-ethyl 1-(bis(4methoxy-3,5-dimethylphenyl)methyl)-3-phenylaziridine-2-carboxylate 37a MEDAM N O + 36a N OEt toluene, 25 °C, 24 h N2 Ph 11 1.2 equiv Ph + 67a(68a) Catalyst toluene, 80 °C, 1 h 80 °C, 0.5 h 70 CO2Et Ph(H) 0.1 mm Hg (S)-VAPOL NH (Ph)H CO2Et 37a B(OPh)3 (4.0 equiv) H2O (1.0 equiv ) MEDAM MEDAM 5 mol% Catalyst (2R,3R)-ethyl-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-phenylaziridine-2carboxylate 37a: To a 25 mL flame-dried home-made Schlenk flask (Figure 2.3) equipped with a stir bar and flushed with argon was added (S)-VAPOL (27 mg, 0.05 mmol) and B(OPh)3 (58 mg, 0.2 mmol). Under an argon flow through the side arm of the Schlenk flask, dry toluene (2 mL) was added through the top of the Teflon valve to dissolve the two reagents and this was followed by the addition of water (0.9 µL, 0.05 mmol). The flask was sealed by closing the Teflon valve, and then placed in an 80 ºC (oil bath) for 1 h. After 1 h, a vacuum (0.5 mm Hg) was carefully applied by slightly opening the Teflon valve to remove the volatiles. After the volatiles are removed completely, a full vacuum is applied and is maintained for a period of 30 min at a temperature of 80 ºC (oil bath). The flask was then allowed to cool to room temperature and opened to argon through the side arm of the Schlenk flask. To the flask containing the catalyst was first added the aldimine 36a (387 mg, 1.0 mmol) and then dry toluene (2 mL) under an argon flow through side arm of the Schlenk flask. The reaction mixture was stirred for 5 min to give a light orange solution. To this solution was rapidly added ethyl diazoacetate (EDA) 11 (124 µL, 1.2 mmol) followed by closing the Teflon valve. The resulting mixture was stirred for 24 h at room temperature. Immediately upon addition of ethyl diazoacetate the reaction mixture became an intense yellow, which changed to light yellow towards the completion of the reaction. The reaction was dilluted by addition of hexane (6 mL). The reaction mixture was then transferred to a 100 mL round bottom flask. The reaction flask was rinsed with dichloromethane (5 mL × 2) and the rinse was added to the 100 mL round bottom flask. The resulting solution was then concentrated in vacuo followed by exposure to high vacuum (0.05 mm Hg) for 1 h to afford the crude aziridine as an off-white solid. 71 A measure of the extent to which the reaction went to completion was estimated from the 1 H NMR spectrum of the crude reaction mixture by integration of the aziridine ring methine protons relative to either the imine methine proton or the proton on the imine carbon. The 1 cis/trans ratio was determined by comparing the H NMR integration of the ring methine protons for each aziridine in the crude reaction mixture. The cis (J = 7-8 Hz) and the trans (J = 2-3 Hz) coupling constants were used to differentiate the two isomers. The yields of the acyclic enamine 1 side products 67a and 68a were determined by H NMR analysis of the crude reaction mixture by integration of the N-H proton relative to the that of the cis-aziridine methine protons with the aid of the isolated yield of the cis-aziridine. Purification of the crude aziridine by silica gel chromatography (35 mm × 400 mm column, 9:1 hexanes/EtOAc as eluent, gravity column) afforded pure aziridine 37a as a white solid (mp 107-108 ºC on 99.8% ee material) in 98% isolated yield (396 mg, 0.98 mmol); cis/trans: >50:1. Enamine side products: 2 % yield of 67a and 1.9% yield of 68a. The optical purity of 37a was determined to be 99.8% ee by HPLC analysis (CHIRALCEL OD-H column, 99:1 hexane/2-propanol at 226nm, flow-rate: 0.7 mL/min): retention times; Rt = 9.26 min (major enantiomer, 37a) and Rt = 12.52 min (minor enantiomer, ent-37a). The AZ reaction of imine 36a with (R)-VANOL gave ent-37a in 94% yield with 97% ee and cis/trans of >50:1. Performing the reaction with (R)-BINOL gave ent-37a in 72% yield with 38% ee and cis/trans of >17:1. 1 Spectral data for 37a: Rf = 0.42 (1:9 EtOAc/hexane). H-NMR (CDCl3, 500 MHz) δ 0.98 (t, 3H, J = 7.1 Hz), 2.18 (s, 6H), 2.24 (s, 6H), 2.55 (d, 1H, J = 6.8 Hz), 3.10 (d, 1H, J = 6.6 Hz), 72 3.62 (s, 3H), 3.66 (s, 1H), 3.68 (s, 3H) 3.87-3.97 (m, 2H), 7.09 (s, 2H), 7.18 (s, 2H), 7.21-7.24 (m, 3H), 7.36 (d, 2H, J = 7.3 Hz); 13 C-NMR (CDCl3, 125 MHz) δ 14.01, 16.16, 16.22, 46.26, 48.20, 59.52, 59.58, 60.47, 77.04, 127.21, 127.41, 127.70, 127.80,127.85, 130.59, 130.60, 135.33, 137.79, 137.96, 155.95, 156.10, 168.01; IR (thin film) 2961 vs, 1750 vs, 1414 vs, 1202 -1 vs cm ; Mass spectrum: m/z (% rel intensity) 473 M+ (0.27), 284(78), 283 (100), 268 (34), 253 (20), 237 (11), 210(10), 117 (18), 89 (11); Anal calcd for C30H35NO4: C, 76.08; H, 7.45; N, 2.96. Found: C, 76.31; H, 7.28; N, 2.82; [α ]23 +41.3 (c 1.0, EtOAc) on 99% ee material D (HPLC). These spectral data match those previously reported for this compound. 3 € MEDAM aziridines 37b-h were also prepared according to Method A utilizing 5-10 mol% catalyst loading. These results including the yields and optical purity for all of MEDAM aziridines 37 are given in Table 2.2 in Chapter 2. MEDAM O + NH2 N 4 Å MS MEDAM toluene, 25 °C, 3 h 66 O MEDAM N + 10 mol% Catalyst OEt MEDAM N toluene, 25 °C, 24 h N2 36h 36h MEDAM CO2Et + (n-C H )H 3 7 n-C3H7(H) CO2Et 27h 11 1.2 equiv NH 67h(68h) (E)-N-butylidene-1,1-bis(4-methoxy-3,5-dimethylphenyl)methanamine 36h: To a 10 mL flame-dried round bottom flask filled with 73 argon was added bis(4-methoxy-3,5- dimethylphenyl)methanamine 66 (299 mg, 1.00 mmol), 4Å MS (250 mg, freshly dried) and dry toluene (1.5 mL). After stirring for 10 min, butanal (78 mg, 1.05 mmol, freshly distilled) was added. The reaction mixture was stirred at room temperature for 3 h. The resulting imine 36h was used without further purification. 1 Spectral data for 36h: H-NMR (CDCl3 500 MHz) δ 0.94 (t, 3H, J = 7.3 Hz), 1.58 (sextet, 2H, J = 7.3 Hz), 2.23 (s, 12H), 2.28-2.32 (m, 2H), 3.67 (s, 6H), 5.09 (s, 1H), 6.92 (s, 4H), 7.75 (t, 1H, J = 4.9 Hz); 13 C-NMR (125 MHz, CDCl3) δ 13.81, 16.17, 19.50, 37.84, 59.59, 77.71, 127.75, 130.55, 139.24, 155.73, 164.88. (2R,3R)-ethyl-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-propylaziridine-2carboxylate 37h: To a 25 mL flame-dried home-made Schlenk flask (see Figure 2.3) equipped with a stir bar and flushed with argon was added (S)-VAPOL (54 mg, 0.1 mmol) and B(OPh)3 (116 mg, 0.4 mmol). Under an argon flow through the side arm of the Schlenk flask, dry toluene (2 mL) was added through the top of the Teflon valuve to dissolve the two reagents and this was followed by the addition of water (1.8 µL, 0.1 mmol). The flask was sealed by closing the Teflon valve, and then placed in an 80 ºC oil bath) for 1 h. After 1 h, a vacuum (0.5 mm Hg) was carefully applied by slightly opening the Teflon valve to remove the volatiles. After the volatiles were removed completely, a full vacuum was applied and maintained for a period of 30 min at a temperature of 80 ºC (oil bath). The flask was then allowed to cool to room temperature and opened to argon through side arm of the Schlenk flask. The toluene solution of imine 36h (354 mg, 1.0 mmol, prepared as described above) was then directly transferred from the reaction flask in which it was prepared to the flask containing 74 the catalyst utilizing a filter syringe (Corning® syringe filters, Aldrich) to remove the 4Å Molecular Sieves. The flask, which had imine 36h, was then rinsed with toluene (0.5 mL) and the rinse was transferred to the flask containing the catalyst under argon flow through side-arm of the Schlenk flask. The reaction mixture was stirred for 5 min to give a light yellow solution. To this solution was rapidly added ethyl diazoacetate (EDA) 11 (124 µL, 1.2 mmol) followed by closing the Teflon valve. The resulting mixture was stirred for 24 h at room temperature. The reaction was dilluted by addition of hexane (6 mL). The reaction mixture was then transferred to a 100 mL round bottom flask. The reaction flask was rinsed with dichloromethane (5 mL × 2) and the rinse was added to the 100 mL round bottom flask. The resulting solution was then concentrated in vacuo followed by exposure to high vacuum (0.05 mm Hg) for 1 h to afford the crude aziridine as a pale yellow semi solid. Purification of the crude aziridine by silica gel chromatography (35 mm × 400 mm column, 4:2:0.1 hexanes/CH2Cl2/EtOAc as eluent, gravity column) afforded pure cis-aziridine 37h as a semi solid in 64 % isolated yield (281 mg, 0.64 mmol); cis/trans: not determined. Enamine side products: 15.3 % yield of 67h and 8.3 % yield of 68h. The optical purity of 37h was determined to be 93% ee by HPLC analysis (CHIRALCEL OD-H column, 99:1 hexane/2-propanol at 226nm, flow-rate: 0.7 mL/min): retention times; Rt = 4.73 min (major enantiomer, 37h) and Rt = 5.68 min (minor enantiomer, ent-37h). The AZ reaction of imine 36h with (S)-VAPOL at 0 °C gave 37h in 72% yield with 97% ee. With (R)VANOL, ent-37h was obtained in 73% yield with 94% ee (at room temperature) and 75% yield and 95% ee (at 0 °C). For the reaction at 0 °C, the catalyst was precooled to 0 °C followed by the addition of the imine solution and EDA at 0 °C. 75 1 Spectral data for 37h: Rf = 0.28 (4:2:0.1 hexanes/CH2Cl2/EtOAc); H-NMR (CDCl3, 500 MHz) δ 0.72 (t, 3H, J = 7.6 Hz), 0.98-1.08 (m, 1H), 1.11-1.20 (m, 1H), 1.23 (t, 3H, J = 7.1 Hz), 1.38-1.45 (m, 1H), 1.49-1.55 (m, 1H), 1.95 (q, 1H, J = 6.6 Hz), 2.18 (d, 1H, J = 6.8 Hz) 2.22 (s, 12H), 3.39 (s, 1H), 3.65 (s, 3H), 3.67 (s, 3H), 4.12-4.23 (m, 2H), 6.99 (s, 2H), 7.07 (s, 2H); 13 C- NMR (125 MHz, CDCl3) δ 13.57, 14.33, 16.09, 16.16, 20.33 29.93, 43.53, 46.76, 59.56, 59.60, 60.64, 77.32, 127.41, 128.07, 130.44, 130.47, 137.75, 138.18, 155.81, 156.12, 169.69; IR (thin -1 + film) 2957vs, 1744s, 1483s, 1221s, 1182vs cm ; HRMS (ESI-TOF) m/z 440.2817 [(M+H ); calcd. for C27H38NO4 : 440.2801]; [α ]23 +95.3 (c 1.0, EtOAc) on 97 % ee material (HPLC). D O BUDAM € + BUDAM NH2 N 4 Å MS toluene, 25 °C, 4 h 60 O BUDAM N + 10 mol% Catalyst OEt N2 38h 38h toluene, 0 °C, 24 h 11 1.2 equiv BUDAM BUDAM N + (n-C H )H 3 7 CO2Et 56h NH CO2Et n-C3H7(H) 67h'(68h') (E)-N-butylidene-1,1-bis(3,5-di-tert-butyl-4-methoxyphenyl)methanamine 38h: To a 10 mL flame-dried round bottom flask filled with argon was added bis-(3,5-di-tert-butyl-4methoxyphenyl)methanamine 60 (468 mg, 1.00 mmol), 4Å MS (250 mg, freshly dried) and dry toluene (1.5 mL). After stirring for 10 min, butanal (78 mg, 1.05 mmol, freshly distilled) was 76 added. The reaction mixture was stirred at room temperature for 4 h. The resulting imine 38h was used without further purification. 1 Spectral data for 38h: H-NMR (CDCl3 500 MHz) δ 0.98 (t, 3H, J = 7.3 Hz), 1.35 (s, 36H), 1.63 (sextet, 2H, J = 7.3 Hz), 2.31-2.35 (m, 2H), 3.64 (s, 6H), 5.22 (s, 1H), 7.05 (s, 4H), 7.87 (t, 1H, J = 4.9 Hz) (2R,3R)-ethyl-1-(bis(3,5-di-tert-butyl-4-methoxyphenyl)methyl)-3-propylaziridine-2carboxylate 56h: To a 25 mL flame-dried home-made Schlenk flask (see Figure 2.3) equipped with a stir bar and flushed with argon was added (S)-VAPOL (54 mg, 0.1 mmol) and B(OPh)3 (116 mg, 0.4 mmol). Under an argon flow through the side arm of the Schlenk flask, dry toluene (2 mL) was added through the top of the Teflon valve to dissolve the two reagents and this was followed by the addition of water (1.8 µL, 0.1 mmol). T he flask was sealed by closing the Teflon valve, and then placed in an 80 ºC oil bath for 1 h. After 1 h, a vacuum (0.5 mm Hg) was carefully applied by slightly opening the Teflon valve to remove the volatiles. After the volatiles were removed completely, a full vacuum was applied and maintained for a period of 30 min at a temperature of 80 ºC (oil bath). The flask was then allowed to cool to 0 ºC and opened to argon through side arm of the Schlenk flask. The toluene solution of imine 38h (522 mg, 1.0 mmol, prepared as described above) was then directly transferred from the reaction flask in which it was prepared to the flask containing the catalyst utilizing a filter syringe (Corning® syringe filters, Aldrich) to remove the 4Å Molecular Sieves. The flask, which had imine 38h, was then rinsed with toluene (0.5 mL) and the rinse was transferred to the flask containing the catalyst under argon flow through the side arm of the Schlenk flask. The reaction mixture was stirred for 5 min to give a light yellow 77 solution. To this solution was rapidly added ethyl diazoacetate (EDA) 11 (124 µL, 1.2 mmol) followed by closing the Teflon valve. The resulting mixture was stirred for 24 h at room temperature. The reaction was dilluted by addition of hexane (6 mL) at 0 ºC. The reaction mixture was then warmed to room temperature and transferred to a 100 mL round bottom flask. The reaction flask was rinsed with dichloromethane (5 mL × 2) and the rinse was added to the 100 mL round bottom flask. The resulting solution was then concentrated in vacuo followed by exposure to high vacuum (0.05 mm Hg) for 1 h to afford the crude aziridine as a pale yellow semi solid. Purification of the crude aziridine by silica gel chromatography (35 mm × 400 mm column, 4:2:0.1 hexanes/CH2Cl2/EtOAc as eluent, gravity column) afforded pure cis-aziridine 56h as a semi solid in 69 % isolated yield (419 mg, 0.69 mmol); cis/trans: not determined. Enamine side products: 10.3 % yield of 67h' and 4.4 % yield of 68h'. The optical purity of 56h was determined to be 95% ee by HPLC analysis (PIRKLE COVALENT (R, R) WHELK-O 1 column, 99.5:0.5 hexane/2-propanol at 226nm, flow-rate: 0.7 mL/min): retention times; Rt = 7.46 min (major enantiomer 56h) and Rt = 6.60 min (minor enantiomer, ent-56h). The AZ reaction of imine 38h with (R)-VANOL gave ent-56h in 75% yield with 93% ee. 1 Spectral data for 56h: Rf = 0.23 (2:1 hexane/CH2Cl2); H-NMR (CDCl3, 300 MHz) δ 0.82 (t, 3H, J = 7.5 Hz), 1.31 (t, 3H, J = 7.1 Hz), 1.50-1.74 (m, 2H), 1.45 (s, 18h), 1.46 (s, 18h) 1.551.73 (m, 2H), 2.15 (q, 1H, J = 6.6 Hz), 2.36 (d, 1H, J = 6.6 Hz), 3.68 (s, 1H), 3.70 (s, 3H), 3.72 (s, 3H), 4.12-4.29 (m, 2H), 7.22 (s, 2H), 7.36 (s, 2H); 13 C-NMR (CDCl3, 75 MHz) δ 13.68, 14.39, 20.57, 29.94, 32.13, 32.18, 35.75, 35.79, 43.39, 47.28, 60.69, 64.09, 64.14, 77.57, 125.60, 126.24, 136.39, 137.00, 142.88, 142.92, 158.29, 158.69, 169.96; IR (thin film) 2961vs, 1747s, 78 -1 + 1448s, 1221s, 1182 vs cm ; HRMS (ESI-TOF) m/z 608.4665 [(M+H ); calcd. for C39H62NO4: 608.4679]; [α ]23 –61.6 (c 1.0, EtOAc) on 93 % ee material (HPLC) of ent-56h. D € 2.8.5 General Procedure for the synthesis of MEDAM aziridines 37 (via Method A, without water) - Illustrated for the synthesis of (2R, 3R)-ethyl 1-(bis(4-methoxy-3,5dimethylphenyl)methyl)-3-(o-tolyl)aziridine-2-carboxylate 37b. MEDAM MEDAM O N + 36b (S)-VAPOL 3 mol% Catalyst N OEt N2 toluene, 25 °C, 24 h 11 1.2 equiv CO2Et 37b B(OPh)3 (4.0 equiv ) 0.1 mm Hg Catalyst 80 °C, 0.5 h toluene, 80 °C, 1 h (2R,3R)-ethyl-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-(o-tolyl)aziridine-2- carboxylate 37b: Imine 36b (401.5 mg, 1.0 mmol) was reacted according to the general Method A described above with (S)-VAPOL as ligand with the following differences: a) water was excluded during the preparation of the catalyst and b) 3 mol % catalyst loading was utilized. Purification of the crude aziridine by silica gel chromatography (35 mm × 400 mm column, 9:1 hexanes/EtOAc as eluent, gravity column) afforded pure cis-aziridine 37b as a white solid (mp 59-60 ºC on 98% ee material) in 91 % isolated yield (444 mg, 0.91 mmol); cis/trans: 33:1. Enamine side products: 4.5 % yield of 67b and 2.7 % yield of 68b. The optical purity of 37b 79 was determined to be 98% ee by HPLC analysis (CHIRALCEL OD-H column, 99:1 hexane/2propanol at 226nm, flow-rate: 0.7 mL/min): retention times; Rt = 9.45 min (major enantiomer, 37b) and Rt = 12.21 min (minor enantiomer, ent-37b). The AZ reaction of imine 36b with (R)VANOL (via Method A and 5 mol% catalyst loading) gave ent-37b in 90% yield with 97% ee and cis/trans of 50:1. 1 Spectral data for 37b: Rf = 0.38 (1:9 EtOAc/hexane). H-NMR (CDCl3, 500 MHz) δ 0.89 (t, 3H, J = 7.1 Hz), 2.20 (s, 6H), 2.24 (s, 6H), 2.26 (s, 3H), 2.61 (d, 1H, J = 6.8 Hz), 3.08 (d, 1H, J = 6.6 Hz), 3.62 (s, 3H), 3.66 (s, 1H), 3.68 (s, 3H), 3.88 (q, 2H, J = 7.1 Hz), 7.01 (d, 1H, J = 6.6 Hz), 7.06-7.09 (m, 2H), 7.13 (s, 2H), 7.18 (s, 2H), 7.53 (d, 1H, J = 6.3 Hz); 125 MHz) 13 C-NMR (CDCl3, δ 13.90, 16.16, 16.22, 18.76, 45.55, 47.15, 59.53, 59.59, 60.36, 77.34, 125.28, 127.05, 127.33, 127.95, 128.62, 129.08, 130.61, 130.63, 133.45, 136.03, 137.85, 138.01, 155.92, -1 156.18, 168.16; IR (thin film) 2937vs, 1749s, 1485s, 1221s, 1192vs cm ; HRMS (ESI-TOF) + m/z 488.2801 [(M+H ); calcd. for C31H38NO4 : 488.2801]; [α ]23 +46.4 (c 1.0, EtOAc) on 97% D ee material (HPLC). € MEDAM aziridines 37d, 37e, 37i, 37j and 37k were also prepared according to the Method A (without water) utilizing 2-3 mol% catalyst loading. The results regarding the yields and optical purity for all of MEDAM aziridines 37 are given in Table 2.2 in Chapter 2. 80 MEDAM O MgSO4 MEDAM + NH2 4 N CH2Cl2, 25 °C, 3 h 4 36k 66 MEDAM N 4 36k O + MEDAM 3 mol% Catalyst N OEt toluene, 25 °C, 24 h N2 4 11 1.2 equiv MEDAM + H(n-C H ) 6 7 CO2Et NH CO2Et n-C6H7(H) 67k(68k) 37k (E)-N-heptylidene-1,1-bis(4-methoxy-3,5-dimethylphenyl)methanamine 36k: To a 10 mL flame-dried round bottom flask filled with argon was added bis(4-methoxy-3,5- dimethylphenyl)methanamine 66 (299 mg, 1.0 mmol), MgSO4 (200 mg, 1.7 mmol, freshly flame-dried) and dry CH2Cl2 (3 mL). After stirring for 10 min, heptanal (120 mg, 1.05 mmol, freshly distilled) was added. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was filtered through Celite and the Celite bed was washed with CH2Cl2 (1 mL × 3) and then the filtrate was concentrated by rotary evaporation to give the crude imine as a pale yellow viscous oil which was dried under high vacuum (~ 0.2 mm Hg) for 1 h to remove any excess aldehyde, 100% crude yield. The resulting imine 36k was used without further purification. 1 Spectral data for 36k: H-NMR (CDCl3, 300 MHz) δ 0.84 (t, 3H, J = 6.7 Hz), 1.25-1.33 (m, 6H) 1.50-1.55 (m, 2H), 2.22 (s, 12H), 2.28-2.34 (m, 2H), 3.66 (s, 6H), 5.08 (s, 1H), 6.91 (s, 4H), 7.74 81 (t, 1H, J = 5.0 Hz); 13 C-NMR (CDCl3, 75 MHz) δ 13.97, 16.14, 22.55, 26.02, 28.94, 31.59, 35.87, 59.56, 77.68, 127.74, 130.53, 139.21, 155.71, 165.03 (2R,3R)-ethyl 1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-hexylaziridine-2-carboxylate 37k: To a 25 mL flame-dried home-made Schlenk flask (see Figure 2.3) equipped with a stir bar and flushed with argon was added (S)-VAPOL (16 mg, 0.03 mmol) and B(OPh)3 (35 mg, 0.12 mmol). Under an argon flow through the side arm of the Schlenk flask, dry toluene (2 mL) was added through the top of the Teflon valve to dissolve the two reagents. The flask was sealed by closing the Teflon valve, and then placed in an 80 ºC oil bath for 1 h. After 1 h, a vacuum (0.5 mm Hg) was carefully applied by slightly opening the Teflon valve to remove the volatiles. After the volatiles were removed completely, a full vacuum was applied and maintained for a period of 30 min at a temperature of 80 ºC (oil bath). The flask was then allowed to cool to room temperature and opened to argon through the side arm of the Schlenk flask. Meanwhile, to the flask containing imine 36k (396 mg, 1.0 mmol, prepared as described above) was added dry toluene (1.5 mL) and the resultant toluene solution of imine 36k was then directly transferred from the reaction flask in which it was prepared to the flask containing the catalyst. The flask, which had imine 26k, was then rinsed with toluene (0.5 mL) and the rinse was transferred to the flask containing the catalyst under argon flow through the side arm of the Schlenk flask. The reaction mixture was stirred for 5 min to give a light yellow solution. To this solution was rapidly added ethyl diazoacetate (EDA) 11 (124 µL, 1.2 mmol) followed by closing the Teflon valve. The resulting mixture was stirred for 24 h at room temperature. The reaction was dilluted by addition of hexane (6 mL). The reaction mixture was then transferred to a 100 82 mL round bottom flask. The reaction flask was rinsed with dichloromethane (5 mL × 2) and the rinse was added to the 100 mL round bottom flask. The resulting solution was then concentrated in vacuo followed by exposure to high vacuum (0.05 mm Hg) for 1 h to afford the crude aziridine as a pale yellow semi solid. Purification of the crude aziridine by silica gel chromatography (35 mm × 400 mm column, 4:2:0.1 hexanes / CH2Cl2 /EtOAc as eluent, gravity column) afforded pure cis-aziridine 37k as a semi solid in 67 % isolated yield (323 mg, 0.67 mmol); cis/trans: not determined. Enamine side products: not determined. The optical purity of 37k was determined to be 90% ee by HPLC analysis (CHIRALCEL OD-H column, 99:1 hexane/2-propanol at 226nm, flow-rate: 0.7 mL/min): retention times; Rt = 9.27 min (major enantiomer, 37k) and Rt = 11.17 min (minor enantiomer, ent-37k). 1 Spectral data for 37k: Rf = 0.30 (4:2 hexane/CH2Cl2); H-NMR (CDCl3, 300 MHz) δ 0.84 (t, 3H, J = 7.2 Hz), 0.99-1.03 (m, 1H), 1.14-1.24 (m, 7H), 1.27 (t, 3H, J = 7.1 Hz), 1.48-1.56 (m, 2H), 1.97-2.00 (m, 1H), 2.23 (d, 1H, J = 6.8 Hz), 2.26 (s, 12H), 3.43 (s, 1H), 3.69 (s, 3H), 3.70 (s, 3H), 4.16-4.25 (m, 2H), 7.04 (s, 2H), 7.12 (s, 2H); 13 C-NMR (CDCl3, 75 MHz) δ 13.90, 14.22, 15.99, 16.05, 22.33, 27.08, 27.83, 28.70, 31.69, 43.46, 46.88, 59.42, 60.53, 77.24, 127.27, 128.01, 130.31, 130.36, 137.68, 138.10, 155.69, 156.04, 169.57 (one sp3 carbon not located); IR -1 (thin film) 2928vs, 1746s, 1483s, 1221s, 1181s cm ; Mass spectrum: m/z (% rel intensity) 481 M+ (0.5), 283 (100), 268 (13), 253 (7), 142 (7), 55 (13), 41 (16); [α ]23 +78.3 (c 1.0, CH2Cl2) on D 90 % ee material (HPLC). € 83 2.8.6 General Procedure for the synthesis of MEDAM aziridines 37 (via Method B) Illustrated for the synthesis of (2R,3R)-ethyl 1-(bis(4-methoxy-3,5- dimethylphenyl)methyl)-3-phenylaziridine-2-carboxylate 37a. O N (S)-VAPOL (5 mol%) MEDAM OEt MEDAM N2 11 1.2 equiv 36a B(OPh)3 (20 mol%) toluene, 25 °C, 10 min 25 °C, 24 h N Ph CO2Et 37a (2R,3R)-ethyl-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-phenylaziridine-2carboxylate 37a: To a 25 mL flame-dried round bottom flask equipped with a stir bar and flushed with argon was added (S)-VAPOL (27 mg, 0.05 mmol) and B(OPh)3 (58 mg, 0.20 mmol) and aldimine 36a (387 mg, 1.0 mmol). Dry toluene (2 mL) was added to dissolve the reagents. The reaction mixture was stirred for 10 min at room temperature under argon atmosphere. To this solution was rapidly added ethyl diazoacetate (EDA) 11 (124 µL, 1.2 mmol). The resulting mixture was stirred for 24 h at room temperature. Immediately upon addition of ethyl diazoacetate the reaction mixture became an intense yellow, which changed to light yellow towards the completion of the reaction. The reaction was dilluted by addition of hexane (6 mL). The reaction mixture was then transferred to a 100 mL round bottom flask. The reaction flask was rinsed with dichloromethane (5 mL × 2) and the rinse was added to the 100 mL round bottom flask. The resulting solution was then concentrated in vacuo followed by exposure to high vacuum (0.05 mm Hg) for 1 h to afford the crude aziridine as an off-white solid. Purification of the crude aziridine by silica gel chromatography (35 mm × 400 mm 84 column, 9:1 hexanes/EtOAc as eluent, gravity column) afforded pure cis-aziridine 37a as a white solid in 93 % isolated yield (440 mg, 0.93 mmol); cis/trans: >50:1. The optical purity of 37a was determined to be 98.0 % ee by HPLC analysis (CHIRALCEL OD-H column, 99:1 hexane/2propanol at 226nm, flow-rate: 0.7 mL/min): retention times; Rt = 9.26 min (major enantiomer, 37a) and Rt = 12.52 min (minor enantiomer, ent-37a). MEDAM aziridines 37d, 37e and 37k were also prepared according to the Method B (both under argon and open to air condition) utilizing 5 mol% catalyst loading. The results regarding the yields and optical purity for all of MEDAM aziridines 37 are given in Table 2.3 in Chapter 2. 2.8.7 Procedure for the synthesis of MEDAM aziridines 37e (via Method B'). 1) (S)-VAPOL (2 mol%) N Bn O 69 (0.02 mmol) B(OPh)3 (8 mol%) toluene, 25 °C, 10 min MEDAM N2 11 1.2 equiv N 25 °C, 24 h 2) N Br OEt CO2Et MEDAM Br 36e 37e To a 25 mL flame-dried round bottom flask equipped with a stir bar and flushed with argon was added (S)-VAPOL (11 mg, 0.02 mmol) and B(OPh)3 (23 mg, 0.08 mmol) and aldimine 69 (5 mg, 0.02 mmol). Dry toluene (2 mL) was added to dissolve the reagents. The reaction mixture was stirred for 10 min at room temperature under argon atmosphere. To this solution was rapidly added aldimine 36e (466 mg, 1.0 mmol) and ethyl diazoacetate (EDA) 11 (124 µL, 1.2 85 mmol). The resulting mixture was stirred for 24 h at room temperature. The reaction was dilluted by addition of hexane (6 mL). The reaction mixture was then transferred to a 100 mL round bottom flask. The reaction flask was rinsed with dichloromethane (5 mL × 2) and the rinse was added to the 100 mL round bottom flask. The resulting solution was then concentrated in vacuo followed by exposure to high vacuum (0.05 mm Hg) for 1 h to afford the crude mixture as yellow solid. The NMR yield of 37e was 15% using Ph3CH as internal standard. 2.8.8 Procedure for the synthesis of MEDAM aziridines 37e (via Method C). 1) (S)-VAPOL (2 mol%) B(OPh)3 (8 mol%) H2O (2 mol%), toluene, 80 °C, 1 h N Br MEDAM MEDAM N 36e, 10 min CO2Et O 2) OEt N2 11 1.2 equiv Br 37e 25 °C, 24 h To a 25 mL flame-dried home-made Schlenk flask (see Figure 2.3) equipped with a stir bar and flushed with argon was added (S)-VAPOL (11 mg, 0.02 mmol) and B(OPh)3 (23 mg, 0.08 mmol) and water (0.36 µL, 0.02 mmol). Under an argon flow through the side arm of the Schlenk flask, dry toluene (2 mL) was added through the top of the Teflon valve to dissolve the reagents. The flask was sealed by closing the Teflon valve, and then placed in an 80 ºC oil bath for 1 h. The catalyst mixture was then allowed to cool to room temperature and opened to argon through the side arm of the Schlenk flask. To this solution was added aldimine 36e (466 mg, 1.0 mmol) and the resulting mixture was stirred for 10 min at room temperature. To the reaction 86 mixture was added ethyl diazoacetate (EDA) 11 (124 µL, 1.2 mmol) followed by closing the Teflon valve. The resulting mixture was stirred for 24 h at room temperature. The reaction was dilluted by addition of hexane (6 mL). The reaction mixture was then transferred to a 100 mL round bottom flask. The reaction flask was rinsed with dichloromethane (5 mL × 2) and the rinse was added to the 100 mL round bottom flask. The resulting solution was then concentrated in vacuo followed by exposure to high vacuum (0.05 mm Hg) for 1 h to afford the crude aziridine as yellow solid. The NMR yield of 37e was 18% using Ph3CH as internal standard. The above reaction procedure was repeated without water Imine 36e (466 mg, 1.0 mmol) was reacted according to the general Method C described above with (S)-VAPOL as ligand except water was excluded during the preparation of the catalyst. The NMR yield of 37e was 64% using Ph3CH as internal standard. 2.8.9 General Procedure for the synthesis of MEDAM aziridines 37 (via Method D) Illustrated for the synthesis of (2R,3R)-ethyl 1-(bis(4-methoxy-3,5- dimethylphenyl)methyl)-3-phenylaziridine-2-carboxylate 37a. O N (S)-VAPOL (3 mol%) MEDAM 36a B(OPh)3 (12 mol%) toluene, 80 °C, 1 h MEDAM OEt MEDAM N2 11 1.2 equiv 25 °C, 15 min 87 N Ph + CO2Et 37a NH CO2Et (Ph)H Ph(H) 67a(68a) (2R,3R)-ethyl-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-phenylaziridine-2carboxylate 37a: To a 25 mL flame-dried home-made Schlenk flask (see Figure 2.3) equipped with a stir bar and flushed with argon was added (S)-VAPOL (16 mg, 0.03 mmol) and B(OPh)3 (35 mg, 0.12 mmol) and aldimine 36a (387 mg, 1.0 mmol). Under an argon flow through the side arm of the Schlenk flask, dry toluene (2 mL) was added through the top of the Teflon valve to dissolve the reagents. The flask was sealed by closing the Teflon valve, and then placed in an 80 ºC oil bath for 1 h. The catalyst mixture was then allowed to cool to room temperature and opened to argon through the side arm of the Schlenk flask. To this solution was rapidly added ethyl diazoacetate (EDA) 11 (124 µL, 1.2 mmol) followed by closing the Teflon valve. The resulting mixture was stirred for 15 min at room temperature. Immediately upon addition of ethyl diazoacetate the reaction mixture became an intense yellow, which changed to light yellow towards the completion of the reaction. The reaction was dilluted by addition of hexane (6 mL). The reaction mixture was then transferred to a 100 mL round bottom flask. The reaction flask was rinsed with dichloromethane (5 mL × 2) and the rinse was added to the 100 mL round bottom flask. The resulting solution was then concentrated in vacuo followed by exposure to high vacuum (0.05 mm Hg) for 1 h to afford the crude aziridine as an off-white solid. Purification of the crude aziridine by silica gel chromatography (35 mm × 400 mm column, 9:1 hexanes/EtOAc as eluent, gravity column) afforded pure cis-aziridine 37a as a white solid (mp 107-108 ºC on 99.8% ee material) in 93 % isolated yield (440 mg, 0.93 mmol); cis/trans: >50:1. Enamine side products: 2.5 % yield of 67a and 2.0% yield of 68a. The optical purity of 37a was determined to be 98.5 % ee by HPLC analysis (CHIRALCEL OD-H column, 99:1 hexane/2- 88 propanol at 226nm, flow-rate: 0.7 mL/min): retention times; Rt = 9.26 min (major enantiomer, 37a) and Rt = 12.52 min (minor enantiomer, ent-37a). Spectral data for 37a: See page 17 O N (S)-VAPOL (3 mol%) MEDAM OEt N2 11 1.2 equiv 36b 25 °C, 24 h B(OPh)3 (12 mol%) toluene, 80 °C, 1 h MEDAM N CO2Et 37b (2R,3R)-ethyl-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-(o-tolyl)aziridine-2- carboxylate 37b: Imine 36b (401.5 mg, 1.0 mmol) was reacted according to the general Method D described above with (S)-VAPOL as ligand. Purification of the crude aziridine by silica gel chromatography (35 mm × 400 mm column, 9:1 hexanes/EtOAc as eluent, gravity column) afforded pure cis-aziridine 37b as a white solid (mp 59-60 ºC on 98% ee material) in 87 % isolated yield (424 mg, 0.87 mmol); cis/trans: 33:1. Enamine side products: 5.0 % yield of 67b and 3.2 % yield of 68b. The optical purity of 37b was determined to be 96% ee by HPLC analysis (CHIRALCEL OD-H column, 99:1 hexane/2-propanol at 226nm, flow-rate: 0.7 mL/min): retention times; Rt = 9.45 min (major enantiomer, 37b) and Rt = 12.21 min (minor enantiomer, ent-37b). 89 O N (S)-VAPOL (3 mol%) MEDAM OEt N2 11 1.2 equiv 36c 25 °C, 30 min B(OPh)3 (12 mol%) toluene, 80 °C, 1 h MEDAM N CO2Et 37c (2R,3R)-ethyl-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-(p-tolyl)aziridine-2carboxylate 37c: Imine 36c (401.5 mg, 1.0 mmol) was reacted according to the general Method D described above with (S)-VAPOL as ligand. Purification of the crude aziridine by silica gel chromatography (35 mm × 400 mm column, 9:1 hexanes/EtOAc as eluent, gravity column) afforded pure cis-aziridine 37c as a white solid (mp 116-117 ºC on 99.5% ee material) in 94 % isolated yield (458 mg, 0.94 mmol); cis/trans: >50:1. Enamine side products: 3.0 % yield of 67c and 1.2 % yield of 68c. The optical purity of 37c was determined to be 99% ee by HPLC analysis (CHIRALCEL OD-H column, 99:1 hexane/2-propanol at 226nm, flow-rate: 0.7 mL/min): retention times; Rt = 9.22 min (major enantiomer, 37c) and Rt = 11.62 min (minor enantiomer, ent-37c). 1 Spectral data for 37c: Rf = 0.30 (1:9 EtOAc/hexanes). H-NMR (CDCl3, 500 MHz) δ 1.01 (t, 3H, J = 7.1 Hz), 2.18 (s, 6H), 2.24 (s, 6H), 2.26 (s, 3H), 2.52 (d, 1H, J = 6.6 Hz), 3.07 (d, 1H, J = 6.8 Hz), 3.62 (s, 3H), 3.64 (s, 1H), 3.68 (s, 3H) 3.93 (dq, 2H, J = 3.2 Hz, 7.1 Hz), 7.02 (d, 2H, J = 7.8 Hz), 7.08 (s, 2H), 7.17 (s, 2H), 7.24 (d, 2H, J = 8.0 Hz); 13 C-NMR (CDCl3, 125 MHz) δ 14.05, 16.16, 16.22, 21.11, 46.20, 48.21, 59.52, 59.58, 60.44, 77.11, 127.43, 127.72, 127.81, 90 128.41, 130.54, 130.57, 132.28, 136.78, 137.86, 138.00, 155.93, 156.08, 168.10; IR (thin film) -1 + 2978vs, 1748s, 1483s, 1221s, 1190vs cm ; HRMS (ESI-TOF) m/z 488.2806 [(M+H ); calcd. for C31H38NO4 : 488.2801]; [α ]23 +29.4 (c 1.0, EtOAc) on 99.8 % ee material (HPLC). D O € N (S)-VAPOL (3 mol%) MeO MEDAM OEt MEDAM N2 11 1.2 equiv 36d N 25 °C, 24 h B(OPh)3 (12 mol%) toluene, 80 °C, 1 h CO2Et MeO 37d (2R,3R)-ethyl-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-(4-methoxyphenyl)aziridine2-carboxylate 37d: Imine 36d (417.5 mg, 1.0 mmol) was reacted according to the general Method D described above with (S)-VAPOL as ligand. Purification of the crude aziridine by silica gel chromatography (35 mm × 400 mm column, 9:1 hexanes/EtOAc as eluent, gravity column) afforded pure cis-aziridine 37d as a white solid (mp 56-57 ºC on 98 % ee material) in 83 % isolated yield (418 mg, 0.83 mmol); cis/trans: >50:1. Enamine side products: 1.2 % yield of 67d and 2.1 % yield of 68d. The optical purity of 37d was determined to be 97% ee by HPLC analysis (CHIRALCEL OD-H column, 99:1 hexane/2-propanol at 226nm, flow-rate: 0.7 mL/min): retention times; Rt = 12.07 min (major enantiomer, 27d) and Rt = 19.20 min (minor enantiomer, ent-37d). 91 1 Spectral data for 37d: Rf = 0.28 (1:9 EtOAc/hexane). H-NMR (CDCl3, 500 MHz) δ 1.02 (t, 3H, J = 7.1 Hz), 2.19 (s, 6H), 2.24 (s, 6H), 2.51 (d, 1H, J = 6.8 Hz), 3.06 (d, 1H, J = 6.8 Hz), 3.63 (s, 3H), 3.65 (s, 1H), 3.68 (s, 3H), 3.74 (s, 3H), 3.89-3.99 (m, 2H), 6.77 (d, 2H, J = 9.5 Hz), 7.09 (s, 2H), 7.18 (s, 2H), 7.29 (d, 2H, J = 8.8 Hz); 13 C-NMR (CDCl3, 125 MHz) δ 14.08, 16.16, 16.21, 46.20, 47.89, 55.19, 59.52, 59.57, 60.45, 77.05, 113.18, 127.43, 127.79, 128.93, 130.55, 130.57, 137.83, 138.01, 155.93, 156.07, 158.86, 168.14 (one sp2 carbon not located); IR (thin -1 + film) 2942vs, 1743s, 1514s, 1250s, 1180vs cm ; HRMS (ESI-TOF) m/z 504.2744 [(M+H ); calcd. for C31H38NO5 : 504.2750]; [α ]23 –25 (c 1.0, EtOAc) on 96 % ee material (HPLC) on D ent-37d. € O N (S)-VAPOL (3 mol%) Br MEDAM OEt MEDAM N2 11 1.2 equiv 36e N 25 °C, 2 h B(OPh)3 (12 mol%) toluene, 80 °C, 1 h CO2Et Br 37e (2R,3R)-ethyl-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-(4-bromophenyl)aziridine-2carboxylate 37e: Imine 36e (466.4 mg, 1.0 mmol) was reacted according to the general Method D described above with (S)-VAPOL as ligand. Purification of the crude aziridine by silica gel chromatography (35 mm × 400 mm column, 5:1 hexanes/EtOAc as eluent, gravity column) afforded pure cis-aziridine 37e as a white solid (mp 145-146 ºC on 99.6 % ee material) in 94 % isolated yield (519 mg, 0.94 mmol); cis/trans: >50:1. Enamine side products: 1.5 % yield of 67e and 1.9 % yield of 68e. The optical purity of 37e was determined to be 99% ee by HPLC 92 analysis (CHIRALCEL OD-H column, 99:1 hexane/2-propanol at 226nm, flow-rate: 0.7 mL/min): retention times; Rt = 8.41 min (major enantiomer, 37e) and Rt = 11.96 min (minor enantiomer, ent-37e). 1 Spectral data for 37e: Rf = 0.32 (1:9 EtOAc/hexane). H-NMR (CDCl3, 500 MHz) δ 1.02 (t, 3H, J = 7.1 Hz), 2.18 (s, 6H), 2.24 (s, 6H), 2.56 (d, 1H, J = 6.6 Hz), 3.03 (d, 1H, J = 6.8 Hz), 3.62 (s, 3H), 3.66 (s, 1H), 3.68 (s, 3H), 3.89-3.98 (m, 2H), 7.06 (s, 2H), 7.16 (s, 2H), 7.26 (d, 2H, J = 8.5 Hz), 7.35 (d, 2H, J = 8.5 Hz); 13 C-NMR (CDCl3, 125 MHz) δ 14.08, 16.18, 16.23,46.35, 47.54, 59.55, 59.59, 60.64, 121.23, 127.35, 127.68, 129.62, 130.69, 130.83, 134.37, 137.57, 2 3 137.76, 156.01, 156.17, 167.69 (one sp and one sp carbon not located); IR (thin film) 2942vs, -1 + 1745vs, 1485vs, 1221vs cm ; HRMS (ESI-TOF) m/z 552.1733 [(M+H ); calcd. for 79 C30H35NO4 Br : 552.1749]; [α ]23 +12.8 (c 1.0, EtOAc) on 99% ee material (HPLC). D O N € (S)-VAPOL (3 mol%) O2N MEDAM OEt MEDAM N2 11 1.2 equiv 36f N 25 °C, 45 min B(OPh)3 (12 mol%) toluene, 80 °C, 1 h CO2Et O2N 37f (2R,3R)-ethyl-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-(4-nitrophenyl)aziridine-2carboxylate 37f: Imine 36f (432.5 mg, 1.0 mmol) was reacted according to the general Method D described above with (S)-VAPOL as ligand. Purification of the crude aziridine by silica gel chromatography (35 mm × 400 mm column, 5:1 hexanes/EtOAc as eluent, gravity column) 93 afforded pure cis-aziridine 37f as a white solid (mp 174-175 ºC on 99.7% ee material) in 95 % isolated yield (493 mg, 0.95 mmol); cis/trans: >50:1. Enamine side products: 1.2 % yield of 67f and 2.0 % yield of 68f. The optical purity of 37f was determined to be 99% ee by HPLC analysis (CHIRALCEL OD-H column, 99:1 hexane/2-propanol at 226nm, flow-rate: 0.7 mL/min): retention times; Rt = 17.12 min (major enantiomer, 37f) and Rt = 27.13 min (minor enantiomer, ent-37f). 1 Spectral data for 37f: Rf = 0.30 (1:9 EtOAc/hexane). H-NMR (CDCl3, 500 MHz) δ 1.02 (t, 3H, J = 7.1 Hz), 2.18 (s, 6H), 2.25 (s, 6H), 2.68 (d, 1H, J = 6.8 Hz), 3.15 (d, 1H, J = 6.8 Hz), 3.62 (s, 3H), 3.68 (s, 3H), 3.71 (s, 1H), 3.93 (dq, 2H, J = 2.2, 7.1 Hz), 7.06 (s, 2H), 7.16 (s, 2H), 7.57 (d, 2H, J = 8.8 Hz), 8.10 (d, 2H, J = 8.8 Hz); 13 C-NMR (CDCl3, 125 MHz) δ 14.08, 16.19, 16.24, 46.81, 47.26, 59.55, 59.59, 60.85, 76.89, 122.98, 127.26, 127.59, 128.81, 130.81, 130.86, 137.25, 137.48, 142.82, 147.28, 156.13, 156.28, 167.20; IR (thin film) 2984 vs, 1745 vs, -1 + 1603 s, 1522 vs, 1221 vs cm ; HRMS (ESI-TOF) m/z 519.2505 [(M+H ); calcd. for C30H35N2O6 : 519.2495]; [α ]23 – 4.8 (c 1.0, EtOAc) on 99.8% ee material (HPLC). D O € N (S)-VAPOL (3 mol%) MEDAM OEt N2 11 1.2 equiv 36i 25 °C, 3 h B(OPh)3 (12 mol%) toluene, 80 °C, 1 h MEDAM N CO2Et 37i 94 (2R,3R)-ethyl-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-cyclohexylaziridine-2carboxylate 37i: Imine 36i (393.5 mg, 1.0 mmol) was reacted according to the general Method D described above with (S)-VAPOL as ligand. Purification of the crude aziridine by silica gel chromatography (35 mm × 400 mm column, 2:1 hexanes/CH2Cl2 as eluent, gravity column) afforded pure cis-aziridine 327i as a white solid (mp 47-49 ºC on 91% ee material) in 96 % isolated yield (461 mg, 0.96 mmol); cis/trans: 50:1. Enamine side products: not determined. The optical purity of 37i was determined to be 89% ee by HPLC analysis (CHIRALCEL OD column, 99:1 hexane/2-propanol at 223 nm, flow-rate: 0.7 mL/min): retention times; Rt = 10.06 min (major enantiomer, 37i) and Rt = 12.37 min (minor enantiomer, ent-37i). 1 Spectral data for 37i: Rf = 0.21 (2:1 hexane/CH2Cl2); H-NMR (CDCl3, 300 MHz) δ 0.46-0.57 (m, 1H), 0.87-1.19 (m, 4H), 1.21 (t, 3H, J = 7.1 Hz), 1.22-1.32 (m, 2H), 1.40-1.60 (m, 4H), 1.711.76 (m, 1H), 2.16 (m, 1H), 2.19 (s, 6H), 2.20 (s, 6H), 3.35 (s, 1H), 3.60 (s, 3H), 3.63 (s, 3H), 4.10-4.25 (m, 2H), 6.95 (s, 2H), 7.10 (s, 2H); 13 C-NMR (CDCl3, 75 MHz) δ 13.85, 15.56, 15.67, 24.91, 25.09, 25.73, 29.65, 30.38, 35.88, 42.97, 51.76, 59.01, 59.07, 60.12, 77.01, 126.90, 128.10, 129.84, 129.95, 137.16, 137.71, 155.31, 155.83, 169.30; IR (thin film) 2928vs, 1744s, -1 1483s, 1221s, 1181s, 1017m cm ; Mass spectrum: m/z (% rel intensity) 479 M+ (0.7), 283 (100), 268 (25), 253 (12), 237 (7), 210 (7), 195 (9), 141 (8), 95 (10), 67 (16), 55 (10), 41 (16); [α ]23 +107.4 (c 1.0, CH2Cl2) on 89 % ee material (HPLC). D € 95 O N (S)-VAPOL (3 mol%) MEDAM OEt N2 11 1.2 equiv 36j 25 °C, 24 h B(OPh)3 (12 mol%) toluene, 80 °C, 1 h MEDAM N CO2Et 37j (2R,3R)-ethyl-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-t-butylaziridine-2carboxylate 37j: Imine 36j (367.5 mg, 1.0 mmol) was reacted according to the general Method D described above with (S)-VAPOL as ligand. Purification of the crude aziridine by silica gel chromatography (35 mm × 400 mm column, 50:1 hexanes/EtOAc as eluent, gravity column) afforded pure cis-aziridine 37j as a semi solid in 93% isolated yield (422 mg, 0.93 mmol); cis/trans: 50:1. Enamine side products: not determined. The optical purity of 37j was determined to be 92% ee by HPLC analysis (CHIRALCEL OD column, 99:1 hexane/2-propanol at 226 nm, flow-rate: 1.0 mL/min): retention times; Rt = 6.8 min (major enantiomer, 37j) and Rt = 10.55 min (minor enantiomer, ent-37j). 1 Spectral data for 37j: Rf = 0.28 (1:2 hexane/CH2Cl2); H-NMR (CDCl3, 300 MHz) δ 0.72 (s, 9H), 1.29 (t, 3H, J = 7.1 Hz), 1.70 (d, 1H, J = 7.3 Hz), 2.11 (d, 1H, J = 7.2 Hz), 2.24 (s, 6H), 2.26 (s, 6H), 3.38 (s, 1H), 3.63 (s, 3H), 3.66 (s, 3H), 4.05-4.26 (m, 2H), 7.04 (s, 2H), 7.30 (s, 2H); 13 C-NMR (CDCl3, 75 MHz) δ 13.92, 15.84, 15.96, 27.24, 31.39, 43.16, 55.94, 59.20, 59.27, 60.24, 78.20, 127.30, 128.18, 130.01, 137.77, 138.74, 155.51, 155.98, 169.66 (one sp2 -1 carbon not located); IR (thin film) 2953vs, 1747s, 1481s, 1221s, 1181s, 1017m cm ; Mass spectrum: m/z (% rel intensity) 453 M+ (1), 283 (100), 268 (45), 253 (26), 237 (17), 225 (11), 96 210 (13), 195 (17), 164 (9) 141 (26), 132 (11), 127 (12), 91 (11), 69 (18), 55 (37), 41 (55); [α ]23 D +110.0 (c 1.0, CH2Cl2) on 94 % ee material (HPLC). € MEDAM O N OEt (S)-VAPOL (3 mol%) 4 36k B(OPh)3 (12 mol%) toluene, 80 °C, 1 h MEDAM N2 11 1.2 equiv 25 °C, 24 h N CO2Et 4 37k (2R,3R)-ethyl-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-hexylaziridine-2carboxylate 37k: To a 25 mL flame-dried home-made Schlenk flask (see Figure 2.3) equipped with a stir bar and flushed with argon was added (S)-VANOL (16 mg, 0.3 mmol) and B(OPh)3 (35 mg, 0.12 mmol). Meanwhile, to the flask containing imine 36k (396 mg, 1.0 mmol, see page 80 for its synthesis) was added dry toluene (1.5 mL) and the resultant toluene solution of imine 36k was then directly transferred from the reaction flask in which it was prepared to the flask containing the ligand and B(OPh)3. The flask, which had imine 36k, was then rinsed with toluene (0.5 mL) and the rinse was transferred to the flask containing the ligand and B(OPh)3 under argon flow through the side-arm of the Schlenk flask. The flask was sealed by closing the Teflon valve, and then placed in an 80 ºC oil bath for 1 h. The catalyst mixture was then allowed to cool to room temperature and opened to argon through the side arm of the Schlenk flask. To this solution was rapidly added ethyl diazoacetate (EDA) 11 (124 µL, 1.2 mmol) followed by closing the Teflon valve. The resulting mixture was stirred for 24 h at room temperature. The reaction was dilluted by addition of hexane (6 mL). The reaction mixture was then transferred to 97 a 100 mL round bottom flask. The reaction flask was rinsed with dichloromethane (5 mL X 2) and the rinse was added to the 100 mL round bottom flask. The resulting solution was then concentrated in vacuo followed by exposure to high vacuum (0.05 mm Hg) for 5 min to afford the crude aziridine as a pale yellow semi solid. Purification of the crude aziridine by silica gel chromatography (35 mm × 400 mm column, 4:2:0.1 hexanes / CH2Cl2 /EtOAc as eluent, gravity column) afforded pure cis-aziridine 37k as a semi solid in 64 % isolated yield (308 mg, 0.64 mmol); cis/trans: not determined. Enamine side products: 10 % yield of 67k and 0 % yield of 68k. The optical purity of 37k was determined to be 86% ee by HPLC analysis (CHIRALCEL OD-H column, 99:1 hexane/2-propanol at 226nm, flow-rate: 0.7 mL/min): retention times; Rt = 9.27 min (major enantiomer, 37k) and Rt= 11.17 min (minor enantiomer, ent-37k). 1 Spectral data for 37k: Rf = 0.30 (4:2 hexane/CH2Cl2); H-NMR (CDCl3, 300 MHz) δ 0.84 (t, 3H, J = 7.2 Hz), 0.99-1.03 (m, 1H), 1.14-1.24 (m, 7H), 1.27 (t, 3H, J = 7.1 Hz), 1.48-1.56 (m, 2H), 1.97-2.00 (m, 1H), 2.23 (d, 1H, J = 6.8 Hz), 2.26 (s, 12H), 3.43 (s, 1H), 3.69 (s, 3H), 3.70 (s, 3H), 4.16-4.25 (m, 2H), 7.04 (s, 2H), 7.12 (s, 2H); 13 C-NMR (CDCl3, 75 MHz) δ 13.90, 14.22, 15.99, 16.05, 22.33, 27.08, 27.83, 28.70, 31.69, 43.46, 46.88, 59.42, 60.53, 77.24, 127.27, 128.01, 130.31, 130.36, 137.68, 138.10, 155.69, 156.04, 169.57 (one sp3 carbon not located); IR -1 (thin film) 2928vs, 1746s, 1483s, 1221s, 1181s cm ; Mass spectrum: m/z (% rel intensity) 481 M+ (0.5), 283 (100), 268 (13), 253 (7), 142 (7), 55 (13), 41 (16); [α ]23 +78.3 (c 1.0, CH2Cl2) on D 90 % ee material (HPLC). € 98 2.8.10 General Procedure for the deprotection of N-MEDAM aziridines 37 to give N-H aziridines 59 - Illustrated for the synthesis of (2R,3R)-ethyl 3-phenylaziridine-2carboxylate 59a: MEDAM N H TfOH (5 equiv) N anisole, 2h, 25 ºC Ph Ph CO2Et 37a CO2Et 59a (2R,3R)-ethyl 3-phenylaziridine-2-carboxylate 59a: To a 25 mL flame-dried round bottom flask filled with argon was added aziridine 37a (237 mg, 0.5 mmol, 99% ee) and anisole (5.4 mL, freshly distilled ) at room temperature. The flask was cooled to 0 ºC and triflic acid (200 µL, 2.5 mmol) was added. The ice-bath was removed and the reaction mixture was stirred for 2 h. The reaction mixture was quenched by addition of saturated aqueous Na2CO3 solution until the pH was greater than 9. After addition of ether (3 mL) and water (1 mL), the organic layer was separated and the water layer was extracted with ether (5 mL × 3). The combined organic layer was washed with saturated aqueous NaCl solution (10 mL × 3) and dried over anhydrous MgSO4. The ether was removed by rotary evaporation and most of the anisole was removed by high vacuum for a short period of time (~ 15 min) leaving an off-white sticky residue. Exposure to high vacuum for extended periods results in loss of 59a to sublimation. Purification by silica gel chromatography (18 mm × 230 mm, 1:1 ether / hexanes as eluent) afforded 59a as a white solid (mp 58-59 ºC) in 95% isolated yield (91 mg, 0.475 mmol). The optical purity of 59a was determined to be 99% ee by HPLC analysis (CHIRALCEL OD-H column, 98:2 hexane/2- 99 propanol at 228nm, flow-rate: 1.0 mL/min): retention times; Rt = 3.99 min (major enantiomer, 12a) and Rt = 3.47 min (minor enantiomer, ent-59a). 1 Spectral data for 59a: Rf = 0.13 (1:1 Et2O/hexane); H-NMR (CDCl3, 300 MHz) δ 0.99 (t, 3H, J = 7.1 Hz), 1.87 (br, s, 1H), 3.00 (d, 1H, J = 6.1 Hz), 3.47 (d, 1H, J = 6.1 Hz), 3.90-4.00 (m, 2H), 7.24-7.33 (m, 5H); 13 C-NMR (CDCl3, 75 MHz) δ 13.90, 29.65, 37.14, 61.07, 127.47, 127.62, 128.01, 134.80, 169.02; [α ]23 –12.4 (c 1.0, EtOAc) on 99% ee material (HPLC). These D spectral data match those previously reported for this compound. 5 € MEDAM H TfOH (5 equiv) N N anisole, 1 h, 25 ºC CO2Et CO2Et 37b 59b (2R,3R)-ethyl 3-(o-tolyl)aziridine-2-carboxylate 59b: Aziridine 37b (244 mg, 0.5 mmol, 99 % ee) was reacted according to the general method described above except that the reaction time was 1 h. Purification by silica gel chromatography (18 mm × 230 mm, 1:1 ether / hexanes as eluent) afforded 59b as a white solid (mp 84.5-85.5 ºC) in 97% isolated yield (100 mg, 0.485 mmol). The optical purity of 59b was determined to be 99% ee by HPLC analysis (CHIRALCEL OD-H column, 90:10 hexane/2-propanol at 228nm, flow-rate: 0.7 mL/min): retention times; Rt = 6.4 min (major enantiomer, 59b) and Rt = 5.5 min (minor enantiomer, ent-59b). 100 1 Spectral data for 12b: Rf =0.11 (1:1 Et2O/hexane); H-NMR (CDCl3, 300 MHz) δ 0.94 (t, 3H, J = 7.1 Hz), 1.72 (br, s, 1H), 2.32 (s, 3H), 3.04 (d, 1H, J = 6.1 Hz), 3.35 (d, 1H, J = 6.1 Hz), 3.92 (q, 2H, J = 7.1 Hz), 7.09-7.17 (m, 3H), 7.23-7.24 (m, 1H); 13 C-NMR (CDCl3, 75 MHz) δ 13.85, 18.83, 29.66, 36.48, 61.05, 125.49, 127.16, 127.60, 129.53, 133.26, 136.86, 169.29; [α ]23 –96.9 D (c 1.0, EtOAc) on 99% ee material (HPLC). These spectral data match those previously reported for this compound. 5 € MEDAM H TfOH (5 equiv) N N anisole, 1 h, 25 ºC CO2Et Br CO2Et 37e Br 59e (2R,3R)-ethyl 3-(4-bromophenyl)aziridine-2-carboxylate 59e: Aziridine 37e (276 mg, 0.5 mmol, 99.5 % ee) was reacted according to the general method described above except that the reaction time was 1 h. Purification by silica gel chromatography (18 mm × 230 mm, 1:1 ether / hexanes as eluent) afforded 59e as a white solid (mp 78.5-79 ºC) in 96% isolated yield (130 mg, 0.48 mmol). The optical purity of 59e was determined to be 99.5% ee by HPLC analysis (CHIRALCEL OD-H column, 90:10 hexane/2-propanol at 228nm, flow-rate: 0.7 mL/min): retention times; Rt = 8.24 min (major enantiomer, 59e) and Rt = 7.07 min (minor enantiomer, ent-59e). 101 5 1 Spectral data for 59e : Rf = 0.12 (1:1 Et2O/hexane); H-NMR (CDCl3, 300 MHz) δ 1.02 (t, 3H, J = 7.1 Hz), 1.67 (br, s, 1H), 3.01 (d, 1H, J = 6.6 Hz), 3.40 (d, 1H, J = 6.4 Hz), 3.93-3.98 (m, 2H), 7.20 (d, 2H, J = 8.5 Hz), 7.41 (d, 2H, J = 8.5 Hz); 13 C-NMR (CDCl3, 75 MHz) δ 13.88, 37.05, 38.98, 61.06, 121.45, 129.18, 130.98, 133.85, 168.62; [α ]23 +11.92 (c 1.0, EtOAc) on D 99.5% ee material (HPLC). These spectral data match those previously reported for this compound. 5 € MEDAM H TfOH (5 equiv) N N anisole, 1 h, 25 ºC CO2Et O2N CO2Et 37f O2N (2R,3R)-ethyl 3-(4-nitrophenyl)aziridine-2-carboxylate 59f: 59f Aziridine 37f (259 mg, 0.5 mmol, 97 % ee) was reacted according to the general method described above except that the reaction time was 1 h. Purification by silica gel chromatography (18 mm × 230 mm, 1:1 ether / hexanes as eluent) afforded 59f as a white solid (mp 89-90.5 ºC) in 97% isolated yield (115 mg, 0.485 mmol). The optical purity of 59f was determined to be 97% ee by HPLC analysis (CHIRALCEL OD-H column, 90:10 hexane/2-propanol at 228nm, flow-rate: 0.7 mL/min): retention times; Rt = 13.75 min (major enantiomer, 59f) and Rt = 11.92 min (minor enantiomer, ent-59f). 102 1 Spectral data for 59f: Rf = 0.07 (1:1 Et2O/hexane); H-NMR (CDCl3, 300 MHz) δ 1.01 (t, 3H, J = 7.1 Hz), 1.80 (br, s, 1H), 3.13 (d, 1H, J = 6.3 Hz), 3.56 (d, 1H, J = 6.6 Hz), 3.92-3.97 (m, 2H), 7.54 (d, 2H, J = 8.3 Hz), 8.15 (d, 2H, J = 8.8 Hz); 13 C-NMR (CDCl3, 75 MHz) δ 13.80, 29.45, 37.39, 61.09, 122.94, 128.55, 142.58, 147.08, 168.08; [α ]23 –15.6 (c 1.0, EtOAc) on 97% D ee material (HPLC). These spectral data match those previously reported for this compound. 5 € MEDAM N H TfOH (5 equiv) CO2Et anisole, 1 h, 65 ºC 37h N CO2Et 59h (2R,3R)-ethyl 3-propylaziridine-2-carboxylate 59h: Aziridine 37h (220 mg, 0.5 mmol, 93% ee) was reacted according to the general method described above except that the reaction time was 1 h, the reaction temperature was 65 ºC and an air condenser was utilized. Purification by silica gel chromatography (18 mm × 230 mm, 1:3 ether / pentane as eluent) afforded 59h as a light yellow liquid in 72% isolated yield (57 mg, 0.36 mmol). The optical purity of 59h was determined to be 93% ee by HPLC analysis (CHIRALCEL OD-H column, 98:2 hexane/2propanol at 222nm, flow-rate: 0.7 mL/min): retention times; Rt = 5.06 min (major enantiomer, 59h) and Rt = 5.88 min (minor enantiomer, ent-59h). The yield of 59h was determined to be 76% by 1H NMR analysis of the crude reaction mixture with Ph3CH as internal standard. 103 1 Spectral data for 59h: Rf = 0.13 (1:1 Et2O/hexane); H-NMR (CDCl3, 300 MHz) δ 0.79 (t, 3H, J = 7.1 Hz), 1.16 (t, 3H, J = 7.1 Hz), 1.22-1.40 (m, 3H), 1.40-1.50 (m, 2H), 2.04-2.10 (m, 1H), 2.49 (d, 1H, J = 6.0 Hz), 4.08 (q, 2H, J = 7.1 Hz); 13 C-NMR (CDCl3, 75 MHz) δ 13.46, 13.99, 20.73, 29.60, 34.27, 38.31, 60.97, 170.73. These spectral data match those previously reported for this compound. 5 MEDAM N H N TfOH (5 equiv) CO2Et anisole, 0.5 h, 65 ºC CO2Et 37i 59i (2R,3R)-ethyl 3-(4-nitrophenyl)aziridine-2-carboxylate 59i: Aziridine 37i (240 mg, 0.5 mmol, 99 % ee) was reacted according to the general method described above except that the reaction time was 0.5 h, the reaction temperature was 65 ºC and an air condenser was utilized. Purification by silica gel chromatography (18 mm × 230 mm, 1:1 ether / hexanes as eluent) afforded 59i as a white solid (mp 58-59 ºC) in 90% isolated yield (89 mg, 0.45 mmol). The optical purity of 59i was determined to be 99% ee by HPLC analysis (CHIRALCEL OD-H column, 98:2 hexane/2-propanol at 228nm, flow-rate: 1.0 mL/min): retention times; Rt = 3.99 min (major enantiomer, 59i) and Rt = 3.47 min (minor enantiomer, ent-59i). 1 Spectral data for 59i: Rf = 0.19 (1:1 Et2O/hexane); H-NMR (CDCl3, 300 MHz) δ 0.90 (br, s, 1H), 1.09-1.20 (m, 6H), 1.24 (t, 3H, J = 7.1 Hz), 1.43-1.46 (m, 1H), 1.61-1.70 (m, 3H), 1.86-1.92 (m, 2H), 2.60 (d, 1H, J = 6.1 Hz), 4.18 (q, 2H, J = 7.1 Hz); 104 13 C-NMR (CDCl3, 75 MHz) δ 14.14, 25.39, 25.40, 26.01, 30.84, 31.61, 34.24, 36.91, 43.98, 61.06, 170.95; [α ]23 –62.3 (c 1.0, D EtOAc) on 99% ee material (HPLC). These spectral data match those previously reported for this compound. 5 € MEDAM H TfOH (5 equiv) N CO2Et anisole, 0.5 h, 65 ºC 37j N CO2Et 59j (2R,3R)-ethyl 3-(tert-butyl)aziridine-2-carboxylate 59j: Aziridine 37j (227 mg, 0.5 mmol, 99 % ee) was reacted according to the general method described above except that the reaction time was 0.5 h, the reaction temperature was 65 ºC and an air condenser was utilized. Purification by silica gel chromatography (18 mm × 230 mm, 1:1 ether / hexanes as eluent) afforded 59j as colorless oil in 88% isolated yield (75 mg, 0.44 mmol). The optical purity of 59j was determined to be 97% ee by HPLC analysis (CHIRALCEL OD-H column, 99:1 hexane/2-propanol at 228nm, flow-rate: 1.0 mL/min): retention times; Rt = 9.95 min (major enantiomer, 59j) and Rt= 8.38 min (minor enantiomer, ent-59j). 1 Spectral data for 59j: Rf = 0.10 (1:1 Et2O/hexane); H-NMR (CDCl3, 300 MHz) δ 0.89 (s, 9H), 1.23 (t, 3H, J = 6.9 Hz), 1.48 (br, s, 1H), 2.09 (d, 1H, J = 6.1 Hz), 2.61 (d, 1H, J = 6.6 Hz), 4.044.23 (m, 2H); 13 C-NMR (CDCl3, 75 MHz) δ 14.00, 27.42, 31.46, 35.25, 47.36, 60.98, 170.20; [α ]23 –23.7 (c 1.0, EtOAc) on 97% ee material (HPLC). These spectral data match those D previously reported for this compound. 5 € 105 2.8.11 Procedure for the deprotection of aziridines 58a and 37a and trapping of dianisyl cation to give N-H aziridines 59a and alcohol 73. 1) TfOH (10 equiv) DAM H CH3CN, 50 min, 25 ºC N Ph CO2Et 58a MeO N 2) sat. NaHCO3 Ph OMe + CO2Et 59a OH 73a (2R,3R)-ethyl 3-phenylaziridine-2-carboxylate 59a: To a 25 mL flame-dried round bottom flask filled with argon was added aziridine 58a (209 mg, 0.5 mmol, 98% ee) and acetonitrile (5.0 mL, freshly distilled) at room temperature. The flask was cooled to 0 ºC and triflic acid (400 µL, 5.0 mmol) was added. The ice-bath was removed and the reaction mixture was stirred for 50 min at room temperature. The reaction mixture was quenched by addition of saturated aqueous Na2CO3 solution until the pH was greater than 9. After addition of ether (3 mL) and water (1 mL), the organic layer was separated and the water layer was extracted with ether (5 mL × 3). The combined organic layer was washed with saturated aqueous NaCl solution (10 mL × 3) and dried over anhydrous MgSO4. The ether was removed by rotary evaporation and most of the anisole was removed by high vacuum for a short period of time (~ 15 min) leaving an off-white sticky residue. Exposure to high vacuum for extended periods results in loss of 59a to sublimation. Purification by silica gel chromatography (18 mm × 230 mm, 1:1 ether / hexanes as eluent) afforded 59a as a white solid (mp 58-59 ºC) in 86% isolated yield (82 mg, 0.43 mmol) and bis(4-methoxyphenyl)methanol 73a in 62 % yield (76 mg, 0.31 mmol) as white solid (mp 106 69-70 ºC). The optical purity of 59a was determined to be 99% ee by HPLC analysis (CHIRALCEL OD-H column, 98:2 hexane/2-propanol at 228nm, flow-rate: 1.0 mL/min): retention times; Rt = 3.99 min (major enantiomer, 12a) and Rt = 3.47 min (minor enantiomer, ent-59a). 1 Spectral data for 59a: Rf = 0.13 (1:1 Et2O/hexane); H-NMR (CDCl3, 300 MHz) δ 0.99 (t, 3H, J = 7.1 Hz), 1.87 (br, s, 1H), 3.00 (d, 1H, J = 6.1 Hz), 3.47 (d, 1H, J = 6.1 Hz), 3.90-4.00 (m, 2H), 7.24-7.33 (m, 5H); 13 C-NMR (CDCl3, 75 MHz) δ 13.90, 29.65, 37.14, 61.07, 127.47, 127.62, 128.01, 134.80, 169.02; [α ]23 –12.4 (c 1.0, EtOAc) on 99% ee material (HPLC). These D spectral data match those previously reported for this compound. 5 € 1 Spectral data for 73a: Rf = 0.42 (1:3 EtOAc/hexanes); H-NMR (300 MHz, CDCl3) δ 2.08 (d, 1H, J = 2.3 Hz), 3.76 (s, 6H), 5.76 (d, 1H, J = 2.3 Hz), 6.84 (d, 4H, J = 9.0 Hz), 7.25 (d, 4H, J = 8.8 Hz); 13 C-NMR (75 MHz, CDCl3) δ 55.22, 75.30, 113.79, 127.76, 136.47, 158.91. 1) TfOH (10 equiv) MEDAM N Ph CO2Et 37a H CH3CN, 15 min, 65 ºC 2) sat. NaHCO3 MeO N Ph OMe + CO2Et 59a OH 73b The N-MEDAM aziridine 37a (95 mg, 0.2 mmol) was reacted with triflic acid (160 µL, 2.0 mmol 10.0 equiv) in acetonitrile / water medium following the procedure described above for the 107 reaction of N-DAM aziridine 58a except the reaction temperature was 65 ºC. The reaction resulted N-H aziridine 59a and alcohol 73b in 86% yield and 40% yield respectively as 1 determined by H NMR with Ph3CH as internal standard. 1 Spectral data for 73b: H-NMR (300 MHz, CDCl3): δ 1.26 (d, J = 1.8 Hz, 1H), 2.27 (s, 12H), 3.70 (s, 6H), 5.62 (s, 1H), 7.01 (s, 4H). 108 REFERENCES 109 REFERENCES (1) Zhang, Y.; Lu, Z.; Wulff, W. D. Synlett 2009, 2715. (2) (a) Antilla, J. C.; Wulff, W. D. J. Am. Chem. Soc. 1999, 121, 5099; (b) Antilla, J. C.; Wulff, W. D. Angew. Chem., Int. Ed. 2000, 39, 4518; (c) Zhang, Y.; Desai, A.; Lu, A.; Hu, G.; Ding, Z.; Wulff, W. D. Chem–Eur. J. 2008, 14, 3785. (3) Zhang, Y.; Lu, Z.; Desai, A.; Wulff, W. D. Org. Lett. 2008, 10, 5429. (4) Lu, Z. PhD Dissertation, Michigan State University, 2008. (5) Lu, Z.; Zhang, Y.; Wulff, W. D. J. Am. Chem. Soc. 2007, 129, 7185. (6) Mukherjee, M.; Gupta, A. K.; Lu, Z.; Zhang, Y.; Wulff, W. D. J. Org. Chem. 2010, 75, 5643. (7) Friedman, L.; Shechter, H. J. Org. Chem. 1961, 26, 2522. (8) (a) Hu, G.; Huang, L.; Huang, R. H.; Wulff, W. D. J. Am. Chem. Soc. 2009, 131, 15615; (b) Hu, G.; Gupta, A. K.; Huang, R. H.; Mukherjee, M.; Wulff, W. D. J. Am. Chem. Soc. 2010, 132, 14669. (9) Gang, H.; Wulff, W. D. Unpublished Results. (10) (a) Ritter, J. J. J. Am. Chem. Soc. 1948, 70, 4253; (b) Ritter, J. J.; Kalish, J. J. Am. Chem. Soc. 1948, 70, 4048. (11) Schaller, H. F.; Tishkov, A. A.; Feng, X. L.; Mayr, H. J. Am. Chem. Soc. 2008, 130, 3012. (12) Gupta, A. K.; Mukherjee, M.; Wulff, W. D. Org. Lett. 2011, 13, 5866. (13) Desai, A. A.; Wulff, W. D. J. Am. Chem. Soc. 2010, 132, 13100. (14) Bao, J. M.; Wulff, W. D.; Dominy, J. B.; Fumo, M. J.; Grant, E. B.; Rob, A. C.; Whitcomb, M. C.; Yeung, S. M.; Ostrander, R. L.; Rheingold, A. L. J. Am. Chem. Soc. 1996, 118, 3392. (15) Vougioukalakis, G. C.; Chronakis, N.; Orfanopoulos, M. Org. Lett. 2003, 5, 4603. (16) Kuebel-Pollak, A.; Ruttimann, S.; Dunn, N.; Melich, X.; Williams, A. F.; Bernardinelli, G. Helv. Chim. Acta 2006, 89, 841. (17) (a) Carreno, M. C.; Ruano, J. L. G.; Sanz, G.; Toledo, M. A.; Urbano, A. J. Org. Chem. 1995, 60, 5328; (b) Dhami, K. S.; Stothers, J. B. Can. J. Chem. 1966, 44, 2855. (18) Pohland, A.; Sullivan, H. R. J. Am. Chem. Soc. 1953, 75, 5898. 110 CHAPTER 3   APPLICATION OF THE CATALYIC ASYMMETRIC AZIRIDINATION REACTION: SYNTHESIS OF ALL FOUR ISOMERS OF SPHINGANINE 3.1 Biological properties of sphinganies The sphingolipids are essential components of the plasma membrane of eukaryotic cells. 1 They are most abundant in mammalian cells. 3 2 They are also found in plants, marine 4 organisms, bacteria and fungi . They play an important role in many physiological processes including molecular and cellular recognition, signal transduction and modulation of immune 5 6 response. The error in their metabolism is associated with several diseases including diabetes, 7 8 9 cancer, Alzheimer’s disease, infection by microorganisms, heart disease 10 and many others. Structurally, sphingolipids consist of three distinct subunits (Figure 3.1), a) the hydrophilic headgroup which can be a saccharide, phosphate or sulfate and which is predominantly located on the external surface of the membrane. b) The lipophilic fatty acyl chain that acts as a membrane membrane anchor. c) The sphingoid base to which the fatty acyl chain is linked via an amide bond. 111 Figure 3.1 Subunits of sphingolipids Polar head group OH Sphingoid base Sphingolipid O NH O Fatty acyl chain The sphingoid bases are often called ‘long-chain bases’ hundreds of different amino alcohols. 12 The 11 and are known to contain sphingosines 76, sphinganines 74 (dihydrosphingosines) and phytosphingosines 75 (Figure 3.2) are the most common long-chain structural constituents of sphingolipids. Despite their structural diversity, naturally occurring sphingoid bases share a common (2S,3R)-D-erythro amino alcohol moiety as shown in Figure 3.2A. Figure 3.2 A list of: (A) naturally occurring sphingoid bases. (B) Unnatural isomers of sphinganine 74 (A) 12 OH * * OH NH2 74 sphinganines OH * * OH 12 * OH NH2 75 phytosphingosines OH 12 OH * OH 12 * NH2 76 sphingosines OH OH OH NH2 74a D-erythro-sphinganine OH 12 OH NH2 75a D- ribo- phytosphingosine 112 12 OH NH2 76a D-erythro-sphingosine Figure 3.2 (cont’d) (B) OH OH 12 OH NH2 74b L-threo-sphinganine OH OH 12 12 NH2 74c D-threo-sphinganine OH NH2 74d L-erythro-sphinganine However, it has been found that stereochemistry plays a vital role in their biological activities. For example, the L-threo isomer of sphinganine, which is also known as safingol 74b (Figure 3.2B), is an antipsoriatic and antineoplastic drug 14 protein kinase C . 13 and has the ability of inhibiting Since, the biological activity can be heavily dependent on the stereochemistry, all four isomers of sphingosines and sphiganines have been previously synthesized and their biological activity has been investigated. 3.2 11a,12 Previous approaches towards the synthesis of sphinganines Approaches to the preparation of sphinganines has been recently reviewed by Howell et. 15 al. in 2004, which covers the period starting from the first synthesis in 1951 up to 2004. After 2004 many other syntheses of sphinganines have been reported. 16 The early reports of sphinganine syntheses were non-selective and involved separation of diastereomers and resolution of enantiomers from mixtures. Until now very few syntheses of sphinganines involving asymmetric catalytic reactions have been reported. In 1995, Shibasaki et. al. reported the shortest synthesis (two steps from hexadecanal) of sphinganine, which involves an 17 asymmetric catalytic nitro aldol reaction (Henry reaction) as the key step (Scheme 3.1) . 113 Scheme 3.1 L-threo-sphinganine 74b synthesis via asymmetric catalytic nitro aldol reaction   O 13 77 + H 13 THF, –40 ºC, 163 h NO2 HO OH catalyst 80 (10 mol%) OH NO2 13 EtOH 79 78% yield 91:9 dr, 97% ee 78 OH H2, Pd-C OH NH2 74b L-threo -sphinganine 71% yield Et3Si Li * O O O La Li O * O O OH Li * OH OH = OH * catalyst 80 Et3Si (R)- 81 This reaction resulted in very good diastereoselectivity (91:9) and good asymmetric induction (97% ee). The reaction is limited since it only useful for producing one diastereomer and because very long reaction times are required (163 h or ~ 7 days). Later, it was found that this method was impractical to perform on large scale (100 g). 16l Recently, in 2010 another synthesis of sphinganine was reported which involves catalytic asymmetric hydrogenation of β16k ketoester 82 (Scheme 3.2). However, this synthesis is not amenable to both diastereomers. 114 Scheme 3.2 D-erythro-sphinganine 74a synthesis via asymmetric catalytic hydrogenation   O H2 (6 atm) [(R)-BinapRu]Br2 (2 mol%) O OMe 13 OH O MeOH, 50 ºC OMe 13 82 OH 7 steps 83 90%, 95% ee OH NH2 74a D-erythro -sphinganine 13 The Sharpless asymmetric dihydroxylation and Sharpless asymmetric epoxidation are the most successful catalytic asymmetric approaches towards the synthesis of sphinganines (Scheme 3.3). 15 However, the syntheses of all four isomers of sphinganines were not demonstrated by these methods. Scheme 3.3 D-erythro-sphinganine 74a synthesis via Sharpless asymmetric dihydroxylation and epoxidation OH 13 (DHQD)2-PHAL, OsO4 OH 86 91% yield, 99% ee O (–)-DET, TBHP OH OH 13 84 K3Fe(CN)6, K2CO3, MeSO2NH2 Sharpless dihydroxylation 13 OH 85 Sharpless epoxidation 88% yield, 95% ee OH 10 steps from 86 13 OH NH2 7steps from 86 74a D-erythro -sphinganine The aim of the present work is to synthesize all four isomers of sphinganines via the catalytic asymmetric aziridination reaction. 115 3.3 Retro-synthetic analysis of sphinganines A retro-synthetic analysis of the four stereoisomers of sphinganines is presented in Scheme 3.4. The synthesis of threo-isomer 74b and its enantiomer could be possible via the ring opening of the appropriate cis-aziridines 87 with an oxygen nucleophile. Similarly the ring opening of appropriate trans-aziridine 88 with an oxygen nucleophile should lead to the erythro-isomer 74a and its enantiomer. Alternatively, the synthesis of the erythro-isomer can be planned via the ring expansion of N-Boc-protected aziridines to the oxazolidinone 89. Subsequent hydrolysis of oxazolidinone 89 and reduction of the corresponding ester should give the erythro- isomer 74a. Scheme 3.4 Retro-synthetic analysis: erythro-sphinganine and threo-sphinganine ring opening with 'O' nucleophile and reduction OH 13 P N OH NH2 13 74b L-threo -sphinganine (safingol) 13 89 NH ring expansion COOEt OH P N OH NH2 ring opening with 'O' nucleophile 74a and reduction D-erythro -sphinganine (sphinganine) 3.4 87 O O 13 COOEt 13 COOEt 88 Synthesis of aziridine 37l via catalytic asymmetric cis-aziridination The requisite aziridine 37l was synthesized from N-MEDAM imine 36l (Table 3.1) derived from 116 hexadecanal 77. Table 3.1 Asymmetric aziridination with alkyl imine 36l a Ar O Ar Ar N 14 + OEt N2 13 11 36l ligand temp(ºC) Ar Ar + N toluene temp, 24 h Ar = entry Ar (S)-ligand borate catalyst (10 mol%) Ar Ar N NH (C15H31)H CO2Et + CO2Et 13 C15H31(H) 67l (68l) 37l 13 OMe % yield c % ee cisd % yield cis-37l 37l 67l (68l) % yield e f 90 1 (R)-VANOL 25 40 –88 nd 20 2 (S)-VAPOL 25 40 88 0 (4) 18 b (S)-VAPOL 0 60 90 5 (4) 10 3 a 90 Unless otherwise specified, all reactions were carried out with 1.0 mmol of 36l at 0.5 M in toluene with 1.2 equiv of 11 at 25 °C and went to completion in 24 h. The ligand-borate catalyst was prepared by heating the mixture of the ligand and 4 equiv of commercial B(OPh)3 at 80 ºC for an hour followed by the subsequent removal of volatiles on exposure to vacuum. b imine 36l was directly transferred to the catalyst through filter syringe (see experimental for Chapter 3) 117 c Table 3.1 (cont’d) Isolated yield of cis-37l after chromatography on silica gel. d Determined on purified cis-37l by HPLC on a PIRKLE COVALENT (R, R) WHELK-O1 column. e Determined by integration of 1 the NH signals of 67l and 68l relative to the methine proton of cis-37l in the H NMR spectrum of the crude reaction mixture. f Determined by integration of the γ sp2 C-H signal of the 1 conjugated imine 90 relative to the methine proton of cis-37l in the H NMR spectrum of the crude reaction mixture. The reaction with isolated impure imine 36l in the presence of both VAPOL and VANOL derived catalysts resulted in poor yield (40%) and moderate asymmetric induction (88% ee) at room temperature (Table 3.1, entries 1 and 2). It was found that the imines derived from aliphatic aldehydes tend to decompose while kept under vacuum. To minimize the decomposition of imine 36l, the imine was directly transferred without being isolated to a flask containing the ligand borate catalyst with the help of a filter syringe. With this method an improved yield (60%) and asymmetric induction (90% ee) was observed (Table 3.1 entry 3) at 0 ºC. In all these reactions substantial amounts of the conjugated imine 90 was formed which is a self-condensation product of imine 36l (similar to the reaction shown in Scheme 3.5). This mixture of species produced in this process appears to stop the reaction probably due to binding of one or more of these species to the active catalyst. This imposes a serious limitation on the utilization of the aziridination reaction with aliphatic imines. 118 3.5 Synthesis of aziridine starting material via multi-component catalytic asymmetric cisaziridination In the process of dealing with this problem with aliphatic imines, a multi-component catalytic asymmetric aziridination reaction was developed by Anil Gupta, a current group 18 member. The obvious advantage of this multi-component protocol is that the imine preparation step can be avoided. Moreover, the process of aziridination became more operationally simplified. The scope of the aziridination reaction is now broadened to include the unstable imines that cannot be purified. In many cases no aziridine product was observed when the aziridination was attempted starting from pre-formed imines derived from unbranched aliphatic aldehydes. It was found in these cases, that the imines couldn’t be generated in a clean fashion. For example, treatment of aldehyde 91 with MEDAM amine 66 generates conjugated imine 93 long before complete formation of imine 92 can be realized (Scheme 3.5). 18 Scheme 3.5 Self-condensation of imine 91 Ar H2N O Ph 91 H Ar 66 toluene 25 °C, 4 Å MS Ar Ar N Ph N Ar + 92 + Ph Ph Ar Ar OMe 93 Ar H2N Ar 66 The multi-component aziridination reaction provides an effective solution to the longstanding problem with imines derived from unbranched aliphatic aldehydes encountered in two- 119 component methods. The multi-component aziridination protocol was employed to synthesize the requisite aziridine 37l for the synthesis of sphinganines (Table 3.2). a Table 3.2 Multi-component catalytic asymmetric aziridination with hexadecanal 77 O 2) 1) Ligand (x mol%) Ar Ar 13 toluene, 80 °C, 0.5 h 66 Ar = entry ligand Ar Ar 77 4 Å MS B(OPh)3 (3x mol%) NH2 Ar H 3) EDA (11) temp, 24 h N Ar + CO2Et 13 Ar Ar N NH (C15H31)H CO2Et + 67l (68l) 37l 13 C15H31(H) 13 90 OMe catalyst Temp equiv % yield x mol% (ºC) 11 37l b % ee 37l c % yield 67l (68l) % yield e 90 f 1 (S)-VAPOL 10 0 1.2 70 95 9.0 (6.0) 6.0 2 (S)-VAPOL 10 –10 1.2 80 96 nd < 1.0 d (S)-VAPOL 10 –10 2.0 85 95 0.0 (3.0) < 1.0 g (S)-VAPOL 10 –10 2.0 90 96 1.0 (1.0) < 1.0 g (S)-VAPOL 5 –10 2.0 85 96 1.7 (1.7) < 1.0 g (S)-VAPOL 10 –20 2.0 85 95 nd < 1.0 g (S)-VANOL 10 –10 2.0 85 95 1.7 (nd) < 1.0 3 4 5 6 7 a Unless otherwise specified, all reactions were performed with 0.5 mmol amine 66 (0.5 M in 120 Table 3.2 (cont’d) toluene) and 1.05 equiv of n-hexadecanal 77 and 1.2 equiv EDA 11 and went to 100% completion. Before adding the aldehyde and EDA 11 a solution of amine 66 with x mol% ligand and 3x mol% B(OPh)3 was stirred for 30 min at 80 °C under nitrogen. nd = not determined. Isolated yield after chromatography on silica gel. c b Determined on purified cis-37l by HPLC on d PIRKLE COVALENT (R, R) WHELK-O1 column. The scale of the reaction was 4.5 mmol. e Determined by integration of the NH signals of 67l and 68l relative to the methine proton of cis1 37l in the H NMR spectrum of the crude reaction mixture. f Determined by integration of the γ 1 sp2 C-H signal of the conjugated imine 90 relative to the methine proton of cis-37l in the H NMR spectrum of the crude reaction mixture. g concentration of the reaction was 0.2M in amine 66 and the aldehyde 77 was added in as a solution in toluene. There is a significant enhancement in both yield (70%) and asymmetric induction (95% ee) observed when the aziridination reaction was performed via the multi-component protocol with the VAPOL derived catalyst keeping the other variables constant (Table 3.2 entry 1 vs Table 3.1 entry 3). The yield of the reaction could be further improved to 80% - 85% by lowering the temperature from 0 ºC to –10 ºC and by increasing the amount of ethyl diazoacetate 11 from 1.2 equiv to 2.0 equiv (Table 3.2, entries 2 and 3). There is a slight increase in yield (90%) observed after diluting the reaction mixture from 0.5M to 0.2 M in concentration (Table 3.2, entries 3 vs. 4). There was no significant effect observed on the reaction when the temperature was decreased to –20 ºC (Table 3.2, entry 6). The VANOL derived catalyst shows essentially the same reactivity and asymmetric induction (Table 3.2, entry 7) as the VAPOL derived catalyst. 121 Moreover, the catalyst loading can be decreased to 5 mol% without any detrimental effect on the asymmetric induction (Table 3.2, entry 5). Further, the optical purity of the aziridine 37l (96% ee) can be improved to 98% ee by single crystallization from hexanes (80% yield). 3.6 Ring opening of cis-aziridine with oxygen nucleophile It was mentioned in the retro synthetic analysis of sphinganines that isomers 74b and its enantiomer with relative syn-stereochemistry should be possible via ring opening of the appropriate cis-aziridine with oxygen nucleophile. The phenyl aziridine 37a was used as the model system to study the ring opening of the NMEDAM aziridines with oxygen nucleophiles. In previous studies of trapping the MEDAM cation (Chapter 2) with water, it was observed that in an acidic medium water cause opening of the aziridine ring. Encouraged by this observation, the ring opening of aziridine 37a was examined in the presence of water in a highly acidic medium. Table 3.3 Ring opening of aziridine 37a with water in acidic medium Ar Ar OH triflic acid (x equiv) N Ph CO2Et 37a entry a CH3CN/ H2O (4:1 v/v), temp, time CO2Et Ph HN 94 Ar OMe Ar Ar conc triflic acid temp time (M) (x equiv) (ºC) (h) % yield 94 b (NMR) 0.2 10 50 4 50 c 0.2 5 25 24 nd c 0.4 5 25 24 nd 0.4 5 50 4 60 1 2 3 4 122 Table 3.3 (cont’d) a Unless otherwise specified, all reactions were performed with 0.2 mmol aziridine 37a and triflic acid in acetonitrile water mixture (4:1 v/v) and went to 100% completion. nd = not determined. b NMR yield with Ph3CH as internal standard. c the reaction was not complete after 24 h. The aziridine 37a was treated with 10 equiv of triflic acid in an acetonitrile and water (4:1 v/v) mixture at 50 ºC (Table 3.3, entry 1). As expected, ring opening with water was observed 1 giving a 50 % yield of 94 as determined by H NMR. The NMR yield was determined using Ph3CH as internal standard. Some unidentified products were observed along with the ringopened product. The reaction at room temperature was found to be incomplete even after 24 h when 5 equiv of triflic acid was employed (Table 3.3, entry 2). A similar observation was made when the concentration was increased to 0.4 M (Table 3.3, entry 3). The reaction went to completion at 50 ºC in the presence of 5 equiv of triflic acid giving a 60 % yield of 94 as 1 determined by H NMR at 0.4 M (in aziridine 37a) concentration (Table 3.3, entry 4). At this point it was thought to modify the ring opening reaction conditions so as to effect the removal of the N-MEDAM group in a single step to produce the amino alcohol 95 with a free amine group. As a model reaction, the ring opening of the N-H aziridine 59a was performed at 65 ºC in the presence of 10 equiv of triflic acid in acetonitrile-water (4:1 v/v) medium (Scheme 3.6). The reaction resulted in a 50% isolated yield of β-hydroxy-α-amino ester 95. The lower yield for 95 compared to 94 could possibly be accounted for by the higher solubility of hydroxy amine 95 in water. 123 Scheme 3.6 Ring opening of N-H aziridine 59a with water in acidic medium H N Ph OH triflic acid (10 equiv) CO2Et 59a CO2Et Ph CH3CN/ H2O (4:1 v/v), 65 ºC, 2 h NH2 95 50% yield The protocol was changed to reacting the aziridine 37a with triflic acid in a dry solvent to deprotect the MEDAM group and then a workup with water to open the N-H aziridine ring. This 1 led to amino alcohol 95 in 50% yield as determined by H NMR (Table 3.4 entry 1). Similar results were observed when the solvent was changed to anisole (Table 3.4, entry 2). Table 3.4 Ring opening of aziridine 37a with water in acidic medium via deprotection of Na MEDAM group Ar Ar 1) triflic acid (x equiv) solvent, temp, 2 h N Ph 37a CO2Et Ar OMe OH CO2Et Ph NH2 2) H2O, 65 ºC, time 95 entry triflic acid (x equiv) temp (ºC) time (h) 1 acetonitrile 10 65 3 2 a solvent anisole 5 25 5 % yield b 95 50 55 Unless otherwise specified, the first step of all reactions were performed with 0.2 mmol aziridine 37a and triflic acid in dry solvent. In the following step water was added (solvent: water 4:1 v/v) and the reactions went to 100% completion. standard. 124 b NMR yield with Ph3CH as internal To maximize the solubility of the β-hydroxy-α-amino ester 95 in organic solvent, it was thought to protect the free amine group with Boc. After a few attempts to optimize to the yield of the final product 96, it was found that acetone is the optimum solvent for the deprotection followed by exposure to water to effect ring opening of the aziridine 37a (Table 3.5). Table 3.5 Synthesis of N-Boc-β-hydroxy-α-amino ester 96 from imine 36a without isolation of intermediates a Ar Ph (R)-VAPOL-boroxinate catalyst (3 mol%) O Ar N + OEt N2 11 36a toluene 25 ºC, 24 h Ar Ar OMe Ar N Ph CO2Et ent-37a 1) triflic acid (5 equiv) acetone, 3 h, 60 ºC 2) H 2O, 10 h, 60 ºC OH CO2Et Ph HN 96 Boc NaHCO 3, Boc 2O OH Ph CO2Et NH 2 THF, 25 ºC, 12 h ent-95 not isolated Entry Reaction scale (mmol) % Yied 96 1 Pure 37a used 2.0 (66) 70 2 Crude 37a used 5.0 63 3 a Condition Crude 37a used 5.0 60 d b c d e Unless otherwise specified, the first step of all reactions were performed with aziridine 37a (0.05 M) and 5 equiv of triflic acid in acetone. In the following step water was added (acetone: 125 Table 3.5 (cont’d) water 5:1 v/v) and the reactions went to 100% completion. After 10 h the volume of the reaction mixture was reduced to half of its original volume under reduced pressure and solid NaHCO3 was added followed by Boc2O. b Isolated yield after purification by column chromatography. the yield was calculated from pure aziridine 37a. 36a. e d c the yield was calculated from pure imine yield was calculated from amine 66 (aziridine 37a was synthesized following the multi- component aziridination protocol) Further, it was envisioned that the crude aziridine ent-37a could also be subjected to the deprotection and ring opening sequence mediated by triflic acid and water. This process would directly yield the optically pure N-Boc-β-hydroxy-α-amino ester 96 without any isolation and purification of intermediates. The N-MEDAM aziridine ent-37a was synthesized from 19 preformed MEDAM imine 36a and also following the multi-component protocol starting from MEDAM amine 66 and benzaldehyde. 18 The unpurified aziridines obtained from these two different procedures were then separately subjected to triflic acid deprotection, a water induced ring opening, and a Boc protection sequence, without isolation of any intermediate isolations, to afford the pure N-Boc-β -hydroxyl-α-amino ester 96 in a 63% overall yield from imine 36a (Table 3.5, entry 2) and 60% overall yield from amine 66 (Table 3.5, entry 3) respectively. The same deprotection/ring opening protocol was applied to aziridine 37l (Scheme 3.7) as a key step in the synthesis of sphinaganine 74b (Figure 3.2B). Unfortunately, the aziridine 37l failed to give a satisfactory yield (45%, NMR yield) of the β-hydroxyl-α-amino ester 98. 126 Scheme 3.7 Synthesis of N-Boc-β-hydroxy-α-amino ester 98 from aziridine 37l Ar Ar N 13 CO2Et 37l 1) triflic acid (5 equiv) acetone, 3 h, 60 ºC 2) H 2O, 10 h, 60 ºC OH 13 CO2Et NH 2 NaHCO 3, Boc 2O THF, 25 ºC, 12 h 97 not isolated OH 13 HN CO2Et Boc 98 45% NMR yield Ar = 3,5-Me2-4-OMe-C6H 2 In general, aliphatic aziridines show a lower reactivity toward ring opening reactions with oxygen containing nucleophiles compared to aromatic substituted aziridines. Therefore, it was thought to activate the aziridine ring by introducing an electron-withdrawing group on the nitrogen of the aziridine and this will be described in the next section. 3.7 Synthesis of D and L-threo-sphinganines The N-MEDAM group was deprotected from aziridine 37l with triflic acid in actonitrile and the N-H aziridine was protected with Boc without purifying the intermediate to give the NBoc aziridine 100 in 80% yield in two-steps from 37l (Scheme 3.8A). To our delight, the N-Boc aziridine 100 underwent ring opening reaction in a clean fashion when treated with formic acid (88% by volume) to give the N-formyl amino alcohol 101. The formamide group in the ringopened crude product 101 was hydrolyzed with HCl in methanol to afford β -hydroxyl-α-amino ester •HCl salt 102. The crude salt 102 was finally reduced by LiAlH4 to L-threo-sphinganine 74b with 70% yield over three steps from aziridine 100 (Scheme 3.8A). The same route was followed for synthesis of the D-threo-sphinganine 74c starting from aziridine ent-37l and the yields are given in Scheme 3.8B. It must be noted that the presence of free amine and hydroxyl groups makes the sphinganines 74b and 74c very polar. The final purification of the molecule by column chromatography is troublesome, as the product tends to stick to the silica gel. 127 Scheme 3.8 (A) synthesis of L-threo-sphinganine 74b (B) synthesis of D-threo-sphinganine 74c (A) OMe (S)-VAPOL (5 mol%) B(OPh) 3 (15 mol%) MeO NH 2 66 + H 12 + 11 OH rt, 16 h NH 2 OEt NH 2•HCl 13 74b, L-threo -sphinganine (safingol) 70% yield (over three steps, from 100) N CO2Et 13 100, 80% yield (over two steps from 37l) HCOOH 10 min, rt 1M HCl in MeOH OH O LiAlH 4, THF OH 13 13 Boc 2) Boc 2O, NaHCO 3 CO2Et 37l 85% yield, 96% ee (80% yield, 98% ee, single crystalization from hexane) OEt N2 77 N toluene, –10 ºC O O 1) TfOH, CH3CN 65 ºC MEDAM rt OH O OEt NHCHO 13 102 101 (B) OMe (R)-VAPOL (5 mol%) B(OPh) 3 (15 mol%) MeO NH 2 66 + O O H 12 + OEt N2 77 OH NH 2 N CO2Et 13 ent-37l 85% yield, 96% ee 1) TfOH, CH3CN 65 ºC Boc N 2) Boc 2O, NaHCO 3 13 CO2Et ent-100, 82% yield (over two steps from 37l) 11 OH 13 toluene, –10 ºC MEDAM HCOOH 10 min, rt OH O LiAlH 4, THF rt, 16 h 74c, D-threo -sphinganine 75% yield (over three steps, from ent-100) OEt NH 2•HCl 13 ent-102 128 1M HCl in MeOH rt OH O 13 OEt NHCHO ent-101 The essence of any synthesis lies in the ease of isolation and purification of its intermediates and final product. It is always desirable to have simplified isolation procedures of the products of high yielding reactions. In order to attain the above-mentioned goal, an alternative synthetic route to threo-spinganine was designed involving protected amine intermediates (Scheme 3.10). It was realized that the ring opening of aziridine 37l could be possible without deprotecting the N-MEDAM group to afford 103 in 80% yield as determined by 1 H NMR in presence of p-toluenesulfonic acid in an acetone / water mixture (Scheme 3.9). The NMR yield was calculated by using Ph3CH as internal standard. Scheme 3.9 Ring opening of aziridine 37l with water MEDAM N CO2Et 13 OH p-toluenesulfonic acid acetone/H2O (5:1 v/v) rt, 3 days 37l 13 CO2Et NH MEDAM 103 80 % NMR yield To accelerate the rate of the above mentioned reaction, the reaction was performed at 65 ºC. Although the reaction was complete in 36 h, a decrease in the yield of 103 (50% as 1 determined by H NMR) was observed at 65 ºC. Finally, acceptable yield (75%) of ent-103 was obtained when the ring opening was performed in refluxing dichloromethane in the presence of 1 20 equiv of trifluoroacetic acid followed by treatment with base (Scheme 3.10). The MEDAM protected β-hydroxyl-α-amino ester ent-103 was then reduced to corresponding β-hydroxyl-αamino alcohol ent-104 in 94% isolated yield (Scheme 3.10A). The presence of the bulky MEDAM group on nitrogen makes the intermediates less polar, so monitoring the reaction by 129 TLC and isolation and purification of the products became easier. Finally, the MEDAM group was cleaved by hydrogenolysis in the presence of Boc anhydride to afford N-Boc-D-threospinganine ent-105 in 85% isolated yield. The presence of Boc group in the final product increases the product stability as compared to the corresponding free amine. Scheme 3.10 (A) Synthesis of D-threo-sphinganine 74c (B) Synthesis of N-Boc-L-threosphinganine 105 (A) OMe MeO (R)-VAPOL borate catalyst NH 2 toluene, –10 ºC 66 + O 12 H O 77 N2 N 1) TFA (1 equiv) DCM, 12 h reflux OH CO2Et 13 CO2Et 2) NaOH 13 ent-37l 85% yield, 96% ee OEt + MEDAM NH MEDAM ent-103 75 % yield 11 LiAlH 4, THF rt, 16 h OH 13 CF3COOH OH NH 2 74c, D-threo -sphinganine 85% yield H 2, Pd(OH) 2 on C OH 13 OH HN Boc ent-105 83% yield 130 MeOH, Boc 2O, rt, 24h OH 13 OH HN MEDAM ent-104 94% yield Scheme 3.10 (cont’d) (B) OMe MeO (S)-VAPOL borate catalyst toluene, –10 ºC NH 2 66 + O 12 H O 77 N2 1) TFA (1 equiv) DCM, 48 h, rt N CO2Et 13 2) NaOH 37l 85% yield, 96% ee OEt + MEDAM OH CO2Et 13 NH MEDAM 103 83 % yield 11 LiAlH 4, THF rt, 16 h OH 13 OH HN OH H 2, Pd(OH) 2 on C Boc 105 87% yield MeOH, Boc 2O, rt, 24h 13 OH HN MEDAM 104 96% yield The Boc group was easily removed following the reported procedure in presence of trifluoroacetic acid 21 and the pure sphinganine 74c was obtained by simple filtration of the reaction mixture. The same route was followed for synthesis of the N-Boc-L-threo-spinganine 105 starting from aziridine 37l and the yields are given in Scheme 3.10B. 3.8 Synthesis of erythro-sphinganine The erythro-sphinganine synthesis from cis- aziridine involves ring expansion of the N- carbamoyl aziridine 100 to oxazolidinone 89 (Table 3.6). Although this Lewis acid mediated ring expansion reaction has been reported with retention 131 22 we had previously observed that aziridines with aryl groups in the 3-position can give mixtures of cis- and trans- oxazolidinone isomers. 23 The ring expansion reaction of aziridine 100 with a primary alkyl group at 3-position was tested under the influence of several different Lewis acids (Table 3.6). To our delight, the ring expansion of N-Boc aziridine 100 with Sc(OTf)3 resulted in the oxazolidinone 89 in 90% isolated yield (93% NMR yield) with complete retention of configuration (Table 3.6, entry 1). The reactions with the Lewis acids Cu(OTf)2 and Yb(OTf)3 were very slow and resulted in the formation of oxazolidinone 89 in 60% and 70% NMR yields respectively (Table 3.6, entries 2 and 3). Reaction in presence of BF3•OEt2 resulted in a complex mixture of unidentified products (Table 3.6, entry 4). Table 3.6 Screening of Lewis acids for the ring expansion of aziridine 100 Lewis acid (10 mol % ) Boc N CH2Cl2, rt COOEt time 14 a O O NH 14 COOEt 89 100 b Entry Lewis acid Time (h) 1 Sc(OTf)3 20 93 (90) 2 Cu(OTf)2 48 60 3 Yb(OTf)3 48 70 BF3•OEt2 48 nd 4 d 132 % Yield 89 e c Table 3.6 (cont’d) a Unless otherwise specified all reactions were performed with 0.2 mmol of aziridine 100 (0.2 M) and 10 mol % of Lewis acid in 1 mL of dichoromethane. b Determined from 1H NMR spectra of the crude reaction mixture with Ph3CH as internal standard. nd = not determined. Yield in parenthesis is isolated yield of 90%. d 50 mol % catalyst used. e c A complex mixture of unidentified products obtained. The oxazolidinone 89 was hydrolyzed with lithium hydroxide and the resulting crude mixture was reduced with lithium aluminum hydride to the erythro- sphinganine 74a in 65 % yield over two steps (Scheme 3.11A). The same route was followed for synthesis of the Lerythro-spinganine 74d starting from aziridine ent-100 and the yields are given in Scheme 3.11B. Scheme 3.11 (A) synthesis of D-erythro-sphinganine 74a (B) synthesis of L-erythro-sphinganine 74d (A) O O NH 14 COOEt 89 OH 1) LiOH 2) LiAlH4, THF rt 133 OH NH2 74a, D-erythro -sphinganine 70 % from 89 (two steps) 13 Scheme 3.11 (cont’d) (B) Lewis acid (10 mol % ) Boc N 14 CH2Cl2, rt COOEt time ent-100 O O NH 14 COOEt ent-89 93% yield 1) LiOH 2) LiAlH4, THF rt OH 13 OH NH2 74d, L-erythro -sphinganine 75 % from ent-89 (two steps) As discussed earlier in retro-synthetic analysis, the erythro-sphinganine 74a and its enantiomer can alternatively be synthesized via ring opening of trans-aziridine 88 (Scheme 3.4). To this end, the multi-component trans-aziridination reaction involving n-hexadecanel 77 and different diazoacetamide was studied (Table 3.7). Finally, we were able to find suitable conditions for multi-component trans-aziridination reaction with n-hexadecanal 77 with some optimization. Anil Gupta, a current group member, initiated this study where he used diazoacetamide 106c (Table 3.7, entry 7). A screening of other diazoacetamides was performed as a part of this doctoral research. The yield and asymmetric induction of the trans-aziridination reaction with aldehyde 77 was found to be largely dependent on the diazoacetamide 106. The phenyl diazoacetamide 106a resulted in the corresponding trans-aziridine 88a with 35% yield and 57% ee at –20 ºC in presence of the (S)-VANOL derived catalyst (Table 3.7, entry 1). There 134 was not much improvement in the results when the reaction temperature was increased to 0 ºC (Table 3.7, entry 2). An improved yield and asymmetric induction was observed with benzyl diazoacetamide 106b. The benzyl diazoacetamide 106b resulted in the formation of the corresponding trans-aziridine 88b in 55% yield and 88% ee at 0 ºC in presence of the (S)VANOL derived catalyst (Table 3.7, entry 4). Although there was no significant change in yield observed when the reaction temperature was changed to –20 ºC or to 25 ºC, there was a drop in the asymmetric induction observed in both cases (Table 3.7, entries 3 and 5). Table 3.7 Multi-component catalytic asymmetric trans-aziridination with secondary diazoacetamide 106 a 2) Ar Ar NH2 66 1) (S)-VANOL (10 mol!%) B(OPh)3 (30 mol!%) toluene, 80!°C, 0.5 h O 14 H 77 4 Å MS 3) CONHX N2 106 temp, 24 h Ar Ar Ar N CONHX 14 X= Ph, 88a X= Bn, 88b X= n-Bu, 88c b OMe entry X temp (ºC) 1 Ph (106a) –20 35 2 0 43 3 –20 50 82 0 55 88 5 25 60 83 6 –40 65 90 –20 65 92 4 7 Bn (106b) e 135 % yield trans-88 % ee trans-88 57 d nd c Table 3.7 (cont’d) 8 –10 70 93 9 0 60 90 10 a n-Bu (106c) 25 62 87 Unless otherwise specified, all reactions were performed with 0.5 mmol amine 66 (0.2 M in toluene) and 1.05 equiv of n-hexadecanal 77 and 1.2 equiv diazoacetamide 106 and went to 100% completion. Before adding the aldehyde and EDA 11 a solution of amine 66 with 10 mol% ligand and 30 mol% B(OPh)3 was stirred for 30 min at 80 °C under nitrogen. nd = not determined. b c Isolated yield after chromatography on silica gel. Determined on purified trans- 88 by HPLC on PIRKLE COVALENT (R, R) WHELK-O1 column. d Determined from 1H NMR spectra of the crude reaction mixture with Ph3CH as internal standard. e Reaction performed by Anil Gupta. The n-butyl diazoacetamide 106c proved to be the optimum diazo component for the multi-component trans-aziridination reaction with hexadecanal 77. The reaction with n-butyl diazoacetamide 106c resulted in the trans-aziridine 88c in 70% yield and 93% ee at –10 ºC (Table 3.7, entry 8). No significant effect on yield or enantioselectivity of the reaction was observed when the temperature of the reaction was lowered to –20 ºC or –40 ºC (Table 3.7, entries 6 and 7). However, a slight drop in yield and enantioselectivity (62% yield, 87% ee) was observed at room temperature (Table 3.7, entry 10). The ring opening of the trans-aziridine 88c with water was tried in the presence of ptoluenesulfonic acid in an acetone / water mixture. The nucleophilic attack on the trans-aziridine 136 was not regioselective as it was in the case for cis-aziridnes. The reaction resulted in a 2:1 ratio of C-2 opened product 108 and C-3 opened product 107 (Scheme 3.12A). A similar observation was made when the ring opening reaction of trans-aziridine 88c was performed in dichloromethane in presence of 1 equiv of trifluoroacetic acid followed by treatment with base (Scheme 3.12B). Scheme 3.12 (A) Ring opening of trans-aziridine 88c with water in acidic medium (B) Ring opening of trans-aziridine 88c with TFA (A) Ar p-toluenesulphonic acid(10 equiv) Ar N H N 14 O n-Bu Ar OH O rt, 3 days, acetone/ H 2O (5:1 v/v) Ar 13 N NH H n-Bu Ar + N 13 OH H Ar 107 25% yield 88c Ar = MeO NH O n-Bu 108 55% yield 107:108 = 1:2.2 (from crude NMR) (B) Ar Ar N 14 88c H N O n-Bu 2) NaOH Ar OH O 1) TFA (1 equiv) DCM, 48 h, rt Ar 13 N NH H Ar 107 20% yield n-Bu + Ar NH O N 13 OH H 108 40% yield n-Bu It would be interesting to see whether changing the amide group to carboxylate ester group can solve the regioselectivity issue in this ring opening of the trans-aziridine. The amide group in trans-aziridine 88c was converted to corresponding ethyl ester 109 (Scheme 3.13A). The ring 137 opening reaction of trans-aziridine 109 was performed in dichloromethane in presence of 1 equiv of trifluoroacetic acid followed by treatment with base (Scheme 3.13B). Unfortunately, the ring opening of trans-aziridine 109 was not regioselective as the reaction resulted C-2 opened product 111 and C-3 opened product 110 in 2:1 ratio (Scheme 3.13B). Scheme 3.13 (A) Synthesis of trans-aziridine 110 (B) Ring opening of trans-aziridine 110 with TFA (A) Boc2O (3 equiv), DMAP (2 equiv) MEDAM N 13 O NH n-Bu MEDAM N CH2Cl2, rt 2 d 13 88c O MEDAM NaOEt Boc EtOH, 4 h, 0 ºC N n-Bu N COOEt 13 109 98% yield(brsm) 110 90% yield Ar = MeO (B) MEDAM 1) TFA (1.0 equiv) CH2Cl2, rt, 48 h N 13 OEt O 110 2) NaOH MEDAM OH O 13 NH O OEt NH MEDAM 111 + 13 OEt OH 112 111:112 = 1:1.9 (from crude NMR) At this point, the only solution to this regioselectivity issue is to activate the trans- 138 aziridine ring by introducing an electron-withdrawing group on the nitrogen of aziridine ring and 24 this should be the subject of future experiments (Scheme 3.14). Scheme 3.14 Proposed solution for regioselective Ring opening of trans-aziridine Ar Ar N 13 3.9 1) Deprotection 2) Boc protection CO2Et Boc 13 110 ring opening N CO2Et 113 OH O 13 NH Boc 114 OEt Study towards synthesis of mycestericin E After the successful completion of the syntheses of the sphinganines, we envisioned to plan the synthesis of a more complex molecule mycestericin E. The proposed synthetic route to mycestericin E would be similar to that of sphinganines involving the Wulff catalytic asymmetric aziridination reaction as the key component of the strategy. The mycestericin family includes eight members isolated from Mycelia sterilia and which share immunosuppressant activity. 25 There have been a few total syntheses of the mycestericins reported with none of them particularly efficient. 26 Most have involved starting from the chiral pool or a combination of chemical and enzymatic steps. 3.10 Retro-synthetic analysis of mycestericin E A retro-synthetic analysis of the mycestericin E 125 is presented in Scheme 3.15. The synthesis of mycestericin E 125 could be possible via the ring opening of the appropriate cisaziridines 124 with an oxygen nucleophile. The aziridine 124 could be possible to synthesize via 139 C2 alkylation of aziridine 123 with formaldehyde. A multi-component aziridination reaction of aldehyde 122 would yield aziridine 123 in presence of (R)-VAPOL or (R)-VANOL derived catalyst. Scheme 3.15 Retro-Synthetic analysis of mycestericin E OH 5 O CO2H H2N 1) ring opening 2) deprotection OH P N R 125 124 R= 5 OH CO2Et O O 4 C2-alkylation H P MCAZ (R)-VAPOL O 5 O O 4 + P-NH2 + EDA 122 N CO2Et R 123 3.11 Synthesis of aziridine 123 via multi-component aziridination reaction The aldehyde 122 was synthesized from aldehyde 120 which was prepared from the commercial available acid chloride 115 via a known procedure involving 5 steps in 80% overall yield 27 (Scheme 3.16). Addition of vinyl Grignard to 120 proceeds in 80% yield but the subsequent Claisen rearrangement only gives aldehyde 122 in 30% yield. The low yield can be attributed to the incompatibility of aldehyde 122 to the high temperatures associated with the enol ether Claisen. 140 Scheme 3.16 Synthesis of aldehyde 122 OMe N H •HCl Cl pyridine CH2Cl2 4 O 115 OMe N 4 O 116 (not purified) 6 MgBr 118 5 THF, rt, 1h 90% yield 117 HO OH 1.5 equiv 95% yield O 4 O p-TSOH (0.05 equiv) benzene reflux 1) K2OsO4 • 2H2O, NMO acetone/H2O, rt, 12h 5O O 4 120 MgBr (2.3 equiv) THF –78 ºC - 0 ºC 5O 2) NaIO4,CH2Cl2, 1h O 4 O 4 119 94% yield (over 2 steps) 80% yield Hg(OAc)2(5 mol%) HO 5O 121 O 4 OEt 140 ºC, 14 h O 30% yield 5O 122 The multi-component aziridination of aldehyde 122 with the (R)-VAPOL derived catalyst gives aziridine 123 in 90% yield and 97% ee (Scheme 3.17). The asymmetric induction was not confirmed due to unavailability of authenticate sample of ent-123. The final stages of mycestericin E synthesis involve the alkylation of aziridine 123 with formaldehyde and subsequent ring opening of the resulting aziridine and this should be the subject of future experiments. 141 Scheme 3.17 Synthesis of aziridine 123 Ar (R)-VAPOL (10 mol%) Ar NH2 66 B(OPh)3 (30 mol%) toluene, 80 °C, 0.5 h 1) 4 Å MS 2) RCH2CHO 122 (1.05 equiv) –10 ºC 3) EDA (11) (2.0 equiv) –10 ºC, 24 h Ar = 3,5-Me2-4-OMe-C6H2 Ar2CH = MEDAM Ar Ar N R CO2Et 123 90% y, 97%ee R= 5 O O 4 3.12 Conclusions The synthesis of 1,2-amino alcohols and sphingoid bases can be planned via regio- and stereo- selective ring opening of the aziridine 2-carboxylates as described in this work. There is a very extensive list of reports on the synthesis of sphingoid bases but very few involve catalytic asymmetric methods. Moreover, this work demonstrates the application of a catalytic asymmetric method to the synthesis of all isomers of a sphingoid base. This approach should help to make aziridines more attractive intermediates in synthesis of chiral amines that constitute an important class of compounds for pharmaceuticals, bioactive materials or small molecule synthesis. 142 APPENDIX 143 3.13 Experimental procedure 3.13.1 General information Same as Chapter 2. 3.13.2 Preparation of hexadecanal 77 28 PhIO (1.3 equiv), TEMPO (5 mol%) 12 99 OH Yb(OTf)3 (2 mol%), CH2Cl2 0 ºC, 50 min O H 12 77 To a 100 mL flame-dried round bottom flask equipped with a stir bar was added 1-hexadecanol 99 (1.21 g, 5.00 mmol). Dry CH2Cl2 (20 mL) was added to dissolve 99. To the resulting solution were added TEMPO (32 mg, 0.25 mmol) and PhIO (1.43 g, 6.50 mmol). The suspension was cooled to 0 °C and Yb(OTf)3 (62.5 mg, 0.10 mmol) was added. The reaction mixture was stirred at 0 °C for 50 min (until the alcohol was no longer detectable by TLC). The yellow cloudy solution was filtered through Celite pad and concentrated under reduced pressure. Purification of the crude aldehyde by silica gel chromatography (30 mm × 300 mm column, 5:1 hexanes / dichloromethane as eluent, flash column) afforded pure aldehyde 77 as a white solid (mp 36-38 ºC) in 75 % isolated yield (0.90 mg, 3.75 mmol). Spectral data for 77: Rf = 0.5 (1:3 hexanes/DCM). 1 H-NMR (500 MHz, CDCl3): δ 0.88 (t, J = 6.9 Hz, 3H), 1.30-1.25 (m, 24H), 1.62 (quintet, J = 7.3 Hz, 2H), 2.41 (td, J = 7.4, 1.9 Hz, 2H), 9.76 (t, J = 1.8 Hz, 1H). 13 C-NMR (126 MHz, CDCl3): δ 14.09, 22.10, 22.68, 29.17, 29.35, 29.42, 29.57, 29.63, 29.64, 29.65, 29.67, 29.68, 31.92, 43.91 (1 sp3 carbon not located), 202.85. 144 3.13.3 Asymmetric catalytic aziridination of imine 36l to synthesize cis-aziridine 37l (Procedure A) Ar H O + 13 77 Ar Ar NH2 66 Ar 4 Å MS N toluene, 25 ºC, 6 h Ar 13 36l OMe Ar (S)-VAPOL borate catalyst O Ar (10 mol%) + Ar OEt toluene N N2 0 ºC, 24 h 13 11 36l N 13 + CO2Et 37l Ar Ar Ar Ar Ar (C15H31)H N NH CO2Et + 13 C15H31(H) 67l (68l) (E)-N-Hexadecylidene-1,1-bis(4-methoxy-3,5-dimethylphenyl)methanamine 36l: 13 90 To a 10 mL flame-dried round bottom flask filled with argon was added bis(4-methoxy-3,5dimethylphenyl)methanamine 66 (299 mg, 1 mmol), 4Å MS (250 mg, freshly dried) and dried toluene (1.5 mL). After stirring for 10 min, hexadecanal 77 (253 mg, 1.05 mmol) was added. The reaction mixture was stirred at room temperature for 6 h. The resulting imine 36l was used without further purification. (2R,3R)-Ethyl-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-pentadecylaziridine-2carboxylate 37l: To a 10 mL flame-dried home-made Schlenk flask, prepared from a single necked 25 mL pear-shaped flask that had its 14/20 glass joint replaced with a high vacuum threaded Teflon valve, flushed with argon was added (S)-VAPOL (54 mg, 0.1 mmol) and 145 B(OPh)3 (116 mg, 0.4 mmol) . Under an argon flow, dry toluene (2 mL) was added to dissolve the two reagents. The flask was sealed, and then placed in an oil bath at 80 ºC for 1 h. After 1 hour, a vacuum (0.5 mm Hg) was applied carefully to remove the volatiles. The vacuum is maintained for a period of 30 min at a temperature of 80 ºC. The flask was then filled with argon and the catalyst mixture was cooled to 0 ºC. The imine 36l (1 mmol, crude and non-isolated) was then directly transferred from the reaction flask (of imine) to the flask containing the catalyst utilizing the filter syringe (Corning® syringe filters, Aldrich). The flask, which had imine 36l, then rinsed with toluene (0.5 mL) and transferred to the flask containing the catalyst. The reaction mixture was stirred for 5 min at 0 ºC to give a light orange solution. To this solution was rapidly added EDA 11 (124 µL, 1.2 mmol) and the resulting mixture was stirred for 24 h at 0 ºC. The reaction was diluted by addition of hexane (6 mL). The reaction mixture was then transferred to a 100 mL round bottom flask. The reaction flask was rinsed with dichloromethane (5 mL × 2) and the rinse was added to the 100 mL round bottom flask. The resulting solution was then concentrated in vacuo followed by exposure to high vacuum (0.05 mm Hg) for 1 h to afford the crude aziridine as pale yellow semi solid. Purification of the crude aziridine by silica gel chromatography (30 mm × 150 mm column, 4:2:0.1 hexanes/CH2Cl2/Et2O as eluent, gravity column) afforded pure aziridine 37l as a semi solid in 60% isolated yield (365 mg, 0.60 mmol); cis/trans: not determined. Enamine side products: 5% yield of 67l and 4% yield of 68l. Imine condensation product: 10% yield of 90. The optical purity of 37l was determined to be 90% ee by HPLC analysis (PIRKLE COVALENT (R, R) WHELK-O1column, 99.5:0.5 hexane/2propanol at 226nm, flow-rate: 0.7 mL/min): retention times; Rt = 18.26 min (major enantiomer, 37l) and Rt = 33.43 min (minor enantiomer, ent-37l). 146 1 Spectral data for 37l: Rf = 0.31 (2:1:0.2 hexanes/CH2Cl2/Et2O); H NMR (500 MHz, CDCl3) δ 0.86 (t, J = 7.0 Hz, 3H), 1.14-1.28 (m, 2H), 1.43-1.50 (m, 29H), 1.93 (q, J = 6.5 Hz, 1H), 2.18 (d, J = 6.5 Hz, 1H) 2.22 (s, 12H), 3.38 (s, 1H), 3.65 (s, 3H), 3.67 (s, 3H), 4.12-4.23 (m, 2H), 6.99 (s, 2H), 7.07 (s, 2H); 13 C NMR (126 MHz, CDCl3) δ 14.09, 14.34, 16.11, 16.16, 22.68, 27.24, 27.96, 29.18, 29.35, 29.51, 29.61, 29.62, 29.65, 29.68, 31.92, 43.56, 47.01, 59.57, 59.58, 60.64, 77.35, 127.41, 128.10, 130.42, 130.47, 137.78, 138.18, 155.81, 156.15, 169.69 (3 Sp3 carbon not located); IR (thin film) 2925vs, 1746s, 1484s, 1221s, 1183vs cm-1; HRMS (ESI-TOF) m/z 608.4683 [(M+H+); calcd. for C39H62NO4 : 608.4679]; [α ]20 +59.0 (c 1.0, EtOAc) on 98 % ee D material (HPLC). € 3.13.4 Asymmetric catalytic multi-component aziridination of aldehyde 77 to synthesize cis-aziridine 37l (Procedure B) 1) 4 Å MS 2) MEDAM NH2 66 (S)-VAPOL (5 mol%) B(OPh)3 (15 mol%) toluene, 80 °C, 0.5 h H O 13 77 (1.05 equiv) –10 ºC 3) EDA (11) (2.0 equiv) –10 ºC, 24 h Ar Ar N 13 CO2Et 37l (2R,3R)-Ethyl-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-pentadecylaziridine-2carboxylate 37l: To a 25 mL flame-dried Schlenk flask equipped with a stir bar and filled with argon was added (S)-VAPOL (14 mg, 0.025 mmol), B(OPh)3 (22 mg, 0.075 mmol) and amine 147 66 (149.7 mg, 0.500 mmol). Under an argon flow through the side arm of the Schlenk flask, dry toluene (1 mL) was added. The flask was sealed by closing the Teflon valve, and then placed in an oil bath (80 ºC) for 0.5 h. The flask was then allowed to cool to room temperature and open to argon through side arm of the Schlenk flask. To the flask containing the catalyst was added the 4Å Molecular Sieves (150 mg, freshly flame-dried). The flask was then allowed to cool to – 10 ºC and a solution of aldehyde 77 (126 mg, 0.525 mmoL, 1.05 equiv) in toluene (1.0 mL) was added to the reaction mixture. The flask containing aldehyde 77 was washed with another 0.5 mL of dry toluene and solution was transferred to the reaction mixture. To the resulting reaction mixture was added ethyl diazoacetate (EDA) 11 (104 µL, 1.0 mmoL, 2.0 equiv). The resulting mixture was stirred for 24 h at –10 ºC. The reaction was dilluted by addition of hexane (6 mL). The reaction mixture was then filtered through a silica gel plug to a 250 mL round bottom flask. The reaction flask was rinsed with EtOAc (20 mL × 3) and the rinse was filtered through the same silica gel plug. The resulting solution was then concentrated in vacuo followed by exposure to high vacuum (0.05 mm Hg) for 1 h to afford the crude aziridine as yellow colored viscous oil. Purification of the crude aziridine by neutral alumina chromatography (20 mm × 150 mm column, 4:2:0.1 hexanes/CH2Cl2/Et2O as eluent, gravity column) afforded pure aziridine 37l as a white solid (mp 41–42 ºC on 96% ee material) in 85% isolated yield (258 mg, 0.425 mmol); cis/trans: not determined. Enamine side products: 1.7% yield of 67l and 1.7% yield of 68l. Imine condensation product: >1% yield of 90. The optical purity of 37l was determined to be 96% ee by HPLC analysis (PIRKLE COVALENT (R, R) WHELK-O1column, 99.5:0.5 hexane/2-propanol at 226nm, flow-rate: 0.7 mL/min): retention times; Rt = 18.26 min (major 148 enantiomer, 37l) and Rt = 33.43 min (minor enantiomer, ent-37l). Aldehyde 77 was reacted according to the general Procedure B described above with (R)-VAPOL as ligand to afford aziridine ent-37l with 96% ee. The chemically pure aziridine 37l (200 mg, 0.33 mmol, 96% ee) was placed in a 10 mL round bottom flask. An air condenser with a nitrogen balloon was attached to the round bottom flask. Hexanes (0.5 mL) was added to the flask and the mixture was brought to boil with a heat gun as the flask was swirled. The flask with the clear solution was cooled to room temperature and then kept at the refrigerator. The aziridine 37l crystallized out. The first crop was collected (160 mg, 0.264 mmol, 80% recovery) and determined to be 98% ee (mp 42–43 ºC) by HPLC (see condition above). 3.13.5 Ring opening of aziridine cis-37a with water Ar Ar triflic acid (5 equiv) N Ph OH CO2Et CH3CN/ H2O (4:1 v/v), 50 ºC, 4 h 37a CO2Et Ph HN 94 Ar OMe Ar Ar (2R, 3S)-Ethyl 2-((bis(4-methoxy-3,5-dimethylphenyl)methyl)amino)-3-hydroxy-3phenylpropanoate 94: To a solution of the aziridine 37a (95 mg, 0.2 mmol, 99% ee) in an acetonitrile / water (0.5 mL, 4:1 v/v) mixture was added trifluoromethanesulfonic acid (88 µL, 1.0 mmol, 5.0 equiv) at room temperature. The flask was then equipped with an air condenser and a nitrogen balloon at the top of the condenser through a rubber septum. The solution was stirred at 50 ºC for 4 h under 149 nitrogen atmosphere. The reaction mixture was cooled to 0 ºC and was added to a saturated aq. Na2CO3 solution. The water layer was extracted with ethyl acetate (4 × 5 mL). The combined organic layer was dried with MgSO4 and concentrated under reduced pressure. The yield of 94 1 was 60% as determined by H NMR with Ph3CH as internal standard. 1 1 Spectral data for 94 (from crude H NMR): H-NMR (300 MHz, CDCl3): δ 1.02 (t, J = 7.1 Hz, 3H), 2.22 (s, 6H), 2.24 (s, 6H), 3.39 (d, J = 6.9 Hz, 1H), 3.68 (s, 3H), 3.69 (s, 3H), 3.97 (q, J = 7.1 Hz, 2H), 4.60 (s, 1H), 4.77 (d, J = 6.9 Hz, 1H), 6.90 (s, 2H), 6.91 (s, 2H), 7.32-7.27 (m, 5H), (OH and NH protons were not located). 2.13.1 Ring opening of aziridine cis-59a with water H N OH triflic acid (10 equiv) CH3CN/ H2O (4:1 v/v), Ph CO2Et 65 ºC, 2 h 59a Ph CO2Et NH2 95 50% yield To a solution of the aziridine 59a (38 mg, 0.2 mmol) in an acetonitrile / water mixture (1.0 mL, 4:1 v/v) was added trifluoromethanesulfonic acid (177 µL, 2.0 mmol, 10.0 equiv) at room temperature. The flask was then equipped with an air condenser and a nitrogen balloon at the top of the condenser through a rubber septum. The solution was stirred at 65 ºC for 2 h under nitrogen atmosphere. The reaction mixture was cooled to room temperature and diluted with 5 mL of water. The water layer was washed with diethyl ether (5mL). To the water layer was added saturated aq. Na2CO3 solution until pH ~ 9. The resulting water layer was extracted with 150 ethyl acetate (4 × 5 mL). The combined organic layer (ethyl acetate extract) was dried with MgSO4. Upon concentration of the organic layer under reduced pressure afforded 95 as white solid with 50% yield of the crude product. The product was dissolved in 2 M HCl in methanol (1 mL) and the resulting mixture was evaporated under reduced pressure. The hyrochloride salt of 29 95 gave [α ]20 +29.3 (c 1.0, H2O) [Lit D reported [α ]20 +32.6 (c 1.0, H2O)]. D 1 Spectral data for 95: H-NMR (300 MHz, CDCl3): δ 1.16 (t, J = 7.1 Hz, 3H), 2.29-2.62 (m, 3H), € € 3.63 (d, J = 4.4 Hz, 1H), 4.13 (q, J = 7.1 Hz, 2H), 4.87 (d, J = 4.8 Hz, 1H), 7.27-7.38 (m, 5H); [α ]20 +15.0 (c 0.5, CHCl3). D 3.13.6 Ring opening of aziridine cis-37a with water € O Ar Ph N (R)-VAPOL-boroxinate catalyst (3 mol%) Ar + OEt N2 11 36a toluene 25 ºC, 24 h Ar Ar Ar OMe N Ph CO2Et ent-37a 1) triflic acid (5 equiv) acetone, 3 h, 60 ºC 2) H2O, 10 h, 60 ºC OH OH Ph CO2Et HN Boc 96 NaHCO3, Boc2O THF, 25 ºC, 12 h Ph CO2Et NH2 ent-95 not isolated (2S, 3S)-Ethyl-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-phenylaziridine-2- 151 carboxylate ent-37a: To a 25 mL flame-dried homemade Schlenk flask equipped with a stir bar and flushed with argon was added (R)-VAPOL (81 mg, 0.15 mmol) and B(OPh)3 (174 mg, 0.60 mmol) and aldimine 36a (1.94 g, 5 mmol). Under an argon flow through the side arm of the Schlenk flask, dry toluene (10 mL) was added through the top of the Teflon valve to dissolve the reagents. The flask was sealed by closing the Teflon valve and then placed in an 80 ºC oil bath for 1 h. The catalyst mixture was then allowed to cool to room temperature and opened to argon through the side arm of the Schlenk flask. To this solution was rapidly added ethyl diazoacetate (EDA) 11 (622 µL, 6.0 mmol) followed by closing the Teflon valve. The resulting mixture was stirred for 1 h at room temperature. Immediately upon addition of ethyl diazoacetate the reaction mixture became an intense yellow, which changed to light yellow towards the completion of the reaction. The reaction was diluted by addition of hexane (30 mL). The reaction mixture was then transferred to a 500 mL round-bottom flask. The reaction flask was rinsed with dichloromethane (30 mL × 2), and the rinse was added to the 500 mL round-bottom flask. The resulting solution was then concentrated in vacuo followed by exposure to high vacuum (0.1 mmHg) for 2 h to afford the crude aziridine as an off-white solid. The crude aziridine was used in the next step without any further purification. (2S, 3R)-Ethyl-2-((tert-butoxycarbonyl)amino)-3-hydroxy-3-phenylpropanoate 96: To a solution of the crude aziridine ent-37a obtained above in acetone (250 mL) was added trifluoromethanesulfonic acid (2.21 mL, 25 mmol, 5.0 equiv) at room temperature. The flask was then equipped with an air condenser and a nitrogen balloon at the top of the condenser through a rubber septum. The solution was stirred at 60 ºC for 3 h under nitrogen atmosphere. The reaction was monitored by TLC. To the solution was then added water (50 mL), and the 152 resulting mixture was stirred at 60 ºC for 10 h. The solution was then cooled to room temperature, and the volume was reduced to half by rotary evaporation. Water (200 mL) was added to the resulting mixture. The mixture was washed with ether (40 mL × 3). To the water layer was added solid sodium bicarbonate until pH ∼ 9. To the resulting mixture was added THF (85 mL) and di-tert -butyl dicarbonate (1.75 g, 8.5 mmol, 1.6 equiv). The mixture was stirred at room temperature for 12 h. The mixture was then extracted with ethyl acetate (100 mL × 4). The combined organic layer was washed with saturated aqueous NaCl solution (40 mL × 2) and dried over anhydrous MgSO4. The ethyl acetate was removed by rotary evaporation. Purification by flash silica gel chromatography (1:2 ether/hexanes as eluent) afforded 96 as colorless oil in 63% isolated yield (975 mg, 3.15 mmol). 1 Spectral data for 96: Rf = 0.49 (2:1 Et2O/hexanes); H-NMR (300 MHz, CDCl3) δ 1.22 (t, J = 7.1 Hz, 3H), 1.32 (br s, 9H), 2.79 (br s, 1H), 4.17 (q, J = 7.3 Hz, 2H), 4.49 (brd, J = 7.1 Hz, 1H), 5.16-5.19 (m, 1H), 5.28 (brs, 1H), 7.25-7.37 (m, 5H); 13 C-NMR (75 MHz, CDCl3) δ 14.05, 28.14, 59.51, 61.67, 74.15, 80.03, 126.06, 128.02, 128.34, 139.80, 170.83 (one sp2 carbon not located); [α ]20 –7.0 (c 1.1, EtOH). D 3.13.7 Enantioselective synthesis of L-threo-sphinganine 74b and D-threo-sphinganine 74c € via route I 3.13.7.1 Synthesis of N-Boc aziridine 100 and ent-100 Ar Ar 1) TfOH (10 equiv) CH3CN, 50 ºC, 12h N 13 CO2Et 37l 2) Boc2O, Na2CO3, MeOH, 2.5 h, rt 153 Ar OMe Boc N 13 CO2Et 100 80% yield (2R,3R)-1-tert-Butyl 2-ethyl 3-pentadecylaziridine-1,2-dicarboxylate 100: To a 50 mL flamedried round bottom flask equipped with a stir bar and an air condenser with a rubber septum and a nitrogen balloon at the top, was added aziridine 37l (304 mg, 0.50 mmol, 98% ee material). Dry acetonitrile (15 mL) was added to dissolve 37l. Thereafter, triflic acid (450 µL, 5 mmol, 10 equiv) was added slowly to the reaction flask. The flask was placed in a oil (50 ºC) bath and the reaction mixture was stirred for 12 h under nitrogen atmosphere. The flask was then allowed to cool to room temperature and the reaction mixture was added to a saturated aq. Na2CO3 (20 mL). The water layer was extracted with ethyl acetate (4 × 15 mL). The combined organic layer was washed with distilled water (2 × 10 mL) followed by brine (2 × 10 mL ). The resulting organic layer was dried with MgSO4 and concentrated under reduced pressure to afford the crude reaction mixture as white solid. To the solution of the crude reaction mixture in methanol (5 mL) solid NaHCO3 (193 mg, 2.3 mmol, 4.6 equiv) and Boc2O (250 mg, 1.14 mmol, 2.3 equiv) was added. The resulting reaction mixture was stirred for 2.5 h at room temperature under nitrogen atmosphere. The reaction mixture was diluted with diethyl ether (20 mL) and filtered through Celite-pad to a 100 mL round bottom flask. The Celite-pad was washed with ether (3 × 15 mL). The resulting solution was concentrated under reduced pressure followed by exposure to high vacuum (0.05 mm Hg) for 1 h to afford the crude N-Boc aziridine 100 as a light yellow liquid. Purification of the crude aziridine 100 by silica gel chromatography (20 mm×300 mm column, 10:1 hexanes/EtOAc as eluent, flash column) afforded pure ester 100 as a colorless liquid in 80 % isolated yield over two steps (170 mg, 0.4 mmol). 154 1 Spectral data for 100 Rf = 0.24 (1:9 EtOAc / hexanes); H-NMR (300 MHz, CDCl3): δ 0.87 (t, J = 6.7 Hz, 3H), 1.34-1.26 (m, 29H), 1.44 (s, 9H), 1.63-1.56 (m, 2H), 2.64-2.57 (m, 1H), 3.09 (d, J = 6.7 Hz, 1H), 4.28-4.17 (m, 2H). 13 C-NMR (151 MHz, CDCl3): δ 14.07, 14.21, 22.65, 26.94, 27.37, 27.81, 29.04, 29.32, 29.50, 29.51, 29.59, 29.62, 29.64, 29.65, 31.89, 39.83, 43.59, 61.34, 81.84 (2 sp3 carbon not located), 160.77, 167.63; IR (thin film) 2926vs, 2855vs, 1755s, 1738s, -1 + 1298s, 1159vs cm ; HRMS (ESI-TOF) m/z 426.3604 [(M+H ); calcd. for C25H48NO4: 426.3583]; [α ]20 +43.0 (c 1.0, CH2Cl2) on 98 % ee material. D € Ar Ar 1) TfOH (10 equiv) CH3CN, 50 ºC, 12h N 13 CO2Et ent-37l 2) Boc2O, Na2CO3, MeOH, 2.5 h, rt Ar OMe Boc N 13 CO2Et ent-100 82% yield (2S, 3S)-1-tert-Butyl 2-ethyl 3-pentadecylaziridine-1,2-dicarboxylate ent-100: The N-Boc aziridine ent-100 was synthesized from aziridine ent-37l (608 mg, 1.0 mmol, 96% ee material) following the procedure described above for the synthesis of N-Boc aziridine 100. Purification of the crude aziridine ent-100 by silica gel chromatography (30 mm×300 mm column, 10:1 hexanes/EtOAc as eluent, flash column) afforded pure ent-100 as a colorless liquid in 82 % isolated yield (349 mg, 0.82 mmol). 1 The H NMR data matched that for 100 given above. [α ]20 –39.0 (c 1.0, CH2Cl2) on 96 % ee D material. € 155 3.13.7.2 Ring opening of N-Boc aziridine 100 and ent-100 Boc 13 OH O HCOOH (88%) N CO2Et 3 h, 25 ºC 13 100 OEt NHCHO 101 (2R,3S)-ethyl 2-formamido-3-hydroxyoctadecanoate 101: To a 10 mL oven-dried round bottom flask equipped with a stir bar was added N-Boc aziridine 100 (85 mg, 0.2 mmol, 98% ee material) and formic acid (2 mL, 88% by volume). The flask was fitted with a rubber septum and a nitrogen balloon. The resulting solution was stirred at room temperature for 3 h under nitrogen atmosphere. Thereafter, the reaction mixture was concentrated under reduced pressure to afford crude 101 as white solid. Purification of the crude 101 by silica gel chromatography (20 mm×150 mm column, 3:1 hexanes/EtOAc as eluent, flash column) afforded pure 101 as a colorless solid (mp 81-82 ºC) in 98 % isolated yield (73 mg, 0.196 mmol). 1 Spectral data for 101: Rf = 0.05 (1:2 EtOAc / hexanes); H-NMR (600 MHz, CDCl3): δ 0.87 (t, J = 7.0 Hz, 3H), 1.24-1.30 (m, 29H), 1.44-1.49 (m, 2H), 2.81 (brs, 1H), 4.13 (td, J = 6.7, 2.0 Hz, 1H), 4.18-4.26 (m, 2H), 4.70 (dd, J = 9.2, 1.9 Hz, 1H), 6.67 (d, J = 9.1 Hz, 1H), 8.29 (s, 1H). 13 C-NMR (126 MHz, CDCl3): δ 14.10, 14.12, 22.67, 25.56, 29.34, 29.40, 29.49, 29.55, 29.62, 29.64, 29.66, 31.91, 33.80, 54.53, 61.89, 71.88 (3 sp3 carbon not located), 161.25, 170.81; IR (thin film) 3269 br, 2918vs, 2851vs, 1730s, 1705s, 1541s, 1286s cm-1; HRMS (ESI-TOF) m/z + 372.3131 [(M+H ); calcd. for C21H42NO4: 372.3114]; [α ]20 –10.7 (c 1.0, CH2Cl2) on 98 % ee D material. € 156 Boc 13 OH O HCOOH (88%) N CO2Et 3 h, 25 ºC OEt NHCHO 13 ent-100 ent-101 (2S,3R)-Ethyl 2-formamido-3-hydroxyoctadecanoate ent-101: The formamidohydroxy ester ent-101 was synthesized from N-Boc aziridine ent-100 (85 mg, 0.2 mmol, 96% ee material) following the procedure described above for the synthesis of 101. The crude ent-101 (mp 81-82 ºC) was used in the next reaction without further purification. 1 The H NMR data matched that for 101 given above. [α ]20 +9.2 (c 1.0, CH2Cl2) on 96 % ee D material. € 3.13.7.3 Synthesis of L-threo-sphinganine 74b and D-thero-sphinganine 74c via reduction of ester OH O 13 OH O 1M HCl in MeOH OEt NHCHO 13 16h, rt OEt NH2•HCl 13 rt, 16 h 102 101 OH LiAlH4, THF OH NH2 74b, L-threo -sphinganine (safingol) (2R,3S)-ethyl 2-amino-3-hydroxyoctadecanoate hydrochloride 102: To a oven dried 10 mL round bottom flask equipped with a stir bar was added ethyl 2-formamido-3- hydroxyoctadecanoate 101 (63 mg, 0.17 mmol). Methanol (1.0 mL) and HCl methanol mixture (0.6 mL, 1 M solution in methanol) was added to the flask. The flask was fitted with a rubber septum and a nitrogen balloon. The resulting turbid reaction mixture was stirred vigorously under room temperature for 16 h (monitored by TLC) under nitrogen atmosphere. A clear 157 solution of the reaction mixture was observed after 1 h of stirring at room temperature. Upon completion, the reaction mixture was concentrated under reduced pressure to afford crude ethyl 2-amino-3-hydroxyoctadecanoate hydrochloride 102 as white solid. The crude 102 was used in the next reaction without further purification. 1 Spectral data for 102: H-NMR (300MHz, DMSO-d6): δ 0.85 (t, J = 6.6 Hz, 3H), 1.17-1.30 (m, 29H), 1.37-1.48 (m, 2H), 3.89-3.92 (m, 2H), 4.20 (q, J = 7.1 Hz, 2H), 5.63 (d, J = 5.7 Hz, 1H), 8.36 (s, 3H); 13 C-NMR (75 MHz, CDCl3): δ 13.98, 14.11, 22.68, 29.37, 29.67, 29.70, 29.73, 29.76, 31.92, 58.33, 62.95, 69.90, (7 Sp3 carbon not located), 168.35. L-threo-sphinganine 74b: To an ice-cooled suspension of LiAlH4 (18 mg, 0.48 mmol) in freshly distilled THF (2 mL) under nitrogen was injected a solution of crude ester 102 in THF (1 mL). The reaction mixture was stirred at room temperature for 16 h. After being diluted with 10 mL of dry THF and chilled in an ice-water bath, the reaction mixture was filtered through a pad of silica gel (~ 8 g) slurry in hexane in a sintered glass funnel (2 cm × 6 cm) to remove the salt and the excess LiAlH4 by gentle suction. It was found that this workup procedure was very efficient for small-scale reactions. The pad was washed with CHCl3/MeOH/concentrated NH4OH 130:25:4 to collect the product. The resulting solution was concentrated under reduced pressure to afford crude L-threo-sphinganine 74b as white solid. Purification of the crude 74b by silica gel chromatography (20 mm×120 mm column, 130:25:4 CHCl3/MeOH/concentrated NH4OH as eluent, flash column) afforded pure 74b as a white solid. The product was dissolved in CHCl3 and passed through a Cameo filter to remove the dissolved silica gel. 158 Upon concentration of the resulting solution afforded 74b in 70% isolated yield (36.2 mg, 0.12 mmol) from 101. (mp 98-101 ºC) 1 Spectral data for 74b Rf = 0.27 (130:25:4 CHCl3/MeOH/concentrated NH4OH); H-NMR (500 MHz, CD3OD): δ 0.90 (t, J = 6.9 Hz, 4H), 1.23-1.40 (m, 26H), 1.43-1.53 (m, 3H), 2.69 (brs, 1H), 3.49 (dd, J = 10.8, 6.7 Hz, 1H), 3.53-3.56 (m, 1H), 3.62 (dd, J = 10.7, 4.6 Hz, 1H). 13 C- NMR (126 MHz, CD3OD): δ 14.40, 23.70, 26.92, 30.44, 30.53, 30.75, 33.04, 34.90, 57.95, 64.55, 72.26 (7 sp3 carbon not located); [α ]20 –12.3 (c 0.3, 1:10 MeOH/ CHCl3) D € OH O 13 OH O 1M HCl in MeOH OEt NHCHO 16h, rt 13 OEt NH2•HCl 13 rt, 16 h ent-102 ent-101 OH LiAlH4, THF OH NH2 74c, D-threo -sphinganine (2S,3R)-Ethyl 2-amino-3-hydroxyoctadecanoate hydrochloride ent-102: The ester ent-102 was synthesized from crude ent-101 following the procedure described above for the synthesis of 102. The crude ent-102 was used in the next reaction without further purification. 1 The H NMR data matched that for 102 given above. D-threo-sphinganine 74c: The ester D-threo-sphinganine 74c was synthesized from crude ent102 following the procedure described above for the synthesis of 74b. Purification of the crude 74c by silica gel chromatography (20 mm×120 mm column, 130:25:4 CHCl3/MeOH/concentrated NH4OH as eluent, flash column) afforded pure 74c as a white solid (99-101 ºC) in 75% isolated yield (45 mg, 0.15 mmol) in three steps starting from ent-100. 159 1 Spectral data for 74c Rf = 0.27 (130:25:4 CHCl3/MeOH/concentrated NH4OH); H-NMR (500 MHz, CD3OD): δ 0.90 (t, J = 6.9 Hz, 4H), 1.24-1.42 (m, 26H), 1.43-1.53 (m, 3H), 2.67 (brs, 1H), 3.44-3.49 (m, 1H), 3.51-3.56 (m, 1H), 3.61 (dd, J = 10.7, 4.9 Hz, 1H). 13 C-NMR (126 MHz, CD3OD): δ 14.40, 23.70, 26.92, 30.44, 30.53, 30.75, 33.04, 34.90, 57.95, 64.55, 72.26 (7 sp3 carbon not located); [α ]20 +12.1 (c 0.3, 1:10 MeOH/ CHCl3) D 3.13.8 Enantioselective synthesis of L-threo-sphinganine 74b and D-threo-sphinganine 74c € via route II 3.13.8.1 Ring opening of N-MEDAM aziridine 37l and ent-37l MEDAM N 13 CO2Et 1) TFA, DCM 25 ºC 48h 2) NaOH 37l OH 13 CO2Et NH MEDAM 103 83 % yield (2R, 3S)-Ethyl 2-((bis(4-methoxy-3,5-dimethylphenyl)methyl)amino)-3hydroxyoctadecanoate 103: To a 10 mL flame-dried round bottom flask equipped with a stir bar and a rubber septum with a nitrogen balloon at the top, was added aziridine 37l (304 mg, 0.50 mmol, 96% ee material). Dry CH2Cl2 (1.0 mL) was added to dissolve 37l. Thereafter, trifluoroacetic acid (38.2 µL, 0.5 mmol, 1.0 equiv) was added to the reaction flask. The resulting reaction mixture was stirred at room temperature for 48 h (monitored by TLC). The reaction mixture was concentrated under reduced pressure to afford colorless viscous oil. The crude product was dissolved in ethanol (2 mL). To 160 the solution was added a sodium hydroxide (20 mg, 0.5 mmol, 1 equiv) solution in ethanol water mixtre (1.25 mL, 2:1 EtOH/H2O). The resulting mixture was stirred for 20 min (monitored by TLC) at room temperature until the compound with Rf = 0.67 (2:1 hexnanes/Et2O) disappeared. Upon completion, 15 mL water was added to the reaction flask and the water layer was extracted with ether (4 × 20 mL). The combined organic layer was dried with MgSO4 and concentrated under reduced pressure to afford the crude reaction mixture as colorless oil. Purification of the crude 103 by silica gel chromatography (20 mm×150 mm column, 3:1 hexanes/Et2O as eluent, flash column) afforded pure ester 103 as a colorless viscous liquid in 83% isolated yield over two steps (260 mg, 0.415 mmol). The optical purity of 103 was determined to be 96% ee by HPLC analysis (CHIRALCEL OD-H column, 94:6 hexane/2-propanol at 222nm, flow-rate: 0.5 mL/min): retention times; Rt = 4.92 min (major enantiomer, 103) and Rt = 5.89 min (minor enantiomer, ent-103). 1 Spectral data for 103 Rf = 0.35 (1:1 Et2O / hexanes) H-NMR (300 MHz, CDCl3): δ 0.88 (t, J = 6.7 Hz, 3H), 1.25-1.30 (m, 29H), 1.43-1.48 (m, 2H), 2.24 (s, 6H), 2.25 (s, 6H), 3.06 (d, J = 5.7 Hz, 1H), 3.64-3.60 (m, 1H), 3.67 (s, 3H), 3.69 (s, 3H), 4.19 (q, J = 7.1 Hz, 2H), 4.57 (s, 1H), 6.96 (s, 2H), 6.99 (s, 2H) (NH and OH proton not located). 13 C-NMR (126 MHz, CDCl3): δ 14.10, 14.32, 16.19, 16.26, 22.68, 25.62, 29.35, 29.58, 29.62, 29.64, 29.65, 29.67, 29.67, 29.69, 31.92, 33.79 (2 sp3 carbon not located), 59.57, 59.58, 60.90, 63.71, 64.80, 72.44, 127.43, 127.85, 130.70, 130.79, 137.34, 139.22, 156.04, 156.07, 174.08. IR (thin film) 3466br, 2926vs, 2855s 1734s, 1484s, 1221s, 1142s cm-1; HRMS (ESI-TOF) m/z 626.4800 [(M+H+); calcd. for 161 C39H64NO5: 626.4784]; [α ]20 +19.5 (c 1.0, CH2Cl2) on 96% ee material. D MEDAM € N CO2Et 1) TFA, DCM reflux 12h 2) NaOH 13 ent-37l OH 13 CO2Et NH MEDAM ent-103 75 % yield (2S, 3R)-Ethyl 2-((bis(4-methoxy-3,5-dimethylphenyl)methyl)amino)-3- hydroxyoctadecanoate ent-103: The ent-103 was synthesized from aziridine ent-37l (304 mg, 0.50 mmol, 96% ee material) following the procedure described above for the synthesis of 103 except the reaction mixture was refluxed for 32 h in CH2Cl2. Purification of the crude ent-103 by silica gel chromatography (20 mm×150 mm column, 3:1 hexanes/Et2O as eluent, flash column) afforded pure ester ent-103 as a colorless viscous liquid in 75% isolated yield over two steps (235 mg, 0.375 mmol). 1 The H NMR data matched that for 103 given above. [α ]20 –20.2 (c 1.0, CH2Cl2) on 96% ee D material. € 3.13.8.2 Reduction of terminal ester in 104 and ent-104 OH CO2Et 13 NH MEDAM OH LiAlH4 THF rt, 16 h 13 OH HN MEDAM 104 96% yield 103 (2S, 3S)-2-((bis(4-methoxy-3,5-dimethylphenyl)methyl)amino)octadecane-1,3-diol 104: To a 162 10 mL flame-dried round bottom flask equipped with a stir bar and a rubber septum with a nitrogen balloon at the top, was added LiAlH4 (11.4 mg, 0.3 mmol, 1.5 equiv) and dry THF (0.5 mL). the suspension was cooled to 0 ºC in ice water bath. To the LAH suspension was added a solution of 103 (125 mg, 0.2 mmol, 96% ee material) in dry THF (1 mL). The resulting reaction mixture was stirred at room temperature for 16 h (monitored by TLC). Upon completion, the reaction mixture was cooled to 0 ºC. To the reaction mixture was added 0.3 mL water. The reaction mixture was filtered through Celite-pad to a 250 mL round bottom flask. The Celite-pad was washed with ethyl acetate (5 × 15 mL). The resulting solution was concentrated under reduced pressure followed by exposure to high vacuum (0.05 mm Hg) for 1 h to afford the crude 104 as a light yellow liquid. Purification of the crude 104 by silica gel chromatography (20 mm×150 mm column, 3:1 hexanes/EtOAc as eluent, flash column) afforded pure ester 104 as a colorless liquid in 96 % isolated yield (111 mg, 0.19 mmol). 1 Spectral data for 104 Rf = 0.06 (1:1 Et2O / hexanes) H-NMR (500 MHz, CDCl3): δ 0.88 (t, J = 7.0 Hz, 4H), 1.26 (s, 26H), 1.56-1.44 (m, 2H), 2.25 (s, 12H), 2.47 (td, J = 4.2, 3.0 Hz, 1H), 3.58 (dd, J = 11.2, 2.8 Hz, 1H), 3.66-3.67 (m, 1H), 3.68 (m, 6H), 3.77 (dd, J = 11.2, 4.0 Hz, 1H), 4.76 (s, 1H), 7.01 (s, 2H), 7.02 (s, 2H) (NH and OH proton not located). 13 C-NMR (126 MHz, CDCl3): δ 14.10, 16.23, 16.26, 22.68, 25.88, 29.35, 29.64, 29.65, 29.68, 29.69, 29.73, 31.92, 34.44 (4 sp3 carbon not located), 58.75, 59.59, 59.61, 62.35, 63.99, 73.59, 127.42, 127.68, 130.72, 130.79, 138.51, 139.53, 155.97 (one sp2 carbon not located). IR (thin film) 3395br, + 2924vs, 2855s, 1483s, 1221s, 1142s cm-1; HRMS (ESI-TOF) m/z 584.4685 [(M+H ); calcd. for C37H62NO4: 584.4679]; [α ]20 +12.5 (c 1.0, CH2Cl2) on 96% ee material. D € 163 OH CO2Et 13 NH MEDAM ent-103 OH LiAlH4 THF rt, 16 h 13 OH HN MEDAM ent-104 94% yield (2S, 3S)-2-((bis(4-methoxy-3,5-dimethylphenyl)methyl)amino)octadecane-1,3-diol ent-104: The 2-amino-1,3-diol ent-104 was synthesized from ester ent-103 (125 mg, 0.2 mmol, 96% ee material) following the procedure described above for the synthesis of 103. Purification of the crude ent-104 by silica gel chromatography (20 mm×150 mm column, 3:1 hexanes/EtOAc as eluent, flash column) afforded pure ester ent-104 as a colorless liquid in 94 % isolated yield (109 mg, 0.188 mmol). 1 The H NMR data matched that for 104 given above. [α ]20 –12.0 (c 1.0, CH2Cl2) on 96% ee D material. € 3.13.8.3 Reductive deprotection of N-MEDAM group OH 13 OH H2, Pd(OH)2 on C OH 13 HN MEDAM MeOH, Boc2O, rt, 24h 104 OH HN Boc 105 83% yield tert-Butyl ((2S, 3S)-1,3-dihydroxyoctadecan-2-yl)carbamate 105: To a flame dried 25 mL round bottom flask filled with N2 was added the aziridine (90 mg, 0.15 mmol), MeOH (1.5 mL), Pearlman’s catalyst (20% Pd(OH)2 on carbon, moisture ca 60%, 27 mg, 0.016 mmol, 0.10 equiv) and (Boc)2O (66 mg, 0.3 mmol, 2.00 equiv). The flask was equipped with a vacuum transfer 164 adapter connected with vacuum and a H2 balloon. The valve to vacuum was opened for a few seconds and then switched to the H2 balloon. This process was repeated 3 additional times. The suspension was stirred at room temperature under a H2 ballon for 24 hours. Then the mixture was filtered through a Celite pad on a sintered glass funnel and the Celite pad was washed with ethyl acetate (3 × 15 mL). The filtrate was concentrated by rotary evaporation. Purification of the crude 105 by silica gel chromatography (20 mm×150 mm column, 1:1 hexanes/EtOAc as eluent, flash column) afforded pure N-Boc L-threo-sphinganine 105 as a white solid (mp 80-81 ºC) in 83% isolated yield (50 mg, 0.12 mmol). 1 Spectral data for 105 Rf = 0.12 (1:2 EtOAc / hexanes) H-NMR (600 MHz, CDCl3): δ 0.85 (t, J = 7.0 Hz, 3H), 1.28-1.22 (m, 26H), 1.42 (s, 9H), 1.48-1.45 (m, 2H), 2.75 (brs, 2H), 3.55 (brs, 1H), 3.76 (d, J = 4.2 Hz, 2H), 3.87-3.83 (m, 1H), 5.23 (d, J = 6.6 Hz, 1H); 13 C-NMR (151 MHz, CDCl3): δ 14.07, 22.65, 25.55, 28.33, 29.32, 29.53, 29.58, 29.62, 29.65, 29.66, 31.88, 34.16, 30 54.29, 65.22, 72.86, 79.59, 156.50. (4 sp3 carbon not located); [α ]20 +20.0 (c 1.0, CHCl3), Lit D [α ]21 +19.8 (c 1.0, CHCl3). D € OH € . 13 OH H2, Pd(OH)2 on C OH HN MEDAM MeOH, Boc2O, rt, 24h ent-104 165 13 OH HN Boc ent-105 87% yield tert-Butyl ((2R, 3R)-1,3-dihydroxyoctadecan-2-yl)carbamate ent-105: The N-Boc D-threosphinganine ent-105 was synthesized from ent-104 following the procedure described above for the synthesis of 105. Purification of the crude ent-105 by silica gel chromatography (20 mm × 150 mm column, 1:1 hexanes/EtOAc as eluent, flash column) afforded pure ester ent-105 as a white solid (mp 81 ºC) in 87% isolated yield (52 mg, 0.13 mmol). 1 Spectral data for ent-105: H-NMR (600 MHz, CDCl3): δ 0.85 (t, J = 7.0 Hz, 3H), 1.28-1.22 (m, 26H), 1.42 (s, 9H), 1.49-1.46 (m, 2H), 2.75 (brs, 2H), 3.56 (brs, 1H), 3.76 (d, J = 4.2 Hz, 2H), 3.88-3.84 (m, 1H), 5.23 (d, J = 6.6 Hz, 1H); 13 C-NMR (126 MHz, CDCl3): δ 14.10, 22.68, 25.61, 28.36, 29.35, 29.59, 29.63, 29.67, 29.70, 31.92, 34.18, 54.39, 65.04, 72.66, 79.64, 156.58, (5 sp3 carbon not located); [α ]20 –20.6 (c 1.0, CHCl3). D 3.13.9 Enantioselective synthesis of D-erythro-sphinganine 74a and L-erythro-sphinganine € 74d 3.13.9.1 Lewis acid catalyzed ring expansion of N-Boc aziridine 100 and ent-100 Sc(OTf)3 (10 mol % ) Boc N 14 COOEt CH2Cl2, rt, 20 h 100 O O NH 14 COOEt 89 90% yield (4R, 5R)-Ethyl 2-oxo-5-pentadecyloxazolidine-4-carboxylate 89: To a 10 mL flame-dried round bottom flask equipped with a stir bar and a rubber septum with a nitrogen balloon at the top, was added N-Boc aziridine 100 (85 mg, 0.2 mmol, 98% ee material) and dry CH2Cl2 (2 166 mL). To the resulting solution was added Sc(OTf)3(10 mg, 0.02 mmol, 0.1 equiv). The reaction mixture was stirred at room temperature for 20 h (monitored by TLC) under nitrogen atmosphere. Thereafter, the reaction mixture was filtered through a silica gel plug on a sintered glass funnel. The silica plug was washed with ethyl acetate (3 × 10 mL). The filtrate was concentrated under reduced pressure to afford crude oxazolidinone 89 as white solid. Purification of the crude 89 by silica gel chromatography (20 mm × 150 mm column, 3:1 hexanes/EtOAc as eluent, flash column) afforded pure oxazolidinone 89 as a white solid in 90% isolated yield (66 mg, 0.18 mmol). 1 Spectral data for 89 Rf = 0.22 (1:2 EtOAc / hexanes). H-NMR (600 MHz, CDCl3): δ 0.87 (t, J = 7.0 Hz, 3H), 1.25-1.32 (m, 29H), 1.51-1.64 (m, 2H), 4.28-4.23 (m, 2H), 4.37 (d, J = 8.4 Hz, 1H), 4.74 (td, J = 8.9, 3.9 Hz, 1H), 5.85 (s, 1H). 13 C-NMR (151 MHz, CDCl3): δ 14.07, 14.08, 14.09, 14.15, 22.67, 25.56, 25.57, 29.16, 29.33, 29.46, 29.57, 29.62, 29.63, 29.65, 30.62, 31.90, 58.10, 61.97, 78.33, 158.91, 169.18. IR (thin film) 2928vs, 2855vs, 1759s, 1737s, 1299s, -1 + 1159vs cm ; HRMS (ESI-TOF) m/z 370.2953 [(M+H ); calcd. for C21H40NO4: 370.2949]; [α ]20 +16.2 (c 1.0, EtOAc) on 98% ee material D € Sc(OTf)3 (10 mol % ) Boc N 14 COOEt CH2Cl2, rt, 20 h ent-100 167 O O NH 14 COOEt ent-89 93% yield (4S, 5S)-Ethyl 2-oxo-5-pentadecyloxazolidine-4-carboxylate ent-89: The oxazolidinone ent-89 was synthesized from ent-100 (85 mg, 0.2 mmol, 96% ee material) following the procedure described above for the synthesis of 89. Purification of the crude 89 by silica gel chromatography (20 mm × 150 mm column, 3:1 hexanes/EtOAc as eluent, flash column) afforded pure oxazolidinone ent-89 as a white solid in 93% isolated yield (69 mg, 0.186 mmol). 1 The H NMR data matched that for 89 given above. [α ]20 –15.7 (c 1.0, EtOAc). D 3.13.9.2 Synthesis of D- and L-erythro-sphinganines € O O NH 14 COOEt 89 OH 1) LiOH 2) LiAlH4, THF rt 13 OH NH2 74a, D-erythro -sphinganine 70 % from 89 (two steps) D-erythro-sphinganine 74a: To a 10 mL oven-dried round bottom flask equipped with a stir bar and a rubber septum with a nitrogen balloon at the top was added oxazolidinone 89 (72 mg, 0.2 mmol) and ethanol (2.5 mL). To the resulting solution was added lithium hydroxide (39 mg, 1.6 mmol, 8 equiv). The resulting suspension was stirred for 3 h (monitored by TLC) at room temperature under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure. The resulting crude white solid was transferred to a 10 mL flame dried round bottom flask and dry THF (3.0 mL) was added to it. The reaction flask was cooled to 0 ºC and LiAlH4 (23 mg, 0.6 mmol, 3.0 equiv) was added to the reaction flask. The reaction mixture was stirred at room temperature for 24 h (monitored by TLC) under nitrogen atmosphere. Upon completion, the reaction mixture was cooled to 0 ºC. To the reaction mixture was added 0.4 mL 168 water. The reaction mixture was filtered through Celite-pad to a 250 mL round bottom flask. The Celite-pad was washed with 130:25:4 CHCl3/MeOH/concentrated NH4OH mixture (5 × 15 mL). The resulting solution was concentrated under reduced pressure followed by exposure to high vacuum (0.05 mm Hg) for 1 h to afford the crude 74a as white solid. Purification of the crude 74a by silica gel chromatography (20 mm×120 mm column, 130:25:4 CHCl3/MeOH/concentrated NH4OH as eluent, flash column) afforded pure 74a as a white solid. The product was dissolved in CHCl3 and passed through a Cameo filter to remove the dissolved silica gel. Upon concentration of the resulting solution afforded D-erythro-sphinganine 74a in 70% isolated yield over two steps from 89 (42 mg, 0.14 mmol). 1 Spectral data for 74a: Rf = 0.25 (130:25:4 CHCl3/MeOH/concentrated NH4OH); H-NMR (500 MHz, CD3OD): δ 0.89 (t, J = 7.0 Hz, 3H), 1.24-1.42 (m, 26H), 1.43-1.53 (m, 3H), 2.69 (brs, 1H), 3.45-3.49 (m, 1H), 3.50-3.55 (m, 1H), 3.59-3.63 (m, 1H); 13 C-NMR (126 MHz, CD3OD): δ 15.44, 24.73, 27.96, 31.47, 31.56, 31.78, 34.07, 35.93, 58.98, 65.59, 73.29 (7 Sp3 C not located); [α ]20 –1.9 (c 1.0, pyridine) D O € O NH 14 COOEt ent-89 OH 1) LiOH 13 2) LiAlH4, THF reflux OH NH2 74d, L-erythro -sphinganine 75 % over two steps 169 L-erythro-sphinganine 74d: The L-erythro-sphinganine 74d was synthesized from ent-89 (72 mg, 0.2 mmol) following the procedure described above for the synthesis of 74a. Purification of the crude 74d by silica gel chromatography (20 mm × 150 mm column, 130:25:4 CHCl3/MeOH/concentrated NH4OH as eluent, flash column) afforded pure L-erythrosphinganine 74d as a white solid in 75% isolated yield (45 mg, 0.15 mmol) over two steps from oxazolidinone ent-89. Spectral data for 74d: 1 H-NMR (500 MHz, CD3OD): δ 0.89 (t, J = 7.0 Hz, 3H), 1.23-1.41 (m, 26H), 1.43-1.54 (m, 3H), 2.80 (brs, 1H), 3.45-3.49 (m, 1H), 3.50-3.56 (m, 1H), 3.59-3.63 (m, 1H); 13 C-NMR (126 MHz, CD3OD): δ 16.44, 25.73, 28.96, 32.47, 32.56, 32.78, 35.07, 36.93, 59.98, 66.59, 74.29 (7 Sp3 C not located); [α ]20 +2.1 (c 1.0, pyridine) D 3.13.10Asymmetric catalytic multi-component trans-aziridination of aldehyde 77 to synthesize trans-aziridine 88 (Procedure B) € 3.13.10.1 Asymmetric catalytic multi-component trans-aziridination of aldehyde 77 with diazoacetamide 106a 1) 4 Å MS 2) (S)-VANOL (10 mol%) O 13 77 (1.05 equiv) –20 ºC MEDAM NH2 66 B(OPh)3 (30 mol%) toluene, 80 °C, 0.5 h H 3) MEDAM N O NHPh N2 106a (1.20equiv) –20 ºC, 24 h 170 13 CONHPh 88a (2R,3S)-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-pentadecyl-N-phenylaziridine-2carboxamide 88a: Aldehyde 77 was reacted with 2-diazo-N-phenylacetamide 106a (97 mg, 0.6 mmol, 1.2 equiv) according to the general aziridination Procedure B described above with (S)VANOL (22 mg, 0.05 mmol, 10 mol%) as ligand at –20 ºC, to afford trans- aziridines 88a. Purification of the crude aziridine by silica gel chromatography (30 mm × 300 mm column, 3:1 hexanes/Et2O as eluent, gravity column) afforded trans- aziridines 88a as colorless viscous liquid in 35% isolated yield (114 mg, 0.175 mmol). The optical purity of 88a was determined to be 57% ee by HPLC analysis (PIRKLE COVALENT (R, R) WHELK-O1column, 90:10 hexane/2-propanol at 226nm, flow-rate: 0.7 mL/min): retention times; Rt = 5.20 min (major enantiomer, 88a) and Rt = 16.03 min (minor enantiomer, ent-88a). 1 Spectral data for 88a: Rf = 0.37 (1:1 Et2O / hexanes). H-NMR (500 MHz, CDCl3): δ 0.89 (t, J = 7.0 Hz, 3H), 1.19-1.32 (m, 26H), 1.53-1.63 (m, 2H), 2.17 (d, J = 2.9 Hz, 1H), 2.22 (s, 6H), 2.29 (s, 6H), 2.45 (ddd, J = 7.7, 5.1, 2.8 Hz, 1H), 3.65 (s, 3H), 3.71 (s, 3H), 4.19 (s, 1H), 7.01 (s, 2H), 7.12 (s, 2H), 7.31 (t, J = 7.9 Hz, 3H), 7.47-7.49 (m, 2H), 8.53 (s, 1H); 13 C-NMR (126 MHz, CDCl3): δ 14.10, 16.28, 16.32, 22.67, 26.13, 28.06, 29.27, 29.34, 29.46, 29.49, 29.64, 29.68, 31.91, 45.24, 47.52, 59.53, 59.62, 67.59, (4 sp3 carbon not located), 119.43, 123.99, 126.86, 127.62, 128.95, 130.67, 130.99, 137.56, 138.28, 138.37, 155.92, 156.23, 168.55. IR (thin -1 film) 3317br, 2926vs, 2855vs, 1684s, 1444s, 1223s cm ; HRMS (ESI-TOF) m/z 655.4865 + [(M+H ); calcd. for C43H63N2O3: 655.4839]; [α ]20 +13.0 (c 1.0, CH2Cl2) on 57% ee material. D € 171 3.13.10.2 Asymmetric catalytic multi-component trans-aziridination of aldehyde 77 with diazoacetamide 106b 1) 4 Å MS 2) (S)-VANOL (10 mol%) O 13 77 (1.05 equiv) 0 ºC MEDAM NH2 66 B(OPh)3 (30 mol%) toluene, 80 °C, 0.5 h H 3) MEDAM N O NH N H Ph N2 106b (1.20equiv) 13 O 88b Ph (2R,3S)-N-benzyl-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-pentadecylaziridine-2carboxamide 88b: Aldehyde 77 was reacted with N-benzyl-2-diazoacetamide 106b (105 mg, 0.6 mmol, 1.2 equiv) according to the general aziridination Procedure B described above with (S)-VANOL (22 mg, 0.05 mmol, 10 mol%) as ligand at 0 ºC, to afford trans- aziridines 88b. Purification of the crude aziridine by silica gel chromatography (30 mm × 300 mm column, 5:1 hexanes/Et2O as eluent, gravity column) afforded trans- aziridines 88b as colorless viscous liquid in 55% isolated yield (184 mg, 0.275 mmol). The optical purity of 88b was determined to be 88% ee by HPLC analysis (PIRKLE COVALENT (R, R) WHELK-O1column, 90:10 hexane/2-propanol at 226nm, flow-rate: 0.7 mL/min): retention times; Rt = 6.01 min (major enantiomer, 88b) and Rt = 10.14 min (minor enantiomer, ent-88b). 172 Aldehyde 77 was reacted with 106b according to the general Procedure B described above in presence of (S)-VANOL as ligand at different temperature in toluene. The results are represented in Table 3.7 (Chapter 3). 1 Spectral data for 88b: Rf = 0.28 (1:1 Et2O / hexanes). H-NMR (500 MHz, CDCl3): δ 0.89 (t, J = 7.0 Hz, 3H), 1.19-1.33 (m, 26H), 1.52-1.57 (m, 2H), 2.15 (d, J = 2.8 Hz, 1H), 2.18 (s, 6H), 2.22-2.26 (m, 7H), 3.68 (s, 3H), 3.69 (s, 3H), 4.13 (s, 1H), 4.20 (dd, J = 15.2, 4.9 Hz, 1H), 4.59 (dd, J = 15.2, 7.3 Hz, 1H), 6.93-6.97 (m, 3H), 7.06 (s, 2H), 7.13-7.12 (m, 2H), 7.28-7.33 (m, 3H); 13 C-NMR (126 MHz, CDCl3): δ 14.06, 16.17, 16.21, 22.64, 26.02, 28.09, 29.27, 29.31, 29.43, 29.47, 29.61, 29.65, 31.88, 42.50, 44.76, 47.39, 59.50, 59.54, 67.66, (4 sp3 carbon not located), 126.89, 127.06, 127.18, 127.66, 128.59, 130.48, 130.75, 138.33, 138.39, 138.45, 155.77, 156.10, 170.62; IR (thin film) 3306br, 2926vs, 2855vs, 1649s, 1483s, 1221s, 1136s cm1; HRMS (ESI-TOF) m/z 669.5004 [(M+H+); calcd. for C44H65N2O3: 669.4995]; [α ]20 –15.5 D (c 1.0, CH2Cl2) on 83% ee material. € 3.13.10.3 Asymmetric catalytic multi-component trans-aziridination of aldehyde 77 with diazoacetamide 106c 1) 4 Å MS 2) (S)-VANOL (10 mol%) O MEDAM NH2 66 B(OPh)3 (30 mol%) toluene, 80 °C, 0.5 h H 13 77 (1.05 equiv) –10 ºC 3) MEDAM N O N2 N H n-Bu 106c (1.20equiv) –10 ºC, 24 h 173 13 O 88c NH n-Bu (2R,3S)-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-N-butyl-3-pentadecylaziridine-2carboxamide 88c: Aldehyde 77 was reacted with N-butyl-2-diazoacetamide 106c (85 mg, 0.6 mmol, 1.2 equiv) according to the general aziridination Procedure B described above with (S)VANOL (22 mg, 0.05 mmol, 10 mol%) as ligand at –10 ºC, to afford trans- aziridines 88c. Purification of the crude aziridine by silica gel chromatography (30 mm × 300 mm column, 5:1 hexanes/Et2O as eluent, gravity column) afforded trans- aziridines 88c as colorless viscous liquid in 70% isolated yield (222 mg, 0.35 mmol). The optical purity of 88c was determined to be 93% ee by HPLC analysis (PIRKLE COVALENT (R, R) WHELK-O1column, 90:10 hexane/2-propanol at 226nm, flow-rate: 0.7 mL/min): retention times; Rt = 5.09 min (major enantiomer, 88c) and Rt = 8.84 min (minor enantiomer, ent-88c). Aldehyde 77 was reacted with 106c according to the general Procedure B described above in presence of (S)-VANOL as ligand at different temperature in toluene. The results are represented in Table 3.7 (Chapter 3). 1 Spectral data for 88c: Rf = 0.26 (1:1 Et2O / hexanes). H-NMR (500 MHz, CDCl3): δ 0.88 (t, J = 5.7 Hz, 3H), 0.90 (t, J = 6.0 Hz, 3H), 1.20-1.29 (m, 30H), 1.42 (dd, J = 14.5, 7.4 Hz, 2H), 1.48-1.53 (m, 1H), 2.04 (d, J = 2.9 Hz, 1H), 2.21 (s, 6H), 2.27 (s, 6H), 2.99 (dtd, J = 13.3, 6.8, 5.2 Hz, 1H), 3.34 (dq, J = 13.6, 6.9 Hz, 1H), 3.66 (s, 3H), 3.68 (s, 3H), 4.10 (s, 1H), 6.63 (dd, J = 7.1, 5.0 Hz, 1H), 6.94 (s, 2H), 7.07 (s, 2H); 13 C-NMR (126 MHz, CDCl3): δ 13.71, 14.04, 16.14, 16.22, 19.85, 22.62, 26.03, 28.06, 29.25, 29.29, 29.41, 29.44, 29.58, 29.59, 29.63, 31.81, 31.86, 38.23, 44.79, 47.29, 59.44, 59.52, 67.54, (3 sp3 carbon not located), 126.88, 127.60, 130.45, 130.63, 138.53, 138.55, 155.76, 156.04, 170.45; IR (thin film) 3312br, 2926vs, 2855vs, 174 + 1647s, 1484s, 1221s, 1143s cm-1; HRMS (ESI-TOF) m/z 635.5151 [(M+H ); calcd. for C41H67N2O3: 635.5152]; [α ]20 –22.0 (c 1.0, CH2Cl2) on 93% ee material. D 3.13.11Ring opening of trans-aziridine € 3.13.12 Ring opening of trans-aziridine 88c with water MEDAM N 13 O MEDAM p-toluenesulfonic acid (5 equiv) OH O n-Bu + N 13 NH H MEDAM 107 NH acetone/ H2O (5:1 v/v) n-Bu 3 days, rt 88c NH O 13 N OH H n-Bu 108 To an oven dried 10 mL round bottom flask flushed with nitrogen was added trans-aziridine 88c (75 mg, 0.12 mmol, 90% ee) and acetone (0.82 mL). To the resulting solution was added ptoluenesulfonic acid (114 mg, 0.6 mmol, 5.0 equiv) and water (0.18 mL). The reaction mixture was stirred at room temperature for 3 days (monitored by TLC) under nitrogen atmosphere. The reaction mixture was diluted with water (10 mL) and the water layer was extracted with ethyl acetate (4 × 10 mL). The combined water layer was dried with MgSO4 and concentrated under reduced pressure. Purification of the crude aziridine by silica gel chromatography (20 mm × 200 mm column, 4:1 hexanes/EtOAc as eluent, flash column) afforded C3 ring opened product 107 in 28% (22 mg, 0.034 mmol) yield as colorless viscous liquid and C2 ring opened product 108 in 53% yield (41 mg, 0.064 mmol) colorless viscous liquid. 1 Spectral data for 107: Rf = 0.54 (1:2 EtOAc / hexanes); H-NMR (500 MHz, CDCl3): δ 0.88 (t, J = 7.0 Hz, 3H), 0.94 (t, J = 7.3 Hz, 3H), 1.23-1.28 (m, 30H), 1.45-1.50 (m, 2H), 2.24 (s, 6H), 175 2.25 (s, 6H), 2.93 (brs, 1H), 2.99 (d, J = 5.0 Hz, 1H), 3.24-3.29 (m, 2H), 3.68 (s, 3H), 3.69 (s, 3H), 3.76-3.80 (m, 1H), 4.57 (s, 1H), 6.66 (t, J = 5.8 Hz, 1H), 6.96 (s, 2H), 6.97 (s, 2H), (OH proton not located). 13 C-NMR (126 MHz, CDCl3): δ 13.71, 14.08, 16.20, 16.22, 20.09, 22.66, 25.84, 29.33, 29.56, 29.59, 29.61, 29.63, 29.65, 29.66, 29.67, 31.67, 31.90, 33.51, 38.82, 59.55, 59.58, 63.90, 64.79, 72.73, (three sp3 carbon not located), 127.52, 127.59, 130.80, 130.94, 156.06, 156.11, 169.03; IR (thin film) 3339br, 2926vs, 2855vs, 1653s, 1485s, 1221s, 1142vs cm1; HRMS (ESI-TOF) m/z 653.5281 [(M+H+); calcd. for C41H69N2O4: 653.5257]; [α ]20 +3.0 (c D 1.0, CH2Cl2). € 1 Spectral data for 108: Rf = 0.31 (1:2 EtOAc / hexanes); H-NMR (500 MHz, CDCl3): δ 0.88 (t, J = 7.0 Hz, 3H), 0.92 (t, J = 7.3 Hz, 3H), 1.19-1.30 (m, 30H), 1.45-1.50 (m, 2H), 2.24 (s, 6H), 2.26 (s, 6H), 2.94-2.97 (m, 1H), 3.15-3.22 (m, 1H), 3.28-3.35 (m, 1H), 3.68 (s, 3H), 3.70 (s, 3H), 4.01 (d, J = 4.5 Hz, 1H), 4.67 (s, 1H), 6.90-6.93 (m, 3H), 6.94 (s, 2H), (OH and NH protons not located); 13 C-NMR (126 MHz, CDCl3): δ 13.69, 14.09, 16.22, 16.23, 20.08, 22.67, 25.78, 28.66, 29.34, 29.58, 29.64, 29.65, 29.68, 31.62, 31.91, 38.53, 57.68, 59.60, 63.32, 70.82, 127.49, 127.51, 130.78, 130.94, 138.36, 138.51, 156.00, 156.09, 171.90, (6 sp3 carbon not located) ; IR (thin film) 3327br, 2926vs, 2855vs, 1647s, 1483s, 1221s, 1140s cm-1; HRMS (ESI-TOF) m/z + 653.5254 [(M+H ); calcd. for C41H69N2O4: 653.5257]; [α ]20 –6.0 (c 1.0, CH2Cl2). D € 3.13.13 Ring opening of trans-aziridine 88c with TFA 176 MEDAM N 13 O MEDAM 1) TFA (1.0 equiv) CH2Cl2, rt, 48 h OH O NH O n-Bu + N 13 NH H MEDAM 107 NH 2) NaOH n-Bu 88c 13 N OH H n-Bu 108 The ring opening reaction of trans-88c (127 mg, 0.2 mmol) was performed following the procedure described above for the synthesis of 103 from cis-aziridine 37l. Purification of the crude mixture by silica gel chromatography (20 mm×200 mm column, 4:1 hexanes/EtOAc as eluent, flash column) afforded afforded C3 ring opened product 107 in 20% (26 mg, 0.04 mmol) yield as colorless liquid and C2 ring opened product 108 in 40% yield (52 mg, 0.08 mmol) colorless liquid. 3.13.14 Synthesis of trans-aziridine 2- carboxylate 110 MEDAM N 13 O Boc2O (3 equiv), DMAP (2 equiv) CH2Cl2, rt 2 d NH n-Bu MEDAM N 13 O MEDAM N NaOEt Boc EtOH, 4 h, 0 ºC N n-Bu 13 COOEt tert-Butyl ((2R, 3S)-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-pentadecylaziridine-2carbonyl)(butyl)carbamate 109: To an flame dried 10 mL round bottom flask flushed with nitrogen was added trans-aziridine 88c (317 mg, 0.5 mmol) and dichloromethane (2 mL). To the resulting solution was added DMAP (120 mg, 1.0 mmol, 2.0 equiv) and Boc2O (327 mg, 1.5 mmol, 3.0 equiv). The reaction mixture was stirred for 2 days at room temperature under nitrogen atmosphere. Thereafter, the reaction mixture was concentrated under reduced pressure 177 to afford crude dark yellow oil. Purification of the crude mixture by silica gel chromatography (20 mm×200 mm column, 4:1 hexanes/Et2O as eluent, flash column) afforded 109 in 60% (220 mg, 0.3 mmol) yield as colorless viscous liquid and 38% starting material trans-aziridine 88c (120 mg, 0.19 mmol) was recovered. 1 Spectral data for 109: Rf = 0.45 (1:2 Et2O / hexanes); H-NMR (600 MHz, CDCl3): δ 0.85-0.89 (m, 6H), 1.16-1.29 (m, 32H), 1.41 (s, 9H), 2.19 (s, 7H), 2.24 (s, 6H), 2.44-2.46 (m, 1H), 3.363.40 (m, 1H), 3.46-3.49 (m, 1H), 3.63 (s, 3H), 3.67 (s, 3H), 4.42 (s, 1H), 7.00 (s, 2H), 7.10 (s, 2H); 13 C-NMR (151 MHz, CDCl3): δ 13.78, 14.09, 16.14, 16.17, 20.04, 22.68, 27.06, 27.87, 29.24, 29.35, 29.54, 29.59, 29.65, 29.67, 29.69, 30.49, 31.92, 32.59, 44.04, 44.83, 47.68, 59.44, 59.55, 67.40, 82.63, (three sp3 carbon not located), 127.88, 128.30, 129.79, 130.24, 138.37, 139.40, 152.61, 155.56, 155.85, 170.86. (2R, 3S)-Ethyl 1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-pentadecylaziridine-2carboxylate 110: To a flame dried 25 mL round bottom flask flushed with nitrogen was added ethanol (2 mL) and metallic sodium (10 mg, 0.44 mmol, 2.2 equiv). The mixture was stirred for 10 min until sodium was completely dissolved in ethanol. Thereafter, the reaction flask was placed into ice water bath and stirred for another 10 min. To the reaction flask was added a solution of 109 (147 mg, 0.2 mmol) in ethanol (1 mL). The resulting mixture was stirred for 4 h at 0 ºC. To the reaction mixture was added sat. aq. NH4Cl (5 mL ) and brine (10 mL). The aqueous layer was extracted with ether (4 × 10 mL). The combined organic layer was dried with MgSO4 and concentrated under reduced pressure. Purification of the crude mixture by neutral alumina chromatography 178 (20 mm×200 mm column, 4:2:0.1 hexanes/DCM/Et2O as eluent, gravity column) afforded 110 in 90% yield (109 mg, 0.18 mmol) as colorless viscous liquid. 1 Spectral data for 110: Rf = 0.32 (2:1:0.2 hexanes/CH2Cl2/Et2O); H-NMR (500 MHz, CDCl3): δ 0.88 (t, J = 7.0 Hz, 3H), 0.98 (t, J = 7.1 Hz, 3H), 1.21-1.30 (m, 28H), 2.22 (s, 6H), 2.25 (s, 6H), 2.34-2.37 (m, 1H), 2.54 (d, J = 2.9 Hz, 1H), 3.66 (s, 3H), 3.68 (s, 3H), 3.88-4.00 (m, 2H), 4.61 (s, 1H), 7.01 (s, 2H), 7.05 (s, 2H); 13 C-NMR (126 MHz, CDCl3): δ 13.85, 14.11, 16.14, 16.17, 22.69, 27.01, 29.18, 29.36, 29.53, 29.59, 29.63, 29.66, 29.69, 31.92, 32.47, 41.77, 47.61, 59.53, 59.57, 60.66, 67.28, (three sp3 carbon not located), 127.62, 128.24, 130.11, 130.40, 138.30, -1 139.02, 155.61, 155.98, 169.53; IR (thin film) 2930vs, 1748s, 1490s, 1218s, 1186vs cm ; + HRMS (ESI-TOF) m/z 608.4685 [(M+H ); calcd. for C39H62NO4: 608.4679] 3.13.15 Synthesis of aldehyde 122 3.13.15.1 Synthesis of Weinreb amide 116 Cl 4 O 115 OMe N H •HCl pyridine, ,CH2Cl2 OMe N 4 O 116 N-Methoxy-N-methylheptanamide 116: To an oven dried 500 mL round bottom flask was added N,O-dimethylhydroxylamine hydrochloride (7.0 g, 71.8 mmol, 1.07 equiv) and dichloromethane (100 mL). To the mixture was added pyridine (14 mL, 150.8 mmol, 2.25 equiv). the resulting reaction mixture was cooled to 0 ºC. To the reaction flask was added 179 heptanoyl chloride 115 (10.4 mL, 67.2 mmol). The reaction mixture was allowed to warm to room temperature over 2 h. The reaction mixture was diluted with EtOAc (200 mL). The organic layer was washed with 2 N HCl (2 × 100 mL), sat. aq. NaHCO3 (2 × 100 mL) and brine (50 mL). The combined organic layer was dried with MgSO4 and concentrated under reduced pressure to afford the Weinreb amide 116 as colorless oil in 95% (11.2 g, 63.8 mmol) crude yield. The crude product was used for subsequent reaction without any further purification. 1 Spectral data for 116 H-NMR (300 MHz, CDCl3): δ 0.78-0.81 (m, 3H), 1.22 (brs, 6H), 1.521.56 (m, 2H), 2.33 (t, J = 7.4 Hz, 2H), 3.09 (s 3H), 3.60 (s, 3H); 13 C-NMR (75 MHz, CDCl3): δ 13.72, 22.25, 24.30, 28.82, 31.31, 31.64, 31.91, 60.90, 174.82. 3.13.15.2 Synthesis of ketone 117 OMe N 4 O 116 Pentadec-14-en-7-one 117: 27 MgBr 6 118 THF, rt, 1h 5 O 4 117 To a flame dried 100 mL round bottom flask flushed with nitrogen and equipped with a stir bar was added Mg (130 mg, 5.5 mmol, 1.2 equiv) and dry THF (3 mL). To the slurry was added a few drops of 8-bromo-1-octene to initiate the formation of Grignard reagent 118 and the remainder of the 8-bromo-1-octene (950 mg, 5.0 mmol, 1.1 equiv) solution in THF (5.5 mL) was added slowly at room temperature. The mixture was stirred vigorously at room temperature. After most of the Mg had disappeared the mixture was cooled to 0 ºC and a solution of amide 116 (780 mg, 4.5 mmol) in THF (4.5 mL) was slowly added to 180 the Grignard 118. The mixture was warmed to room temperature and stirred for 40 min at room temperature. Thereafter, the reaction mixture was poured to 10% aq NaHSO4 (15 mL). The aqueous layer was extracted with ether (3 × 25 mL). The combined organic layer was dried with MgSO4 and concentrated under reduced pressure. Purification of the crude mixture by silica gel chromatography (30 mm×200 mm column, 20:1 hexanes/Et2O as eluent, flash column) afforded 117 in 90% yield (909 mg, 4.05 mmol) as colorless viscous liquid. 1 Spectral data for 117 Rf = 0.34 (1:20 EtOAc / hexanes); H-NMR (500 MHz, CDCl3): δ 0.84 (t, J = 6.8 Hz, 3H), 1.17-1.30 (m, 10H), 1.30-1.38 (m, 2H), 1.50-1.56 (m, 4H), 1.99 (q, J = 6.8 Hz, 2H), 2.34 (t, J = 7.4 Hz, 4H), 4.88 (dd, J = 10.2, 1.5 Hz, 1H), 4.94 (dd, J = 17.0, 1.5 Hz, 1H), 5.75 (ddt, J = 17.0, 10.2, 6.8 Hz, 1H); 13 C-NMR (126 MHz, CDCl3): δ 14.10, 23.71, 23.86, 23.89, 28.80, 28.90, 29.00, 29.20, 31.71, 33.82, 42.80, 43.00, 114.31, 139.00, 211.50. These spectral data matched those previously reported compound. 27 3.13.15.3 Synthesis of 119 via protection of ketone HO OH 1.5 equiv 5 O 117 4 p-TSOH (0.05 equiv) benzene, reflux 5 O O 4 119 2-hexyl-2-(oct-7-en-1-yl)-1,3-dioxolane 119: To a flame dried 50 mL round bottom flask was added enone 117 (1.06g, 4.74 mmol), ethylene glycol (462 µL; 6.68 mmol, 1.41 equiv), and ptoluenesulphonic acid (46.0 mg, 0.24 mmol, 0.05 equiv). To the mixture was added dry benzene 181 (28 mL). The stirring mixture was heated at reflux under Dean-Stark conditions for 18 hours. The cooled mixture was quenched with sat. aq. NaHCO3 (10mL) and extracted with diethyl ether (3 × 25 mL). The combined organic phase was dried with MgSO4 and concentrated in vacuo giving the corresponding crude cyclic acetal 119. Purification of the crude mixture by silica gel chromatography (30 mm×200 mm column, 20:1 hexanes/Et2O as eluent, flash column) afforded 119 in 95% yield (1.21 g, 4.05 mmol) as colorless viscous liquid. 1 Spectral data for 119: Rf = 0.42 (1:20 EtOAc / hexanes); H-NMR (300 MHz, CDCl3): δ 0.88 (t, J = 6.8 Hz, 3H), 1.38-1.26 (m, 16H), 1.61-1.56 (m, 4H), 2.07-1.99 (m, 2H), 3.92 (s, 4H), 4.92 (ddt, J = 10.2, 2.3, 1.2 Hz, 1H), 5.02-4.95 (m, 1H), 5.81 (ddt, J = 17.0, 10.3, 6.7 Hz, 1H).. 13 C- NMR (75 MHz, CDCl3): δ 14.20, 22.69, 23,92, 24.00, 29.01, 29.21, 29.79, 29.90, 32.01, 33.92, 37.26, 37.29, 65.00, 112.01, 114.31, 139.30. These spectral data matched those previously reported compound. 27 3.13.15.4 Synthesis of aldehyde 120 1) K2OsO4 • 2H2O, NMO acetone/H2O, rt, 12h 5 O O 4 2) NaIO4,CH2Cl2, 1h 119 O 5 O O 4 120 8-(2-hexyl-1,3-dioxolan-2-yl)octane-1,2-diol: To a 500 mL round bottom flask flushed with nitrogen was added acetal 119 (1.20 g, 4.45 mmol) and NMO (1.81 g, 13.4 mmol, 3.0 equiv). 182 The mixture was dissolved in acetone (170 mL). To the resulting solution was added water (17 mL). Thereafter, K2OsO2•2H2O (161 mg, 0.44 mmol, 0.1 equiv) was added in one portion to a stirring solution. atmosphere. The mixture was stirred for 20 h at room temperature under nitrogen The reaction was quenched with sodium sulphite (1.90 g; 15.1 mmol) and water (50 mL), and stirred for 30 minutes. The mixture was filtered to remove the solid, and acetone was removed in vacuo. The aqueous layer was extracted with ethyl acetate (3 × 200 mL). The combined organic phase dried with MgSO4 and upon concentration in vacuo affords yellow oil in 100% crude yield (crude weight 1.44g). The crude product was used in next reaction without any further purification. 1 Spectral data for 8-(2-hexyl-1,3-dioxolan-2-yl)octane-1,2-diol: H-NMR (500 MHz, CDCl3): δ 0.88 (t, J = 6.9 Hz, 3H), 1.27-1.35 (m, 15H), 1.43-1.44 (m, 3H), 1.56-1.60 (m, 4H), 1.95 (s, 2H), 3.43 (dd, J = 11.0, 7.6 Hz, 1H), 3.65 (dd, J = 11.0, 3.1 Hz, 1H), 3.68-3.72 (m, 1H), 3.92 (s, 4H); 13 C-NMR (126 MHz, CDCl3): δ 14.02, 22.51, 23.71, 25.52, 29.53, 29.61, 29.80, 31.80, 33.01, 37.02, 37.11, 64.82, 66.59, 72.21, 111.80, (one sp3 carbon not located). These spectral data matched those previously reported compound. 27 7-(2-hexyl-1,3-dioxolan-2-yl)heptanal 120: To oven dried 50 mL round bottom flask was added prepared crude diol (605 mg, 2.0 mmol) and DCM (17 mL). To the stirred solution was added NaIO4 on silica (4.11 g, 14.6 wt%, 2.8 mmol) in one portion. The heterogeneous mixture was stirred vigorously for 2 h. The mixture was filtered through a sintered glass funnel to a 250 mL round bottom flask. The reaction flask was washed with DCM (3 × 15 mL) and filtered through the same funnel. The filtrate was concentrated under reduced pressure. Purification of 183 the crude mixture by silica gel chromatography (30 mm×200 mm column, 4:1 hexanes/Et2O as eluent, flash column) afforded aldehyed 120 in 94% yield (508 mg, 1.18 mmol) as colorless oil. 1 Spectral data for 120 Rf = 0.36 (1:5 Et2O / hexanes). H-NMR (300 MHz, CDCl3): δ 0.82 (t, J = 6.7 Hz, 3H), 1.11-1.40 (m, 14H), 1.40-1.64 (m, 6H), 2.36 (dt, J = 7.3, 1.8 Hz, 1H), 3.89 (s, 4H), 9.70 (t, J = 2.0 Hz, 1H); 13 C-NMR (126 MHz, CDCl3): δ 13.98, 21.98, 22.53, 23.55, 23.76, 29.07, 29.56, 31.77, 37.00, 37.13, 43.79, 64.82, (one sp3 carbon not located), 111.77, 202.54. These spectral data matched those previously reported compound. 27 3.13.15.5 Synthesis of 121 O 5 O O 4 MgBr 2.3 equiv HO 5 O O 4 THF, –78 ºC - 0 ºC 120 121 9-(2-hexyl-1, 3-dioxolan-2-yl)non-1-en-3-ol 121: To a flame dried 100 mL three neck round bottom flask flushed with nitrogen and equipped with a stir bar and an addition funnel in one of the side neck was added Mg (290 mg, 12.0 mmol, 2.40 equiv) and dry THF (4 mL). the flask was cooled to 0 ºC. To the slurry was slowly added vinyl bromide (0.82 mL, 11.6 mmol, 2.32 equiv) solution in THF (2 mL) via the addition funnel. The mixture was warmed to room temperature and stirred for 1 h at room temperature under nitrogen atmosphere. the freshly prepared vinyl Grignard reagent was cooled to –78 ºC and to the reaction flask was slowly added a solution of aldehyde 120 (1.30 g, 5.0 mmol) in THF (2 mL). The resulting mixture was stirred for 1 h at –78 ºC then warmed to 0 ºC over a period of 20 min. The reaction mixture was poured 184 slowly to the sat. aq. NH4Cl (30 mL) at 0 ºC. The mixture was extracted with diethyl ether (4 × 25 mL). The combined organic layer was dried over MgSO4 and concentrated in vacuo. Purification of the crude mixture by silica gel chromatography (30 mm×200 mm column, 9:1 to 1:1 hexanes/EtOAc as eluent, flash column) afforded 121 in 80% yield (1.20 mg, 4.0 mmol) as colorless oil. 1 Spectral data for 121 Rf = 0.08 (1:9 EtOAc / hexanes); H-NMR (300 MHz, CDCl3): δ 0.88 (t, J = 6.8 Hz, 3H), 1.28-1.37 (m, 18H), 1.56-1.61 (m, 5H), 3.92 (s, 4H), 4.07-4.09 (m, 1H), 5.10 (ddd, J = 10.4, 1.6, 1.2 Hz, 1H), 5.18-5.25 (m, 1H), 5.86 (ddd, J = 17.2, 10.4, 6.2 Hz, 1H); 13 C- NMR (75 MHz, CDCl3): δ 13.97, 22.49, 23.64, 23.69, 25.16, 29.39, 29.49, 29.74, 31.72, 36.82, 36.89, 36.96, 64.74, 73.03, 111.76, 114.31, 141.28; IR (thin film) 3441 br, 2934vs, 2858s, 1716s, -1. 1458s, 1082vs cm 3.13.15.6 Synthesis of aldehyde 122 via Claisen rearrangement Hg(OAc)2(5 mol%) HO 5 O O 121 4 O OEt 140 ºC, 14 h 5 O O 4 122 (E)-11-(2-hexyl-1,3-dioxolan-2-yl)undec-4-enal 122: To a 25 mL flame-dried Schlenk flask equipped with a stir bar and filled with nitrogen was added was added alcohol 121 (128 mg, 0.864 mmol), Hg(OAc)2 (14 mg, 0.043 mmol, 5 mol%) and ethyl vinyl ether (3 mL). The flask 185 was sealed and was place in a oil bath at 140 ºC. The reaction mixture was heated for 14 h. Thereafter, the reaction mixture was cooled to room temperature and was concentrated under reduced pressure. Purification of the crude mixture by silica gel chromatography (30 mm×200 mm column, 9:1 hexanes/EtOAc as eluent, flash column) afforded 122 in 30% yield (84 mg, 0.260 mmol) as colorless oil. 1 Spectral data for 122 Rf = 0.28 (1:9 EtOAc / hexanes); H-NMR (300 MHz, CDCl3): δ 0.87 (t, J = 7.0 Hz, 3H), 1.22-1.40 (m, 18H), 1.50-1.60 (m, 2H), 1.95 (m, 2H), 2.28-2.40 (m, 2H), 2.46 (t, J = 7.0 Hz, 2H), 3.95 (s, 4H), 5.11-5.40 (m, 2H), 9.75 (t, J = 7.0 Hz, 1H); 13 C-NMR (75 MHz, CDCl3): δ 14.01, 22.51, 23.70, 23.73, 25.08, 28.99, 29.22, 29.53, 29.68, 31.74, 32.36, 37.05, 43.44, 64.78, 111.77, (two sp3 carbon not located), 127.57, 131.92, 202.31; IR (thin film) -1 + 2930vs, 2855s, 1728s, 1458s, 1082vs cm ; HRMS (ESI-TOF) m/z 325.2739 [(M+H ); calcd. for C20H37O3: 325.2737] 3.13.16 Multi-component catalytic asymmetric aziridination reaction of aldehyde 122 in presence of (R)-VAPOL 1) 4 Å MS (R)-VAPOL (10 mol%) MEDAM NH2 66 2) R CHO 122 (1.05 equiv) –10 ºC B(OPh)3 (30 mol%) toluene, 80 °C, 0.5 h 3) EDA (11) (2.0 equiv) –10 ºC, 24 h N CO2Et R 123 R= 186 Ar Ar 5 O O 4 (2S,3S)-Ethyl1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-((E)-10-(2-hexyl-1,3-dioxolan2-yl)dec-3-en-1-yl)aziridine-2-carboxylate 123: Aldehyde 123 (34 mg, 0.105 mmol, 1.05 equiv) was reacted with EDA 11 (21 μL, 0.2 mmol, 2.00 equiv) and MEDAM amine 66 (30 mg, 0.1 mmol) according to the general aziridination Procedure B described above with (R)-VAPOL as ligand at –10 ºC, to afford cis- aziridines 123. Purification of the crude aziridine by silica gel chromatography (20 mm × 150 mm column, 4:2:0.1 hexanes/DCM/Et2O as eluent, gravity column) afforded cis- aziridines 123 as colorless viscous liquid in 90% isolated yield (62 mg, 0.09 mmol). The optical purity of 123 was determined to be 97% ee (tentative due to unavailability of authenticate sample of ent-123) by HPLC analysis (PIRKLE COVALENT (R, R) WHELK-O1column, 99.5:0.5 hexane/2-propanol at 226nm, flow-rate: 0.7 mL/min): retention times; Rt = 20.26 min (major enantiomer, 123) and Rt = 30.03 min (minor enantiomer, ent-123). Spectral data for 123: 1 H-NMR (500 MHz, CDCl3): δ 0.88 (t, J = 6.9 Hz, 3H), 1.24-1.33 (m, 19H), 1.57-1.60 (m, 8H), 1.85-1.88 (m, 2H), 1.98 (q, J = 6.3 Hz, 1H), 2.20 (d, J = 6.8 Hz, 1H), 2.23 (s, 6H), 2.24 (s, 6H), 3.40 (s, 1H), 3.67 (s, 3H), 3.68 (s, 3H), 3.92 (s, 4H), 4.15-4.22 (m, 2H), 5.08-5.21 (m, 2H), 7.03 (s, 2H), 7.09 (s, 2H); 13 C-NMR (126 MHz, CDCl3): δ 14.06, 14.34, 16.12, 16.16, 22.58, 23.81, 23.82, 27.86, 29.17, 29.45, 29.60, 29.81, 30.09, 31.82, 32.53, 37.16, 43.47, 46.40, 59.56, 59.59, 60.66, 64.86, 77.30, 111.87, (two sp3 carbon not located), 127.34, 128.05, 128.87, 130.45, 130.46, 131.04, 137.80, 138.25, 155.79, 156.16, 169.65; IR (thin -1 film) 2930vs, 1746s, 1484s, 1458s, 1224s, 1185vs cm ; HRMS (ESI-TOF) m/z 691.4809 + [(M+H ); calcd. for C43H66NO6: 691.4812]. 187 REFERENCES 188 REFERENCES (1) Sandhoff, R. FEBS Lett. 2010, 584, 1907. (2) Lynch, D. V.; Dunn, T. M. New Phytol. 2004, 161, 677. (3) Tadeusz, F. M. Curr. Med. Chem. 2004, 3, 197. 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Chem. 2003, 68, 7675. 191 CHAPTER 4   THE EFFECT OF CHIRAL SUBSTRATES IN THE CATALYIC ASYMMETRIC AZIRIDINATION REACTION 4.1 Introduction The effect of a chiral center on a prochiral reaction center within the same molecule has always been a point of interest in organic synthesis. The interaction of a chiral substrate with a chiral ligand can give rise to three possibilities: a) substrate controlled reaction and b) catalyst 1 controlled reaction c) synergistically controlled by both substrate and catalyst. In the substratecontrolled reaction, there is the strong probability of a matched/mismatched relationship between the chiral catalyst and chiral substrate. This presents an opportunity for a possible kinetic resolution of a racemic substrate. In the catalyst controlled reaction, the stereochemistry of the newly formed chiral centers is independent of the pre-installed chiral centers in the substrate. By a simple change of the enantiomer of the catalyst, the catalyst-controlled reaction can yield different diastereomers with high a diastereomeric ratio from the same substrate. In the present work we found that the Wulff’s aziridination reaction is primarily a catalyst controlled reaction. The Wulff group has developed a general catalytic asymmetric aziridination reaction that 2 is based on the reaction of achiral imines with stabilized diazo compounds. The crystal structure of the active catalyst in this aziridination reaction reveals several non-covalent interactions between the boroxinate anion and the iminium cation (Figure 4.1). The strongest interaction is the hydrogen bonding between the protonated imine and the boroxinate anion. In 192 addition, several CH–π interactions (Figure 4.1, d2-d5) were observed. These CH–π interactions are between the methyl on the MEDAM protecting group and the aromatic regions of the chiral ligand (Figure 4.1, d2 and d4) or the phenyl group of the phenol component (Figure 4.1, d5). Another CH–π interaction is between the ortho hydrogen of the MEDAM group and the phenyl ring of the ligand (d3). One of the most important non-covalent interactions is a π–π stacking interaction between the protonated benzylidine iminium moiety and the phenanthren rings of the VAPOL ligand (Figure 4.1, d7). Figure 4.1 Different interactions in the active catalyst structure d2 d1 d3 OMe Me H Me + N O – B O O B O B O O CH-! CH-O d7 H d2-d5 d6 Me d4 O H-Bond !-! H MeO Me d5 d7 d6 d1 iminium-boroxinate complex At this point it was thought that it would be interesting to study the aziridination of chiral imines of type 127 (Figure 4.2A) to see the different diastereomeric mixtures that would result 193 from the reactions with each enantiomers of the catalyst. Thus, this in effect would be replacing the phenyl group of the imine in Figure 4.1 with a chiral fragment. This would result in the loss of the π–π interaction. Hence, this would serve two purposes: a) give an insight into the possible interactions of the chiral segment with the ligand giving possible matched/ mismatched cases; b) allow making complex organic molecules with more than two chiral centers provided that the aziridination reaction is well behaved in the case of chiral substrates. The former case also presents an additional possibility of no influence of the chiral segment on the reaction, which would fall into the category of catalyst -controlled reactions. The aim for the current project was to screen different chiral aldehydes to observe the impact of chiral substrates in the aziridination reaction with chiral boroxinate catalysts. 4.2 Proposed model and the predicted stereochemical outcome for the AZ reaction of α chiral imines Assuming that the chiral imines 127 will react with EDA 11 in presence of the chiral boroxinate catalysts derived from VAPOL or VANOL to provide aziridines (Figure 4.2A), a prediction of the stereochemical outcome of these aziridination reactions was made with the help 3 of the Felkin-Anh model and the crystal structure of a substrate-catalyst complex in Wulff’s aziridination reaction (Figure 4.2B-4.2D). Figure 4.2 (A) Proposed catalytic asymmetric aziridination reaction with chiral imines 127. (B) Projected approach of the nucleophile to chiral imine 127 using Felkin-Anh model for Re-face attack of the nucleophile (favored). (C) Projected approach of the nucleophile to chiral imine 127 using Felkin-Anh model for Si-face attack of the nucleophile (unfavored). (D) the X-ray 194 Figure 4.2 (cont’d) crystal structure of active catalyst consisting of an iminium cation ( from achiral imine 36a) and the boroxinate anion (from (S)-VAPOL). The boroxinate anion is green in color and the iminimium cation is in traditional color. (A) O P N OEt + RS Chiral boroxinate catalyst RS RM P N RL N2 RM RL 127 RS + RM RL N CO2Et 11 P CO2Et 128a 128b RL = large group RM = medium group RS = small group (B) Nu RS H Nu RL RM N RM RS RM H RL RL NHP P RS EtO2C O 128b OEt Nu = N P N2 for AZ reaction Re-face attack (Conformer A) (C) RL N P NHP RM RL RM Nu RM H RL Nu = Nu OEt N2 for AZ reaction Si-face attack (Conformer B) 195 N P EtO2C O RS RS H RS 128a Figure 4.2 (cont’d) (D) Nucleophile (Si-face attack) OMe N OMe 36a In Figure 4.2B, the Re-face attack of the nucleophile (EDA) along the Bürgi-Dunitz angle would be more favorable, leading to the aziridine of type 128b. On the other hand, in Figure 4.2C, Si-face attack along the Bürgi-Dunitz angle would not be expected to be as likely since conformer B of the imine would be expected to be less stable than conformer A. Therefore the less favorable Si-face attack of nucleophile will lead to the aziridine of type 128a as the minor product. The crystal structure of imine-boroxinate complex (Figure 4.2D) suggests that for imine 36a (achiral imine), a Si-face approach of nucleophile should be favorable when the ligand is (S)-VAPOL and this is in fact the experimentally observed outcome for the non-chiral imines. Assuming a similar interaction between the chiral imine 127 and the chiral boroxinate catalyst, it can be predicted that the Si-face approach would be favored in case of the (S)-VAPOL catalyst. This is in turn suggests that Re-face approach would be most befitting the case of a (R)-VAPOL catalyst. Hence a matched case would be generated when imine 127 with the configuration 196 shown in 127 in Figure 4.2A and when the conformation shown in Figure 4.2B interacts with the (R)-VAPOL catalyst to favor Re-face attack resulting in aziridine 128b. In case of the (S)VAPOL derived catalyst, the conformer of imine 127 shown in Figure 4.2C will be the one expected to most often undergo nucleophilic attack under catalyst control. It must be pointed out that the Si-face attack is less favored for imine 127 due to the arrangements of the groups around the chiral center which should lead to a mismatched substrate catalyst pair. This situation will give rise to a substrate controlled reaction. If the size of RM and RL are comparable then nucleophilic attack from both faces of the imine 127 are equally favorable in the absence of any chiral catalyst. This would lead to attack governed by the stereochemistry of the catalyst. In other words, the reaction will be catalyst controlled resulting in aziridine 128a or 128b depending on the chirality of the catalyst. The stereochemical outcomes of the reactions discussed in the subsequent sections are in well agreement with the model discussed above (Figure 4.2). In addition to the model proposed in Figure 4.2 with simple Felkin-Ahn considerations, other types of factors including non-covalent and H-bonding interactions between catalyst and the substrates might also govern the stereochemical outcome of the aziridination reaction with chiral imines. 4.3 Synthesis of Chiral aldehydes During the investigation of the behavior of the aziridination reactions with chiral imines, it was thought to study the α-chiral imines 129 by varying the ‘R’ group at the α position to include 1º and 2º aliphatic groups as well as an aromatic group (Scheme 4.1). The chiral imines (R)-129 can be synthesized from the corresponding chiral aldehydes (R)-130. 197 Scheme 4.1 Chiral imines (R)-129 for aziridination reaction R OTBS N OTBS Ar R + Ar Ar NH2 CHO Ar Chiral imines Chiral aldehydes amine R = Cy, (R)-129a R = Ph, (R)-129b R = Me, (R)-129c R = Cy, (R)-130a R = Ph, (R)-130b R = Me, (R)-130c 66 The chiral aldehydes (R)-130a and (R)-130b were synthesized following the same synthetic route starting from the corresponding α-hydroxy acids (R)-131a and (R)-131b (Scheme 4.2). The esterification reaction of the α-hydroxy acids (R)-109 with ethyliodide in the presence of CsF-Celite afforded the corresponding α-hydroxy esters (R)-132. The hydroxy group in the esters (R)-132 was protected with a t-butyldimethylsilyl group. This was followed by the reduction of the TBS protected esters (R)-133 to corresponding aldehydes (R)-107 with DIBALH at –78 ºC (yields of each step are given in Scheme 4.2). Scheme 4.2 Synthesis of chiral aldehyde (R)-130a and (R)-130b OH R COOH OH EtI, CsF-Celite acetonitrile reflux, 8 h R = Cy, (R)-131a R = Ph, (R)-131b R yield 65%, R = Cy, (R)-132a yield 70%, R = Ph, (R)-132b TBSCl imidazole OTBS R CHO COOEt OTBS DIBAL-H THF, –78 ºC, 2 h yield 85%, R = Cy, (R)-130a yield 85%, R = Ph, (R)-130b DMF rt, 12 h R COOEt yield 88%, R = Cy, (R)-133a yield 92%, R = Ph, (R)-133b 198 The aldehyde (S)-130c was synthesized from the commercially available (S)-methyl lactate 134 (Scheme 4.3). The hydroxy group in (S)-134 was converted to the corresponding tbutyldimethylsilyl ether (S)-135 upon reaction with t-butyldimethylsilyl chloride and imidazole in 85% yield. The aldehyde (S)-130c was synthesized by reducing the methyl ester (S)-135 with DIBAL-H in 75% yield (Scheme 4.3). Scheme 4.3 Synthesis of chiral aldehyde (S)-130c OH Me COOMe TBSCl imidazole DMF rt, 12 h (S)-134 4.4 OTBS Me COOMe (S)-135 yield 85% OTBS DIBAL-H THF –78 ºC, 1 h Me CHO (S)-130c yield 75% Aziridination reaction with chiral imine (R)-129a: a substrate controlled reaction The aziridination reactions with chiral imine (R)-129a were performed using 5-10 mol% catalyst. The pre-catalyst or the ligand borate catalyst (Table 4.1) was prepared by heating the mixture of ligand with 4 equiv of commercial B(OPh)3 at 80 ºC for an hour followed by the subsequent removal of volatiles on exposure to vacuum. This was then followed by the addition of chiral imine (R)-129a and ethyl diazoacetate 11 and toluene and the resulting mixture was stirred for 24 h at 25 ºC. A diastereomeric mixture of two cis-aziridines 136a and 136b was obtained. There is a strong matched and mismatched relationship between the chiral imine (R)129a and the chiral catalyst was observed. In particular, the reaction of imine (R)-129a with the catalyst derived from (R)-ligand resulted in favorable matched case with the selective formation 199 of 136b (Table 4.1). In presence of 5 mol% of (R)-VANOL and (R)-VAPOL derived catalyst the aziridination reaction of (R)-129a and EDA 11 at room temperature resulted in a mixture of diastereomers 136a and 136b with 1:8 and 1:18 diastereomeric ratio, respectively, in favor of 136b (Table 4.1, entries 1 and 3). The combined yield of the cis-aziridnies was 80 and 85% in case of (R)-VAPOL and (R)-VANOL catalysts respectively. Table 4.1 Aziridination reaction of chiral imine (R)-129a in presence of chiral catalyst OTBS N Ar Ar Ligand-Borate catalyst (5-10 mol%) O OEt + N2 (R)-129a OTBS N toluene 25 ºC, 24 h 11 Ar a OTBS Ar + Ar N COOEt Ar COOEt 136a 136b Ar 1. B(OPh)3 (4 equiv) H2O (1 equiv) VAPOL or VANOL entry toluene, 80 ºC, 1 h 2. 0.1 mm Hg 80 ºC, 0.5 h ligand Ligand-Borate catalyst (mixture of B1 and B2) OMe catalyst (mol%) dr (136a : 136b) d % yield c (136a + 136b) 1 5 1 : 18 80 2 (S)-VAPOL 10 2:1 30 3 (R)-VANOL 5 1:8 85 4 (S)-VANOL 10 2:1 40 5b a (R)-VAPOL Yb(OTf)3 10 1 : 10 25 Unless otherwise specified, all reactions were carried out with 0.5 mmol of (R)-129a (0.5 M in 200 Table 4.1 (cont’d) toluene) with 1.2 equiv of 11 at 25 °C and went to completion in 24 h. The ligand-borate catalyst was prepared by heating a mixture of the ligand and 4 equiv of commercial B(OPh)3 at 80 ºC for an hour followed by the subsequent removal of volatiles upon exposure to vacuum. b The catalyst used for the reaction is Yb(OTf)3. The catalyst was added to a solution of imine in toluene followed by EDA addition. chromatography on silica gel. d c Isolated combined yield of cis-136a and 136b after Determined on crude mixture by HPLC on a PIRKLE 1 COVALENT (R, R) WHELK-O1 column and further confirmed by the H NMR spectrum of the crude reaction mixture. Interestingly, a strong mismatched case was observed in the aziridination reaction of the imine (R)-129a and EDA 11 at room temperature in presence of 10 mol% of (S)-VANOL and (S)-VAPOL derived catalyst. Both reactions resulted in a mixture of 136a and 136b in a 2:1 diastereomeric ratio with 30-40% yield (Table 4.1, entries 2 and 4). The reaction in the presence of a non-chiral catalyst Yb(OTf)3 shows a strong preference for the diastereomer 136b (Table 4.1, entry 5). During the course of this work, a multi-component aziridination reaction was developed 4 in our group by Anil Gupta (Scheme 4.4). An obvious advantage of this multi-component protocol is that the imine preparation step can be avoided thus prevented loss of material during purification, usually by crystallization. Moreover, the process of aziridination becomes much more simple to perform. Therefore, we decided to utilize the multi-component aziridination 201 reaction to study the effect of chiral aldehydes on the aziridination reaction. In order to compare the results obtained from the two-step method (Table 4.1), the multi-component aziridination reaction was performed with the chiral aldehyde (R)-130a, MEDAM amine 66 and EDA 11 in presence of the (S) and (R) isomers of VAPOL and VANOL derived catalysts. The results are presented in Table 4.2. Scheme 4.4 Multi-component asymmetric aziridination reaction Ar Ar NH2 O R Ar O H B(OPh)3 Ar N OEt N2 R CO2Et (S)-VAPOL As expected, the aziridination reaction of aldehyde (R)-130a, at –10 ºC, in the presence of 10 mol% (R)-VANOL and (R)-VAPOL derived catalysts resulted in the cis-aziridine 136b with > 99:1 diastereomeric ratio in 80% and 85% yield, respectively (Table 4.2, entries 2 and 5). The catalyst loading for the reaction with (R)-VAPOL can be reduced to 5 mol% without any detrimental effect on yield or diastereomeric ratio (Table 4.2, entry 3). The mismatched pair of aldehyde (R)-130a with the (S)-VAPOL catalyst resulted in a 1.1:1 diastereomeric ratio of 136a and 136b in 30% combined yield in the aziridination reaction at –10 ºC (Table 4.2, entry 1). Similarly, the (S)-VANOL catalyst resulted in a 1.5:1 diastereomeric ratio of 136a and 136b in only a 15% combined yield at –10 ºC (Table 4.2, entry 4). 202 Table 4.2 Multi-component aziridination reaction of chiral aldehyde (R)-130a in presence of a chiral boroxinate catalyst a 1) Ar Ar CHO Ligand (x mol%) B(OPh) 3 (3x mol%) NH 2 toluene 66 or 80 °C, 0.5 h 137 OTBS (R)-130a (1.1 equiv) 4 Å MS, –10 ºC 2) EDA (11) (1.2 equiv) –10 ºC, 32 h OTBS Ar N OTBS Ar Ar + COOEt Ar ligand Ar COOEt 136a, Ar 2CH = MEDAM 136b, Ar 2CH = MEDAM 136a', Ar 2CH = Bh entry N catalyst (mol%) 136b', Ar 2CH = Bh dr 136a:136b % yield c (136a + 136b) 1d (S)-VAPOL 10 1.1:1(1:1) 30 2 (R)-VAPOL 10 <1:>99(1:99) 85 3 (R)-VAPOL 5 <1:>99(1:99) 83 4d (S)-VANOL 10 1.5:1(2:1) 15 (R)-VANOL 10 <1:>99(1:99) 80 6 (S)-VAPOL 10 7f (R)-VAPOL 10 b OMe 5 d, e, f a nd 1:>99(1:99) nd 80 Unless otherwise specified, all reactions were performed with 0.2 mmol amine 66 (0.4 M in toluene) and 1.1 equiv of (R)-130a and 1.2 equiv EDA 11, and went to 100% completion. Before adding the aldehyde and EDA 11 a solution of amine 66 with x mol% ligand and 3x 203 Table 4.2 (cont’d) mol% commercial B(OPh)3 was stirred for 30 min at 80 °C under nitrogen. nd = not determined. b Isolated combined yield of 136a and 136b after chromatography on silica gel. c Determined on crude reaction mixture by HPLC on PIRKLE COVALENT (R, R) WHELK-O1 column. Diastereomeric ratio in parentheses is for the purified inseparable mixture of 136a and 136b by HPLC on PIRKLE COVALENT (R, R) WHELK-O1 column. completion even after 32 h. imine (R)-129a. f e d Reaction did not go for No aziridine was observed after 32 h. The only product was the The amine component in the reaction is benzhydryl amine 137 and the aziridines are 136a' and 136b'. Commercially available benzhydryl amine 137 was examined in the multi-component aziridination reaction with the aldehyde (R)-130a in the presence of both (R) and (S)-VAPOL catalysts. Matched and mismatched interactions between substrate and ligand were observed that were similar to that with MEDAM amine 66. The reaction in the presence of the (R)-VAPOL catalyst resulted in 136b' with > 99:1 diastereomeric ratio in 80% yield (Table 4.2, entry 7). In the mismatched case with the (S)-VAPOL catalyst, no aziridine was observed (Table 4.2, entry 6). The stereochemical outcome of the aziridination reaction is confirmed with the help of a crystal structure of ent-136b' (Scheme 4.5) obtained by Dr Reddy, a former group member. The aziridine ent-136b' was the major diastereomer with 1:27 diastereomeric ratio in the reaction of 5 the imine (S)-129a' with EDA 11 in the presence of the catalyst derived from (S)-VAPOL. As expected in this case, the (S)-enantiomer of the imine formed a matched pair with the catalyst 204 derived from (S)-ligand. The diastereoselectivity of the aziridination reactions with (R)-130a in the presence of (R) or (S) ligand derived catalyst is in well agreement with the model explained in Figure 4.2, where RL = Cy, RM = OTBS and RS = H. Scheme 4.5 Aziridination reaction with (S)-129a' and the ORTEP diagram of the crystal 5 structure of the major diastereomer ent-136b' (S)-VAPOL-Borate catalyst O (10 mol%) Ph OEt Ph + CH2Cl2 N2 25 ºC, 12 h (S)-129a' 11 OTBS N OTBS Ph N OTBS Ph Ph + N CO2Et CO2Et ent-136b' ent-136a' dr (ent-136b':ent-136a') = 27:1 85% yield Si O H N H O O ent-136b' ORTEP diagram of ent-136b' 205 Ph H 4.5 Aziridination reaction with chiral aldehyde (R)-130b: a catalyst controlled reaction In contrast to the chiral aldehyde (R)-130a, the aldehyde (R)-130b reacted via a catalyst controlled aziridination reaction. The multi-component aziridination reaction of aldehyde (R)130b with MEDAM amine 66, at –10 ºC, in the presence of 10 mol% (R)-VAPOL catalyst afforded the cis-aziridine 138b with 99:1 diastereomeric ratio in 90% yield (Table 4.3 entry 6). Similarly, the reaction in presence of the (R)-VANOL catalyst afforded the cis-aziridine 138b with 98:2 diastereomeric ratio in 85% yield at –10 ºC (Table 4.3 entry 8). Surprisingly, by a simple change to the (S)-enantiomer of the ligand, the aziridination reaction yielded the diastereomeric cis-aziridine 138a as the major diastereomer. The ratio of 138a to 138b is 98:2 for both (S)-VAPOL catalyst and (S)-VANOL catalyst at –10 ºC (Table 4.3, entries 5 and 7) in 90% and 85% yield respectively. Although, an increase in the reaction temperature to 0 ºC or to room temperature has no detrimental effect on yield of the aziridines 138a and 138b, a slight drop in the diastereomeric ratio was observed with both enantiomers of VAPOL at the elevated temperatures. The diastereomeric ratio of 138a to 138b at 0 ºC is 97:3 with the (S)-VAPOL catalyst, while the (R)-VAPOL catalyst afforded the aziridines with 1:99 diastereomeric ratio (Table 4.3, entries 3 and 4). At the room temperature, the diastereomeric ratio of 138a to 138b decreases to 95.7:4.3 with the (S)-VAPOL catalyst and 3:97 with the (R)-VAPOL catalyst (Table 4.3, entries 1 and 2). Switching the amine component to benzhydryl amine 137 also resulted in a catalyst-controlled reaction with aldehyde (R)-130b. While the reaction of aldehyde (R)-130b with benzhydryl amine at –10 ºC afforded the mixture of cis-aziridines 138a' and 138b' with <1:>99 diastereomeric ratio in the presence of the (R)-VAPOL catalyst in 60% yield, a diastereomeric ratio of 15:1 was observed with the (S)-VAPOL catalyst in 65% yield (Table 4.3, entries 10 and 9). 206 Table 4.3 Multi-component aziridination of aldehyde (R)-130b in the presence of chiral catalyst 1) Ar Ar toluene 66 or 80 °C, 0.5 h 137 OTBS CHO Ligand (10 mol%) B(OPh) 3 (30 mol%) NH 2 (R)-130b (1.1 equiv) 4 Å MS, temp 2) EDA (11) (1.2 equiv) temp, 24 h OTBS Ar N OTBS Ar Ar + Ar ligand N COOEt COOEt temp (ºC) 138b', Ar 2CH = Bh dr 138a:138b % yield c (138a + 138b) 1 (S)-VAPOL 25 95.7:4.3(96:4) 90 2 (R)-VAPOL 25 3:97(3:97) 90 3 (S)-VAPOL 0 97:3(98:2) 90 4 (R)-VAPOL 0 1:99(1:99) 92 5 (S)-VAPOL –10 98:2(99:1) 90 6 (R)-VAPOL –10 1:99(1:99) 90 7 (S)-VANOL –10 98:2(99:1) 85 8 (R)-VANOL –10 2:98(1:99) 85 d (S)-VAPOL –10 <1:>99(1:99) 65 d (R)-VAPOL –10 17:1(17:1) 50 OMe 9 10 Ar 138a, Ar 2CH = MEDAM 138b, Ar 2CH = MEDAM 138a', Ar 2CH = Bh entry a 207 b Table 4.3 (cont’d) a Unless otherwise specified, all reactions were performed with 0.2 mmol amine 66 (0.4 M in toluene) and 1.1 equiv of (R)-130b and 1.2 equiv EDA 11 and went to 100% completion. Before adding the aldehyde and the EDA 11, a solution of amine 66 with 10 mol% ligand and 30 mol% commercial B(OPh)3 was stirred for 30 min at 80 °C under nitrogen. of 138a and 138b after chromatography on neutral alumina. c b Isolated combined yield Determined on a sample prepared by passing the crude reaction mixture through a silica plug. Determined by HPLC on PIRKLE COVALENT (R, R) WHELK-O1 column. Diastereomeric ratio in parentheses is for purified inseparable mixture of 138a and 138b and was determined by HPLC on PIRKLE COVALENT (R, R) WHELK-O1 column. d The amine component in the reaction is benzhydryl amine 137 and the aziridines are 138a' and 138b'. The study of other chiral aldehydes in the presence of the chiral boroxinate catalysts was taken forward with MEDAM amine 66 since it gives aziridines with both higher yields and diastereoselectivity. The diastereoselectivity of the aziridination reactions with (R)-130b in the presence of (R) or (S) ligand derived catalyst is in well agreement with the model explained in Figure 4.2, where RL = Ph, RM = OTBS and RS = H. The stereochemical outcome of the aziridination reaction is confirmed with the help of a crystal structure of 138b (Figure 4.3). 208 Figure 4.3 The X-ray crystal structure of 138b O H Si O O N H OO 138b ORTEP diagram of 138b 4.6 Aziridination reaction with chiral aldehyde (S)-130c: a catalyst controlled reaction Another case of a catalyst controlled process was observed for the aziridination reaction of aldehyde (S)-130c with MEDAM amine 66 and EDA 11 in presence of the VANOL and VAPOL boroxinate catalysts. 209 Table 4.4 Multi-component aziridination reaction of chiral aldehyde (S)-130c in the presence of chiral boroxinate catalyst: a catalyst controlled case 1) Ar NH2 66 (S)-130c (1.1 equiv) B(OPh)3 OTBS 4 Å MS, –10 ºC (30 mol%) toluene 80 °C, 0.5 h OTBS CHO Ligand (10 mol%) Ar 2) EDA (11) Ar Ar N OTBS Ar N + COOEt Ar COOEt 139a ligand dr 139a:139b 139b c % yield 139a:139b 1 (S)-VAPOL 91:9(90:10) (R)-VAPOL 4:96(1:99) 87 (R)-VANOL 5:95(1:99) b 85 2 82 3 a Ar (1.2 equiv) –10 ºC, 24 h entry a OMe Unless otherwise specified, all reactions were performed with 0.2 mmol amine 66 (0.4 M in toluene) and 1.1 equiv of (S)-130c and 1.2 equiv EDA 11 and went to 100% completion. Before adding the aldehyde and the EDA 11 a solution of amine 66 with 10 mol% ligand and 30 mol% commercial B(OPh)3 was stirred for 30 min at 80 °C under nitrogen. b Isolated combined yield c of 139a and 139b after chromatography on neutral alumina. Determined on a sample prepared by passing the crude reaction mixture through a silica plug. Determined by HPLC on PIRKLE COVALENT (R, R) WHELK-O1 column. Diastereomeric ratio in parentheses is for purified inseparable mixture of 139a and 139b and was determined by HPLC on PIRKLE COVALENT (R, R) WHELK-O1 column. 210 The reaction in the presence of (R)-VAPOL and (R)-VANOL derived catalyst afforded the cis-aziridines 139a and 139b with diastereomeric ratio of 4:96 and 5:95 respectively with high yields (Table 4.4, entry 2 and 3). The reaction in the presence of (S)-VAPOL derived catalyst resulted in aziridine 139a as the major product. The (S)-VAPOL catalyst gave a 91:9 mixture of 139a and 139b in 85% combined yield. 4.7 Aziridination reaction with the acetonide of glyceraldehyde (R)-140: a catalyst controlled reaction The acetonide of glyceraldehyde (R)-140 was the next substrate of choice for the aziridination reaction as the resulting aziridine 141a can be a potential substrate for the synthesis of (–)-polyoxamic acid. The ring opening of the aziridine 141a followed by hydrolysis of the ring opened product can lead to (–)-polyoxamic acid, which is the enantiomer of the natural occurring (+)-polyoxamic acid (Scheme 4.6). The (+)-polyoxamic acid should be obtainable from the aldehyde (S)-140 in a similar fashion. Polyoxamic acid inhibits chitin synthetase of 6 Candida albicans, a human pathogen. There have been many syntheses reported in the literature for polyoxamic acid. 7 Scheme 4.6 Possible synthetic route for (–)-polyoxamic acid ring opening and hydrolysis OH O HO OH OH NH2 (–)-polyoxamic acid Ar O O N Ar CO2Et 141a 211 aziridination O O CHO (R)-140 The acetonide of glyceraldehyde (R)-140 was synthesized in 90% yield by oxidative cleavage of the diacetonide of D-mannose 142 with sodium periodate (Scheme 4.7). 8 Scheme 4.7 Synthesis of (R)-140 via oxidative cleavage of the diacetonide of D-mannose 142 O OH NaIO4 on silica O O OH O CH2Cl2, 25 °C, 2 h O O CHO (R)-140 90% yield 142 The aziridination reaction with the acetonide of glyceraldehyde (R)-140, MEDAM amine 66 and EDA 11 in the presence of 10 mol% (R)-VAPOL boroxinate catalyst resulted in aziridines 141a and 141b with 1:21 diastereomeric ratio in 83% yield at –10 ºC (Table 4.5, entry 2). The catalyst loading can be decreased to 5 mol% without any detrimental effect on yield or diasteremeric ratio (Table 4.5, entry 3). The reaction of the same aldehyde (R)-140 in the presence of the (S)-VAPOL boroxinate catalyst afforded aziridine 141a as the major diastereomer with an 86:14 ratio in 80% total yield. 212 Table 4.5 Multi-component aziridination reaction of the chiral aldehyde (R)-140 in the presence a of a chiral boroxinate catalyst 1) Ar Ar NH 2 66 Ligand (x mol%) B(OPh) 3 (3x mol%) toluene 80 °C, 0.5 h CHO (R)-140 (1.1 equiv) 4 Å MS, –10 ºC 2) Ar = 3,5-Me2-4-OMe-C6H 2 entry ligand O O Ar O O EDA (11) (1.2 equiv) –10 ºC, time N Ar + Ar O O N COOEt 141a Catalyst (x mol%) Conc. (‘C’ M) time COOEt 141b (h) dr c 141a:141b %yield b 141a:141b 1 (R)-VAPOL 10 0.1 24 5:95(5:95) 85 2 (R)-VAPOL 10 0.2 24 4.5:95.5(4:96) 83 (R)-VAPOL 5 0.2 24 5:95(5:95) 85 (S)-VAPOL 10 0.2 24 86:14(86:14) 80 e (S)-VAPOL 5 0.4 5 86:14(86:14) 80 d (S)-VAPOL 5 1.0 5 85:15(86:14) 80 e (S)-VANOL 10 0.4 5 85:15(86:14) 75 3 e 4 5 6 7 a Ar Unless otherwise specified, all reactions were performed with 0.2 mmol amine 66 with the indicated concentration in toluene and 1.1 equiv of (R)-140 and 1.2 equiv EDA 11 and went to 100% completion. Before adding the aldehyde and the EDA 11, a solution of amine 66 with x mol% ligand and 3x mol% commercial B(OPh)3 was stirred for 30 min at 80 °C under nitrogen. b Isolated combined yield of 141a and 141b after chromatography on neutral alumina. 213 Table 4.5 (cont’d) c Determined on a sample prepared by passing the crude reaction mixture through a silica plug. Determined by HPLC on PIRKLE COVALENT (R, R) WHELK-O1 column. Diastereomeric ratio in parentheses is for purified inseparable mixture of 141a and 141b and was determined by HPLC on PIRKLE COVALENT (R, R) WHELK-O1 column. with 1.0 mmol of amine 66. e d The reaction was performed The reaction was performed with 0.5 mmol of amine 66. The reaction in the presence of 10 mol% (S)-VAPOL boroxinate catalyst resulted in aziridines 141a and 141b with 86:14 diastereomeric ratio in 80% yield at –10 ºC (Table 4.5, entry 4). The reaction concentration does not have substantial effect on the outcome of the reaction with either of the enantiomers of the VAPOL catalyst (Table 4.5, entries 1, 5 and 6). The aziridination reaction of aldehyde (R)-140 in presence of (S)-VANOL afforded an 85:15 diastereomeric ratio of aziridines 141a and 141b in 75% yield. 4.8 Aziridination reaction with Garner’s aldehyde (S)-147: a catalyst controlled reaction Manzacidin B 146, a biologically important marine natural product has been synthesized from the amino alcohol 145 (Scheme 4.8). 9 We envisioned that amino alcohol 145 might be synthesized via ring opening of the aziridine 144 which in turn, can be synthesized via alkylation of aziridine 143 (Scheme 4.8). It would be possible to synthesize the aziridine 143 from the (R)Garner aldehyde provided that the aziridination reaction is well behaved in presence of a carbamate group and the resulting aziridine is produced with a high diastereomeric ratio. 214 Scheme 4.8 Possible synthetic route for Manzacidin B 146 OH O HO2C O N OH H N HO BocHN NH Br Manzacidin B, 146 OH NHBoc 145 ring opening N Boc O C-2 alkylation of aziridine ring Ar N N Boc O Ar Ar N COOEt Ar COOEt 144 143 To our delight commercially available Garner’s aldehyde (S)-147 afforded the cisaziridine 143a with 99% diastereomeric excess in the presence of the (S)-VAPOL catalyst. Also, the cis-aziridine 143b can be obtained in the presence of the (R)-VAPOL catalyst with >99 % diastereomeric excess (Table 4.6 entries 1 and 2). Table 4.6 Multi-component aziridination reaction of Garner’s aldehyde (S)-147 in the presence a of a chiral boroxinate catalyst 1) Ar Ar NH 2 66 Boc O Ligand (10 mol%) B(OPh) 3 (30 mol%) toluene 80 °C, 0.5 h N CHO (S)-147 (1.1 equiv) 4 Å MS, –10 ºC 2) EDA (11) (1.2 equiv) –10 ºC, 24 h N O Boc N Ar Ar + COOEt 143a 215 N O Boc Ar N Ar COOEt 143b Table 4.6 (cont’d) entry Ar ligand dr 143a:143b c % yield 143a:143b 1 (S)-VAPOL 99.4:0.6(99.5:0.5) 70 2 (R)-VAPOL 0.3:99.7(0.3:99.7) b 60 OMe a Unless otherwise specified, all reactions were performed with 0.2 mmol amine 66 (0.4 M in toluene) and 1.1 equiv of (S)-147 and 1.2 equiv EDA 11 and went to 100% completion. Before adding the aldehyde and the EDA 11, a solution of amine 66 with 10 mol% ligand and 30 mol% commercial B(OPh)3 was stirred for 30 min at 80 °C under nitrogen. b Isolated combined yield c of 143a and 143b after chromatography on neutral alumina. Determined on a sample prepared by passing the crude reaction mixture through a silica plug. Determined by HPLC on PIRKLE COVALENT (R, R) WHELK-O1 column. Diastereomeric ratio in parentheses is for purified inseparable mixture of 143a and 143b and was determined by HPLC on PIRKLE COVALENT (R, R) WHELK-O1 column. 4.9 Aziridination reaction with aziridine 2-carboxaldehyde (S, S)-148: a catalyst controlled reaction The polyaziridines are of interest because it might be possible that they could participate in an aziridine cascadein mucg the same way that polyepoxides can be involved in epoxide cascades. 10 Access to polyaziridines can be thought to be possible by employing aziridine 216 carboxaldehydes in the aziridination reaction. The aziridine carboxaldehyde (S,S)-148 can be synthesized from aziridine-2-carboxylate (S,S)-37h by DIBAL-H reduction (Scheme 4.9). Scheme 4.9 Synthesis of aziridine 2-carboxaldehyde (S,S)-148 Ar Ar Ar DIBAL-H N N Et2O, –78 ºC COOEt (S,S)-37h Ar Ar CHO (S,S)-148 70% yield OMe The aziridine carboxaldehyde (S,S)-148 produces the diaziridine 149a with 99% diastereomeric excess in the presence of the (S)-VAPOL catalyst and 149b with 99% diastereomeric excess in the presence of the (R)-VAPOL catalyst with excellent yields (Table 4.7, entries 1 and 2). Table 4.7 Multi-component aziridination reaction of aziridine 2-carboxaldehyde (S,S)-148 in the a presence of a chiral boroxinate catalyst 1) Ar Ar N Ar Ar NH 2 66 Ligand (10 mol%) B(OPh) 3 (30 mol%) toluene 80 °C, 0.5 h nPr CHO (S,S)-148 (1.1 equiv) 4 Å MS, –10 ºC 2) Ar Ar Ar Ar N N nPr EDA (11) (1.2 equiv) –10 ºC, 24 h Ar + COOEt 149a 217 Ar Ar N N Ar nPr COOEt 149b Table 4.7 (cont’d) entry Ar 1 2 a ligand dr 149a:149b c % yield 149a:149b (S)-VAPOL OMe >99:1 (>99:1) 84 (R)-VAPOL <1:>99 (<1:>99) b 80 Unless otherwise specified, all reactions were performed with 0.2 mmol amine 66 (0.4 M in toluene) and 1.1 equiv of (S,S)-148 and 1.2 equiv EDA 11 and went to 100% completion. Before adding the aldehyde and the EDA 11, a solution of amine 66 with 10 mol% ligand and 30 mol% commercial B(OPh)3 was stirred for 30 min at 80 °C under nitrogen. b Isolated combined yield c of 149a and 149b after chromatography on neutral alumina. Determined on a sample prepared by passing the crude reaction mixture through a silica plug. Determined by HPLC on PIRKLE COVALENT (R, R) WHELK-O1 column. Diastereomeric ratio in parentheses is for purified inseparable mixture of 149a and 149b and was determined by HPLC on PIRKLE COVALENT (R, R) WHELK-O1 column. 4.10 Aziridination reaction with 2-phenylpropanal (S)-150: The problem of racemization of the corresponding intermediate imine (S)-152 and its solution In all of the above cases no racemization of the α- chiral center was observed during the multi-component aziridination reaction. However, in the case of 2-phenylpropanal (S)-150, a substantial amount of racemization was observed during the reaction. The multi-component aziridination reaction with (S)-150 resulted in all four possible stereoisomers of the cis-aziridine 218 product (Table 4.8). Interestingly the extent of racemization was found to be largely dependent on the concentration of the reaction mixture. The aziridination reaction of intermediate imine (S)-152 in the presence of the (S)-VAPOL catalyst should result in the cis-aziridine 151a and similarly (R)-152 should give the cis-aziridine ent-151b. Due to the racemization of the imine (S)-152, the reaction in the presence of the (S)VAPOL catalyst would result a substantial amount of aziridine ent-151b that would decrease the diastereomeric ratio, since 151a and ent-151b have diastereomeric relationship. In all the cases, the reaction of (S)-152, in the presence of the (S)-VAPOL catalyst results in 151a, as the major diastereomer and ent-151b as the minor diastereomer (Table 4.8, entries 1-5). Although the imine (S)-152 cannot be observed, it is considered to be forming in-situ in the reaction. The ee of the imine (S)-152 can be calculated by 100*[(r-1)/(r+1)] where r = (151a+151b)/(ent151a+ent-151b) Table 4.8 Multi-component aziridination reaction of 2-phenylpropanal (S)-150 in the presence of a a chiral boroxinate catalyst Ligand (10 mol%) Ar Ar NH2 66 1) EDA (11) (1.2 equiv) (30 mol%) 4 Å MS, temp toluene 80 °C, 0.5 h 2) CH3 Ph N CHO Ar + Ph Ph Ar Ar N ent-151b 219 Ar CH3 Ar + COOEt (S)-152 Ar 151b Ar CH3 N COOEt 151a (S)-150 (1.1 equiv) Ar CH3 COOEt temp, 24 h N Ph CH3 Ph Ar = 3,5-Me2-4-OMe-C6H2 Ar CH3 B(OPh)3 Ph N Ar COOEt ent-151a Table 4.8 (cont’d) entry ligand 1 (S)-VAPOL 25 2 (S)-VAPOL 3 e % ee b 151a % ee b 151b % ee (S)c 152 %yield 0.4 dr (151a+ent151a:151b+e nt-151b) 9:1 95 –83 77 –10 0.4 11:1 96.4 –86 81 85 (S)-VAPOL –10 0.1 13.5:1 96.4 –81 85 95 4 (S)-VAPOL –10 0.04 24:1 99 –80 91.4 92 5 (S)-VAPOL –10 0.01 23:1 99.2 –59 92 90 6 (R)-VAPOL –10 0.4 1:3.5 –35 99.5 69 90 7 (R)-VAPOL –10 0.04 1:5 43 99.9 93 90 f (R)-VAPOL –10 0.4 11:1 –95.6 83 –80 a d 85 87 8 temp Conc. (ºC) (‘C’ M) Unless otherwise specified, all reactions were performed with 0.2 mmol amine 66 (‘C’ M in toluene) and 1.1 equiv of (S)-150 and 4.0 equiv EDA 11 and went to 100% completion. Before adding the aldehyde and the EDA 11, a solution of amine 66 with 10 mol% ligand and 30 mol% commercial B(OPh)3 was stirred for 30 min at 80 °C under nitrogen. b Determined on a sample prepared by passing the crude reaction mixture through a silica plug. Determined by HPLC on PIRKLE COVALENT (R, R) WHELK-O1 column. c Determined on a sample prepared by passing the crude reaction mixture through a silica plug. Determined by HPLC on PIRKLE COVALENT (R, R) WHELK-O1 column. % ee of the imine (S)-152 = 100*[(r-1)/(r+1)] where r = (151a+151b)/(ent-151a+ent-151b). d Isolated combined yield of 151a and 151b after 220 Table 4.8 (cont’d) chromatography on neutral alumina. 1 e The diastereomeric ratio was determined both from the H NMR spectrum and HPLC spectrum of crude reaction mixture and the value was comparable with the HPLC data. From HPLC the calculated dr was as follows: dr = (151a+ent-151a): (151b+ent-151b). f the reaction was performed with (R)-150. At 0.4 M (in 66) concentration, both the diastereoselection and the extent of racemization were found to be independent of temperature (room temperature vs –10 ºC, entry 1 vs 2). However, the diastereomeric ratio of 151a to 151b (including the corresponding enantiomers) increases from 11:1 to ~14:1 (Table 4.8, entry 3) when the reaction mixture was diluted from 0.4 M to 0.1 M concentration. Further, dilution of the reaction mixture to 0.04 M concentration resulted in a diastereomeric ratio of 151a to 151b (including the corresponding enantiomers) of 24:1 (Table 4.8, entry 4). This resulted in the formation of aziridine 151a with 99% ee, ent-151b with 80% ee and from these results the imine (S)-152 is calculated to have 91.4% ee. No further improvement was obtained on diluting the reaction mixture to 0.01 M in 66 (entry 5 vs. entry 4). The aziridination reaction of (S)-150 in the presence of the (R)-VAPOL catalyst results in the maximum racemization of the intermediate imine (S)-152. The reaction resulted in the formation of aziridine 151b with 99.5% ee and ent-151a with 35% ee as the major diastereomers. The diastereomeric ratio of 151a to 151b (including the corresponding enantiomers) is calculated to be 1:3.5 (entry 6). The dilution shows similar effect on the racemization of in situ formed imine (S)-152 when aziridination reaction was performed with (R)-VAPOL derived catalyst at 0.04 M concentration (entry7). The diastereomeric ratio of 151a to 151b (including the corresponding 221 enantiomers) is calculated to be 1:5 (Table 4.8, entry 7). The reaction resulted aziridine 151a with 43% ee, 151b with 99.9% ee and from these results the imine (S)-152 is calculated to have 93% ee. The HPLC standard sample was prepared by reacting the aldehyde (R)-150 with EDA in the presence of (R)-VAPOL derived catalyst (entry 8). The reaction resulted aziridine ent151a with 95.6% ee, 151b with 83% ee and from these results the imine (R)-152 is calculated to have 80% ee. The aziridination reactions with (S)-150 in the presence of (S)-VAPOL derived catalyst resulted in better diastereoselectivity. The fact is in well agreement with the model explained in Figure 4.2, where RL = Ph, RM = CH3 and RS = H. Based on the above discussion, it seems like the rate of racemization of imine (S)-152 decreases with a decrease in concentration of the reaction mixture. This could possibly due to the fact that aziridination reaction and racemization are first and second order reaction respectively, with respect to the imine (S)-152. Hence, there would be a greater impact of dilution on the racemization as compared to the aziridination reaction. 4.11 Aziridination reaction of chiral aldehydes with a β-chiral center: catalyst controlled reaction Interestingly, there was no racemization observed of the β-chiral center in the aziridination reaction with 3-phenylbutanal (S)-155 and 3-((tert-butyldimethylsilyl)oxy)butanal (R)-159. Both aldehydes were found to react under a catalyst controlled process. The 3-phenylbutanal (S)-155 was synthesized by reducing the methyl 3-phenylbutanoate (S)-154 with DIBAL-H (Scheme 4.10). The methyl 3-phenylbutanoate (S)-154 was obtained by methylation of 3-phenylbutanoic acid (S)-153 with trimethylsilyldiazomethane. 222 Scheme 4.10 Synthesis of 3-phenylbutanal (S)-155 COOH Ph TMSCHN2 MeOH (S)-153 Ph DIBAL-H CO2Me Et2O, –78 ºC Ph CHO (S)-155 75% yield (S)-154 94% yield Protection of the hydxoxy group in the ethyl 3-hydroxybutanoate (R)-134 with tertbutyldimethylsilyl group followed by reduction of ethyl ester (R)-135 afforded the corresponding 3-((tert-butyldimethylsilyl)oxy)butanal (R)-136 (Scheme 4.11). Scheme 4.11 Synthesis of 3-((tert-butyldimethylsilyl)oxy)butanal (R)-136 OH CO2Et (R)-157 TBSCl imidazole DMF, rt, 16 h OTBS CO2Et DIBAL-H OTBS CHO Et2O, –78 ºC (R)-158 85% yield (R)-159 80% yield According to the model described in Figure 4.2, the aziridination reaction with (S)-155 and (R)-159 should result in better diastereoselectivity in the presence of the (R)-VAPOL derived catalyst, the same observations were made when the respective reactions were performed. The aziridination reaction with aldehyde (R)-155, MEDAM amine 66 and EDA 11 in the presence of 10 mol% (S)-VAPOL boroxinate catalyst resulted in aziridines 156a and 156b with a 94:6 diastereomeric ratio in 80% yield at –10 ºC (Table 4.9, entry 1). The reaction in the presence of the (R)-VAPOL derived catalyst resulted in aziridine 156b as the major product. 223 The (R)-VAPOL catalyst resulted mixture of 156a and 156b with a diastereomeric ratio of <1:>99 and in 85% combined yield (Table 4.9, entry 2). Table 4.9 Multi-component aziridination reaction of 3-phenylbutanal (S)-155 in the presence of a chiral boroxinate catalyst: a catalyst controlled case a 1) Ar Ar NH 2 toluene 80 °C, 0.5 h 66 entry CHO Ph (S)-155 (1.1 equiv) 4 Å MS, –10 ºC Ph Ligand (10 mol%) B(OPh) 3 (30 mol%) Ar 1 2) Ar N EDA (11) (1.2 equiv) –10 ºC, 24 h Ar Ar + Ph N COOEt 156a ligand dr 156a:156b COOEt 156b c % yield 156a:156b (S)-VAPOL 94:6(94:6) <1:>99 (1:99) b 80 (R)-VAPOL 2 Ar 85 OMe a Unless otherwise specified, all reactions were performed with 0.2 mmol amine 66 (0.4 M in toluene) and 1.1 equiv of (S)-155 and 1.2 equiv EDA 11 and went to 100% completion. Before adding the aldehyde and the EDA 11, a solution of amine 66 with 10 mol% ligand and 30 mol% B(OPh)3 was stirred for 30 min at 80 °C under nitrogen. 156b after chromatography on neutral alumina. c b Isolated combined yield of 156a and Determined on a sample prepared by passing the crude reaction mixture through a silica plug. Determined by HPLC on PIRKLE 224 Table 4.9 (cont’d) COVALENT (R, R) WHELK-O1 column. Diastereomeric ratio in parentheses is for purified inseparable mixture of 156a and 156b and was determined by HPLC on PIRKLE COVALENT (R, R) WHELK-O1 column. In a similar catalyst controlled reaction, the aldehyde (R)-159, in the presence of the (S)VAPOL catalyst resulted in aziridines 160a and 160b in a 98:2 diastereomeic ratio and in 83% yield (Table 4.10, entry 1). The reaction with the same aldehyde (R)-159 in the presence of the (R)-VAPOL catalyst resulted in aziridines 160a and 160b in a 1:99 diastereomeic ratio and in 85% yield (Table 4.10, entry 2). Table 4.10 Multi-component aziridination reaction of aldehyde (R)-159 in the presence of a chiral boroxinate catalyst: a catalyst controlled case 1) Ligand (10 mol%) Ar Ar NH2 66 OTBS CHO (S)-159 (1.1 equiv) B(OPh)3 Ar 4 Å MS, –10 ºC (30 mol%) toluene 80 °C, 0.5 h 2) N Ar Ar Ar + OTBS EDA (11) N Ar OTBS COOEt COOEt (1.2 equiv) 160a –10 ºC, 24 h entry a ligand dr 160a:160b 160b c % yield 160a:160b 1 (S)-VAPOL 98:2(97:3) 83 2 (R)-VAPOL 1:99 (1:99) 85 OMe 225 b Table 4.10 (cont’d) a Unless otherwise specified, all reactions were performed with 0.2 mmol amine 66 (0.4 M) and 1.1 equiv of (R)-159 and 1.2 equiv EDA 11 and went to 100% completion. Before adding the aldehyde and the EDA 11, a solution of amine 66 with 10 mol% ligand and 30 mol% B(OPh)3 was stirred for 30 min at 80 °C under nitrogen. after chromatography on neutral alumina. c b Isolated combined yield of 160a and 160b Determined on a sample prepared by passing the crude reaction mixture through a silica plug. Determined by HPLC on PIRKLE COVALENT (R, R) WHELK-O1 column. Diastereomeric ratio in parentheses is for purified inseparable mixture of 160a and 160b by HPLC on PIRKLE COVALENT (R, R) WHELK-O1 column. 4.12 Conclusions In this work we have realized that all chiral aldehydes but the cyclohexyl substituted aldehyde (R)-130a prefer to undergo a catalyst controlled doubly diastereoselective process, where the absolute stereochemistry of the newly formed stereocenters are the function of the catalyst and are independent on any pre-installed chiral centers present at the α- or β- position in the aldehyde. A variety of functional groups are well tolerated in this aziridination reaction, leading to the controlled synthesis of both diastereomers of complex molecules staring from the same substrate. This protocol has the potential to be used in the synthesis of natural and unnatural diastereomers of many natural products such as phytosphingosine (detailed discussion in Chapter 5), polyoxamic acid, manzacidin B, etc. Finally, this work adds to the not so common examples of catalyst controlled reaction in the field of organic synthesis. Many important catalytic asymmetric reactions do not offer high catalyst control over a broad range of substrates. 226 APPENDIX 227 4.13 Experimental procedure 4.13.1 General information Same as Chapter 2. 4.13.2 Synthesis of chiral aldehydes 4.13.1.1 Esterification of (R)-131a OH COOH (R)-131a OH EtI, CsF-Celite acetonitrile reflux, 8 h (R)-ethyl 2-cyclohexyl-2-hydroxyacetate 132a: 11 COOEt (R)132a To a 250 mL flame-dried round bottom flask equipped with a stir bar and a condenser with a rubber septum and a nitrogen balloon at the top, was added (R)-hexahydromandelic acid (R)-131a (0.80g, 5 mmol). Dry acetonitrile (120 mL) was added to dissolve the acid (R)-131a. Thereafter, CsF-celite (2.6 g) and iodoethane (0.8 mL, 12.5 mmol) was added. The flask was placed in an oil (185 ºC) bath and the reaction mixture was refluxed for 8 h. The flask was then allowed to cool to room temperature. The solvent was evaporated under reduced pressure and the residue was diluted with ethyl acetate (15 mL). The mixture was filtered through a Celite-pad to a 100 mL round bottom flask. The Celite-pad was washed with another 20 mL of ethyl acetate. The resulting solution was concentrated under reduced pressure followed by exposure to high vacuum (0.05 mm Hg) for 1 h to afford the crude ester (R)-132a as a light yellow solid. Purification of the crude ester by silica gel chromatography (30 mm×300 mm column, 20:1 hexanes/EtOAc as eluent, flash column) afforded pure ester (R)-132a as a white solid (mp 39–40 ºC) in 65 % isolated yield (605 mg, 3.25 mmol). 228 1 Spectral data for (R)-132a Rf = 0.34 (1:20 EtOAc / hexanes) H-NMR (500 MHz, CDCl3): δ 1.17-1.28 (m, 5H), 1.31 (t, J = 7.1 Hz, 3H), 1.44-1.45 (m, 1H), 1.64-1.79 (m, 5H), 2.65 (d, J = 6.3 Hz, 1H), 4.00 (dd, J = 6.2, 3.5 Hz, 1H), 4.25 (qd, J = 7.1, 1.3 Hz, 2H); 13 C-NMR (126 MHz, CDCl3) δ 14.26, 26.01, 26.05, 26.27, 26.34, 29.09, 42.01, 61.51, 74.82, 174.88. [α ]20 –17.8 (c D 12 1.54, CHCl3). Lit [α ]25 + 17.7 (c 1.54, CHCl3) on 100% ee material, for S-configuration. D € € 4.13.2.1 TBS protection of α-hydroxy ester (R)-132a OH COOEt OTBS TBSCl, imidazole COOEt DMF, rt, 12 h (R)-132a (R)-133a (R)-Ethyl 2-(tert-butyldimethylsilyloxy)-2-cyclohexylacetate (R)-133a: To a 25 mL flame dried round bottom flask equipped with stir bar and filled with nitrogen was added (R)-ethyl 2cyclohexyl-2-hydroxyacetate (R)-132a (0.5 g, 2.68 mmol). Dry DMF (15 mL, freshly distilled and stored on activated 4 Å MS) was added to dissolve the ester. The resulting solution was cooled to 0 ºC. To the reaction flask was added Imidazole (0.22g, 3.22 mmol, 1.2 equiv) and tert-butyldimethylsilylchloride (0.48g, 3.22 mmol, 1.2 equiv). The flask was fitted with a rubber septum and a nitrogen balloon. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted by addition of hexanes (15 mL). Thereafter, brine (10 mL) was added to the resulting mixture. The organic layer was separated, and the aqueous layer was extracted with hexanes (10 mL × 3). The combined organic layer was then dried over MgSO4 229 and concentrated under reduced pressure to afford the crude product (R)-133a as a colorless liquid. Purification of the crude by silica gel chromatography (30 mm×300 mm column, 100:1 hexanes/EtOAc as eluent, flash column) afforded pure ester (R)-133a as a colorless liquid in 85 % isolated yield (685 mg, 2.28 mmol). 1 Spectral data for (R)-133a: Rf = 0.68 (1:20 EtOAc / hexanes); H-NMR (500 MHz, CDCl3): δ 0.03 (s, 3H), 0.04 (s, 3H), 0.90 (s, 9H), 1.08-1.23 (m, 6H), 1.27 (t, J = 7.1 Hz, 3H), 1.53-1.55 (m, 1H), 1.62-1.74 (m, 5H), 3.93 (d, J = 5.2 Hz, 1H), 4.17 (qd, J = 7.1, 2.9 Hz, 2H); 13 C-NMR (126 MHz, CDCl3): δ –5.39, –5.01, 14.23, 18.26, 25.93, 26.12, 26.21, 27.42, 29.32, 42.38, 60.32, 76.81, (one Sp3 carbon not located), 173.41. 4.13.2.2 Synthesis of aldehyde (R)-130a OTBS COOEt OTBS DIBAL-H CHO THF, –78 ºC, 2 h (R)-133a (R)-130a (R)-2-(tert-butyldimethylsilyloxy)-2-cyclohexylacetaldehyde (R)-130a: To a 100 mL flame dried round bottom flask equipped with stir bar and filled with nitrogen was added (R)-133a (0.6 g, 2.0 mmol). Dry diethyl ether (10 mL) was added to dissolve the ester (R)-133a. The flask was fitted with a rubber septum and a nitrogen balloon. The solution was cooled to –78 ºC. To the reaction flask was added DIBAL-H (4 mL, 1 M solution in hexanes, 2 equiv) over a period of 2 minutes. The resulting reaction mixture was then stirred for 2 h at –78 °C. To the reaction was 230 added methanol and water mixture (0.5 mL, 1:1 v/v), followed by diethyl ether (10 mL) at –78 °C. The resulting mixture was allowed to warm to room temperature. Thereafter, saturated potassium sodium tartrate solution (10 mL) was added to the reaction flask. The resulting cloudy reaction mixture was stirred for 4 h at room temperature until clear biphasic mixture was obtained. The organic layer was separated and the aqueous layer was extracted with diethyl ether (10 mL × 3). The combined organic layer was washed with saturated brine solution (10 mL) then dried over MgSO4 and concentrated under reduced pressure to give the crude aldehyde (R)-130a as a colorless liquid. Purification of the crude by silica gel chromatography (20 mm × 300 mm column, 20:1 hexanes/Et2O as eluent, flash column) afforded pure aldehyde (R)-130a as a colorless liquid in 85 % isolated yield (0.40 g, 1.70 mmol). 1 Spectral data for (R)-130a: Rf = 0.31 (1:20 EtOAc / hexanes) H-NMR (500 MHz, CDCl3): δ 0.05 (s, 3H), 0.06 (s, 3H), 0.93 (s, 9H), 1.12-1.26 (m, 5H), 1.61-1.76 (m, 6H), 3.70 (dd, J = 5.1, 2.2 Hz, 1H), 9.59 (d, J = 2.2 Hz, 1H); 13 C-NMR (CDCl3, 126 MHz) δ –4.82, –4.34 18.45, 1 26.00, 26.20, 26.37, 26.43, 27.53, 29.23, 41.39, 82.01, 205.11. H-NMR and in good agreement with literature reported value. 4.13.2.3 13 13 Esterification of (R)-131b OH COOH (R)-131b OH EtI, CsF-Celite acetonitrile reflux, 8 h 231 COOEt (R)132b C-NMR data are (R)-ethyl 2-hydroxy-2-phenylacetate 110b: (R)-hexahydromandelic acid (R)-131b (760 mg, 5 mmol) was reacted according to the procedure described for the synthesis of ester (R)-131a above with CsF-celite (2.6 g) and iodoethane (0.8 mL, 12.5 mmol) in dry acetonitrile (120 mL). Purification of the crude ester by silica gel chromatography (30 mm×300 mm column, 4:1 hexanes/EtOAc as eluent, flash column) afforded pure ester (R)-132b as a white solid (mp 33–34 ºC) in 70 % isolated yield (631 mg, 3.5 mmol). 1 Spectral data for (R)-132b: Rf = 0.16 (1:4 EtOAc / hexanes) HNMR (300 MHz, CDCl3) δ 1.23 (t, J = 7.2 Hz, 3H), 3.51 (d, J = 6.0 Hz, 1H), 4.17-4.26 (m, 2H), 5.16 (d, J = 6.0 Hz, 1H), 7.337.44 (m, 5H); 13 CNMR (126 MHz, CDCl3) δ 13.92, 62.05, 72.82, 126.43, 128.21, 128.44, 138.34, 173.52; [α ]20 −135.3 (c 3.0, CHCl3); Lit [α ]20 −134 (c 3.0, CHCl3) (Sigma Aldrich). D D € 4.13.2.4 € TBS protection of α-hydroxy ester (R)-132b OH COOEt OTBS TBSCl, imidazole COOEt DMF, rt, 12 h (R)132b (R)133b (R)-ethyl 2-((tert-butyldimethylsilyl)oxy)-2-phenylacetate (R)-133b: The ester (R)-132b (901 mg, 5.0 mmol) was reacted according to the procedure described for the synthesis of (R)-133a above with Imidazole and tert-butyldimethylsilylchloride in dry DMF (15 mL). Purification of the crude ester by silica gel chromatography (30 mm×300 mm column, 50:1 hexanes/Et2O as eluent, flash column) afforded pure ester (R)-133b as a colorless liquid in 92 % isolated yield 232 (1.35 g, 4.6 mmol). 1 Spectral data for (R)-133b: Rf = 0.23 (3:1 hexanes / CH2Cl2); H NMR (300 MHz, CDCl3) δ 0.05 (s, 3H), 0.12 (s, 3H), 0.93 (s, 9H), 1.22 (t, J = 7.1 Hz, 3H), 4.15 (q, J = 7.1 Hz, 2H), 5.23 (s, 1H), 7.50 - 7.27 (m, 5H); 13 C NMR (75 MHz, CDCl3) –6.01, –5.88, 14.05, 18.33, 25.69, 61.00, 74.45, 126.30, 127.97, 128.24, 139.24, 172.13; [α ]20 –38.3 (c 1.50,CHCl3). Lit D 14 [α ]20 +38.8 D (c 1.52, CHCl3 S-isomer). 4.13.2.5 € Synthesis of aldehyde (R)-130b € OTBS OTBS DIBAL-H COOEt CHO THF, –78 ºC, 2 h (R)133b (R)130b (R)-2-((tert-butyldimethylsilyl)oxy)-2-phenylacetaldehyde (R)-130b: The ester (R)-133b (581 mg, 2.0 mmol) was reacted according to the procedure described for the synthesis of aldehyde (R)-130a above with DIBAL-H (4.0 mL, 1 M solution in hexanes, 2 equiv) in dry diethyl ether. Purification of the crude aldehyde by silica gel chromatography (30 mm×300 mm column, 25:1 hexanes / Et2O as eluent, flash column) afforded pure aldehyde (R)-130b as a colorless liquid in 85 % isolated yield (423 mg, 1.70 mmol). 1 Spectral data for (R)-130b: Rf = 0.35 (1:1 CH2Cl2 / hexanes); H-NMR (300 MHz, CDCl3): δ 0.04 (s, 3H), 0.12 (s, 3H), 0.95 (s, 9H), 5.01 (d, J = 2.1 Hz, 1H), 7.30-7.41 (m, 5H), 9.51 (d, J = 233 2.2 Hz, 1H); 13 C-NMR (126 MHz, CDCl3) δ -4.66, -4.54, 16.27, 25.71, 80.00, 126.40, 128.33, 128.69, 136.60, 199.40; [α ]20 –40.1 (c 0.600, ethanol). Lit D 4.13.2.6 15 [α ]22 –39.5° (c 0.612, ethanol). D TBS protection of α-hydroxy ester (S)-134 € € OH TBSCl, imidazole Me COOMe (S)-134 OTBS DMF, rt, 12 h Me COOMe (S)-135 (S)-methyl 2-((tert-butyldimethylsilyl)oxy)propanoate (S)-135: The (S)-methyl lactate (S)-134 (520 mg, 5.0 mmol) was reacted according to the procedure described for the synthesis of (R)133a above with Imidazole and tert-butyldimethylsilylchloride in dry DMF (15 mL). Purification of the crude ester by silica gel chromatography (30 mm×300 mm column, 100:1 hexanes/Et2O as eluent, flash column) afforded pure ester (S)-135 as a colorless liquid in 85% isolated yield (928 mg, 4.25 mmol). 1 Spectral data for (S)-135: Rf = 0.55 (1:9 EtOAc / hexanes; H-NMR (300 MHz, CDCl3): δ 0.07 (s, 3H), 0.10 (s, 3H), 0.90 (s, 9H), 1.40 (d, J = 6.7 Hz, 3H), 3.72 (s, 3H), 4.33 (q, J = 6.7 Hz, 1H); 13 C NMR (75 MHz, CDCl3): δ –5.02, –4.73, 18.51, 21.56, 25.91, 51.96, 68.50, 174.42; 16 [α ]20 –28.0 (c 0.900, CHCl3). Lit D € 4.13.2.7 [α ]26 –26.7 (c 0.860, CHCl3). D Synthesis of aldehyde (S)-130c € OTBS DIBAL-H Me COOMe (S)-135 THF, –78 ºC, 1 h 234 OTBS Me CHO (S)-130c (S)-2-((tert-butyldimethylsilyl)oxy)propanal (S)-130c: The ester (S)-135 (437 mg, 2.0 mmol) was reacted according to the procedure described for the synthesis of aldehyde (R)-130a above with DIBAL-H (4 mL, 1 M solution in hexanes, 2.0 equiv) in dry diethyl ether. Purification of the crude aldehyde by silica gel chromatography (20 mm×300 mm column, 50:1 hexanes/Et2O as eluent, flash column) afforded pure aldehyde (S)-130c as colorless liquid in 75 % isolated yield (282 mg, 1.5 mmol). 1 Spectral data for (S)-130c: Rf = 0.54 (1:6 EtOAc / hexanes) H-NMR (500 MHz, CDCl3): δ 0.09 (s, 3H), 0.11 (s, 3H), 0.92 (s, 9H), 1.28 (d, J = 6.8 Hz, 3H), 4.09 (qd, J = 6.8, 1.0 Hz, 1H), 9.61 (d, J = 1.0 Hz, 1H); 13 C-NMR (126 MHz, CDCl3): δ –4.91, –4.82, 18.22, 18.54, 25.69, 17 73.80, 204.21; [α ]20 +12.3 (c 1.96, CHCl3). Lit D € 4.13.2.8 [α ]25 +12.1 (c 1.96, CHCl3). D € Synthesis of aldehyde (R)-140 OH O NaIO4 on silica O OH O O O O CH2Cl2, rt, 2 h 142 CHO (R)-140 (R)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde (R)-140: To a solution of 1,2,5,6- diisopropylidene-(D)-mannitol 142 (5.0 g, 19.0 mmol) in dichloromethane (50 mL) were added NaIO4 on silica (8.0 g adsorbed on 20 g silica, 38.0 mmol, 2.0 equiv), and the mixture was stirred for 1.5 h (monitored by TLC) at room temperature under nitrogen atmosphere. The reaction mixture was filtered through Celite-pad to a 250 mL round bottom flask and the Celite- 235 pad was washed with dichloromethane (2 × 30 mL). Solvent was evaporated and the residue was purified by distillation under reduced pressure (26 °C, 9 mm Hg) to afford aldehyde (R)-140 as colorless oil in 90% yield (1.17 g, 9.0 mmol). Preparation of NaIO4 on silica gel: NaIO4 (8.0 g, 38.0 mmol) was dissolved in 10 mL of warm water (temp ~ 70 ºc) and 20 g silica gel was added to the solution. The mixture was stirred vigorously until the silica gel appeared to be free flowing. Spectral data for (R)-140: 1 H-NMR (300 MHz, CDCl3): δ 1.42 (s, 3H), 1.48 (s, 3H), 4.07-4.20 (m, 2H), 4.38 (ddd, J = 7.2, 5.0, 2.1 Hz, 1H), 9.72 (d, J = 1.9 Hz, 1H); 13 C-NMR (75 MHz, 8 CDCl3): δ 25.11, 26.22, 65.56, 79.82, 111.25, 201.80; [α ]20 + 53.8 (c 2.0, CHCl3). Lit [α ]20 D D + 53.8 (c 2.0, CHCl3). € 4.13.2.9 € Synthesis of aldehyde 148 Ar Ar Ar N CO2Et 37h 97% ee Ar DIBAL-H Ar N Et2O, –78 ºC 148 CHO OMe (2S,3S)-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-propylaziridine-2-carbaldehyde 148: The aziridine 2-carboxylate 37h (527 mg, 1.2 mmol) was reacted according to the procedure described for the synthesis of aldehyde (R)-130a above with DIBAL-H (2.4 mL, 1 M solution in hexanes, 1.2 equiv) in dry diethyl ether (4 mL) at –78 ºC. Purification of the crude aldehyde by silica gel chromatography (30 mm×300 mm column, 4:1 hexanes/Et2O as eluent, 236 flash column) afforded pure aldehyde 148 as a colorless liquid in 70 % isolated yield (332 mg, 0.84 mmol). 1 Spectral data for 148: Rf = 0.31 (2:1:0.2 hexanes/ CH2Cl2/ Et2O); H-NMR (500 MHz, CDCl3): δ 0.80 (t, J = 7.3 Hz, 3H), 1.12-1.18 (m, 1H), 1.22-1.29 (m, 1H), 1.50-1.57 (m, 1H), 1.63-1.70 (m, 1H), 2.11-2.20 (m, 2H), 2.25 (s, 6H), 2.29 (s, 6H), 3.49 (s, 1H), 3.70 (s, 3H), 3.71 (s, 3H), 7.03 (s, 2H), 7.06 (s, 2H), 9.44 (d, J = 5.6 Hz, 1H); 13 C-NMR (126 MHz, CDCl3): δ 13.51, 16.15, 16.19, 20.65, 31.34, 48.89, 49.86, 59.54, 59.60, 76.86, 127.26, 127.72, 130.63, 130.70, 137.42, 138.04, 156.02, 156.16, 201.03; IR (thin film) 2959vs, 2930vs, 1719s, 1483s, 1221s, + 1140s cm-1; HRMS (ESI-TOF) m/z 418.2343 [(M+Na ); calcd. for C25H34NO3 : 418.2358]; [α ]20 –85.0 (c 1.0, CH2Cl2). D € 4.13.2.10 Synthesis of (S)-2-phenylpropanal (S)-150 OH (S)-161 DMP CH2Cl2, rt, 30 min CHO (S)-150 (S)-2-phenylpropanal (S)-150: To a flame dried 25 mL round bottom flask flush with nitrogen and equipped with a stir bar was added the (S)-161 (149.8 µL, 1.1 mmol) and freshly distilled CH2Cl2 (5.5 mL). To the resulting clear solution was added Dess-Martin periodinane (560 mg, 1.32 mmol, 1.2 equiv). The turbid reaction mixture was stirred for 30 min at room temperature under nitrogen atmosphere. Thereafter, a buffer solution made from dissolving NaH2PO4 (262 237 mg) and Na2HPO4 (366 mg) in 2.5 mL water, was added to the reaction mixture. The resulting mixture was stirred for 5 min at room temperature. The turbid mixture was filtered through a Celite pad to a 100 mL round bottom flask. The reaction flask was washed with CH2Cl2 (3 × 10 mL) and passed through the same Celite pad. The resulting organic layer was washed with sat. aq. NaHCO3 (2× 10 mL) and then with brine (2 × 10 mL). The organic layer was dried over MgSO4 and the solvents were removed in vacuo. Purification of the crude by silica gel chromatography (20 mm×150 mm column, 9:1 hexanes/Et2O as eluent, flash column) afforded pure (S)-150 as a colorless liquid in 70 % isolated yield (103 mg, 0.77 mmol). 1 Spectral data for (S)-150: Rf = 0.14 (1:1 DCM / hexanes) H-NMR (500 MHz, CDCl3): δ 1.45 (d, J = 7.1 Hz, 3H), 3.64 (qd, J = 7.1, 1.3 Hz, 1H), 7.21-7.23 (m, 2H), 7.29-7.32 (m, 1H), 7.377.40 (m, 2H), 9.69 (d, J = 1.5 Hz, 1H); 13 C-NMR (126 MHz, CDCl3): δ 14.61, 53.02, 127.52, 128.30, 129.08, 137.76, 201.03; [α ]20 +290.0 (c 0.45, benzene) Lit D 18 [α ]20 +314.6 (c 0.45, D benzene) 4.13.2.11 € € Synthesis of (S)-methyl 3-phenylbutanoate (S)-154 COOH CO2Me TMSCHN2 MeOH (S)-153 (S)-154 238 (S)-methyl 3-phenylbutanoate (S)-154: To a 100 mL flame dried round bottom flask equipped with stir bar and filled with nitrogen was added (S)-3-phenylbutanoic acid (S)-153 (0.65 g, 4.0 mmol). Methanol (50 mL) was added to dissolve the acid (S)-154. The flask was fitted with a rubber septum and a nitrogen balloon. The solution was cooled to 0 ºC. To the reaction flask was added (trimethylsilyl)diazomethane (2 M in hexanes, 6 mL, 12.0 mmol) over a period of 2 minutes. The resulting mixture was warmed to room temperature and stirred for 1 h at room temperature. The reaction mixture was concentrated under reduced pressure. Purification of the crude methyl ester by silica gel chromatography (20 mm×150 mm column, 1:1 hexanes/Et2O as eluent, flash column) afforded pure ester (S)-154 as a colorless liquid in 94 % isolated yield (0.67 g, 3.76 mmol). 1 Spectral data for (S)-154: Rf = 0.21 (1:9 EtOAc / hexanes) H-NMR (500 MHz, CDCl3): δ 1.32 (d, J = 7.0 Hz, 3H), 2.57 (dd, J = 15.2, 8.2 Hz, 1H), 2.65 (dd, J = 15.2, 6.9 Hz, 1H), 3.30 (sextet, J = 7.3 Hz, 1H), 3.63 (s, 3H), 7.25-7.21 (m, 3H), 7.33-7.30 (m, 2H); 13 C-NMR (126 MHz, CDCl3): δ 21.69, 36.37, 42.66, 51.38, 126.33, 126.63, 128.43, 145.63, 172.73; [α ]20 +43.7, (c D 1.0, benzene). Reported for (R)-isomer [α ]20 −44, (c 1.0, benzene) (Sigma Aldrich). D € 4.13.2.12 Synthesis of (S)-3-phenylbutanal (S)-155 € CO2Me (S)-154 CHO DIBAL-H Et2O, –78 ºC 239 (S)-155 (S)-3-Phenylbutanal (S)-155: To a 100 mL flame dried round bottom flask equipped with stir bar and filled with nitrogen was added (S)-154 (0.58 g, 3.0 mmol). Dry diethyl ether (10 mL) was added to dissolve the ester (S)-154. The flask was fitted with a rubber septum and a nitrogen balloon. The solution was cooled to –78 ºC. To the reaction flask was added DIBAL-H (6 mL, 1 M solution in hexanes) over a period of 2 minutes. The resulting reaction mixture was then stirred for 1 h at –78 °C. To the reaction was added methanol and water mixture (1.0 mL, 1:1 v/v), followed by diethyl ether (15 mL) at –78 °C. The resulting mixture was allowed to warm to room temperature. Thereafter, saturated potassium sodium tartrate solution (15 mL) was added to the reaction flask. The resulting cloudy reaction mixture was stirred for 4 h at room temperature until clear biphasic mixture was obtained. The organic layer was separated and the aqueous layer was extracted with diethyl ether (15 mL × 3). The combined organic layer was washed with saturated brine solution (10 mL) then dried over MgSO4 and concentrated under reduced pressure to give the crude aldehyde (S)-155 as a colorless liquid. Purification of the crude by silica gel chromatography (20 mm × 300 mm column, 50:1 hexanes/Et2O as eluent, flash column) afforded pure aldehyde (S)-155 as a colorless liquid in 75 % isolated yield (333 g, 2.25 mmol). 1 Spectral data for (S)-155: Rf = 0.31 (1:6 Et2O / hexanes); H-NMR (500 MHz, CDCl3): δ 1.33 (d, J = 7.0 Hz, 3H), 2.66 (ddd, J = 16.6, 7.7, 2.2 Hz, 1H), 2.76 (ddd, J = 16.6, 6.8, 1.8 Hz, 1H), 3.36 (dt, J = 14.3, 7.1 Hz, 1H), 7.22-7.24 (m, 3H), 7.30-7.33 (m, 2H), 9.71 (t, J = 2.0 Hz, 1H); 13 C-NMR (126 MHz, CDCl3): δ 22.13, 34.28, 51.70, 126.50, 126.72, 128.64, 145.42, 201.80; 19 [α ]20 –39.5 (c 0.2, Et2O). Lit D € [α ]25 –38.0 (c 0.2, Et2O). D € 240 4.13.2.13 Synthesis of ester (R)-158 OH OTBS COOEt TBSCl, imidazole COOEt DMF, rt, 16 h (R)-157 (R)-158 (R)-Ethyl 3-((tert-butyldimethylsilyl)oxy)butanoate (R)-158: The ester (R)-157 (0.90 mL, 7.0 mmol) was reacted according to the procedure described for the synthesis of (R)-133a above with Imidazole (0.72g, 10.5 mmol, 1.5 equiv) and tert-butyldimethylsilylchloride (1.60 g, 10.5 mmol, 1.5 equiv) in dry DMF (15 mL). Purification of the crude ester by silica gel chromatography (30 mm×300 mm column, 50:1 hexanes/Et2O as eluent, flash column) afforded pure ester (R)-158 as a colorless liquid in 85 % isolated yield (1.47 g, 5.95 mmol). 1 Spectral data for (R)-158 Rf = 0.31 (1:20 EtOAc / hexanes); H-NMR (500 MHz, CDCl3): δ 0.01 (s, 3H), 0.03 (s, 3H), 0.83 (s, 9H), 1.16 (d, J = 6.1 Hz, 3H), 1.23 (t, J = 7.1 Hz, 3H), 2.43 (dd, J = 14.5, 7.6 Hz, 1H), 2.43 (dd, J = 14.5, 7.6 Hz, 1H), 4.14-4.05 (m, 2H), 4.28-4.22 (m, 1H); 13 C- NMR (126 MHz, CDCl3): δ –5.08, –4.56, 14.15, 17.90, 23.88, 25.69, 44.93, 60.16, 65.81, 20 171.54; [α ]20 –26.3 (c 1.0, CH2Cl2). Lit D € 4.13.2.14 [α ]25 –25.5 (c 1.0, CH2Cl2). D € Synthesis of aldehyde (R)-159 OTBS COOEt (R)-158 DIBAL-H Et2O, –78 ºC 241 OTBS CHO (R)-159 (R)-3-((tert-butyldimethylsilyl)oxy)butanal (R)-159: The ester (R)-158 (0.49 g, 2.0 mmol) was reacted according to the procedure described for the synthesis of aldehyde (S)-155 above with DIBAL-H (4 mL, 1 M solution in hexanes, 2.0 equiv) in dry diethyl ether (7 mL) at –78 ºC. Purification of the crude aldehyde 136 by silica gel chromatography (30 mm×300 mm column, 25:1 hexanes//Et2O as eluent, flash column) afforded pure aldehyde (R)-159 as a colorless liquid in 80 % isolated yield (0.32 g, 1.6 mmol). 1 Spectral data for (R)-159: Rf = 0.41 (1:1 CH2Cl2 / hexanes); H-NMR (300 MHz, CDCl3): δ 0.02 (s, 3H), 0.04 (s, 3H), 0.83 (s, 9H), 1.19 (d, J = 6.2 Hz, 3H), 2.38-2.55 (m, 2H), 4.32 (sextet, J = 6.0 Hz, 1H), 9.75 (t, J = 2.3 Hz, 1H); 13 C-NMR (126 MHz, CDCl3): δ –5.03, –4.47, 17.87, 20 24.08, 25.65, 52.90, 64.48, 202.02; [α ]20 –11.6 (c 1.0, CH2Cl2). Lit D [α ]25 –11.3 (c 1.0, D CH2Cl2). € € 4.13.3 Synthesis of chiral imine (R)-129a OTBS CHO + (R)-130a MEDAM NH2 4 Å MS OTBS N MEDAM toluene, rt, 12 h 66 (R)-129a not purified (R,E)-N-(2-((tert-butyldimethylsilyl)oxy)-2-cyclohexylethylidene)-1,1-bis(4-methoxy-3,5dimethylphenyl)methanamine (R)-129a: To a 50 mL flame-dried round bottom flask filled with argon was added bis(4-methoxy-3,5-dimethylphenyl)methanamine 66 (1.25 g, 4.17 mmol), 4Å MS (4 g, freshly dried) and dried toluene (15 mL). After stirring for 10 min, aldehyde (R)130a (1.12 mg, 4.38 mmol, 1.05 equiv) was added. The reaction mixture was stirred at room 242 temperature for 12 h. The reaction mixture was filtered through Celite pad to a 100 mL round bottom flask. The reaction flask was rinsed with ether (2 × 20 mL) and the rinse was filtered through the same Celite pad. The resulting solution was then concentrated in vacuo followed by exposure to high vacuum (0.05 mm Hg) for 4 h to afford the crude imine as colorless viscous oil. The resulting imine (R)-129a was used without further purification. Spectral data for (R)-129a: 1 H-NMR (300 MHz, CDCl3): δ –0.14 (s, 3H), –0.01 (s, 3H), 0.82 (s, 9H), 0.97-1.26 (m, 6H), 1.58-1.84 (m, 5H), 2.23 (s, 6H), 2.24 (s, 6H), 3.68 (s, 3H), 3.70 (s, 3H), 3.96 (t, J = 6.2 Hz, 1H), 5.17 (s, 1H), 6.88 (s, 2H), 6.90 (s, 2H), 7.55 (d, J = 6.2 Hz, 1H); 13 C-NMR (126 MHz, CDCl3): δ –4.88, –4.45, 16.08, 16.13, 18.12, 25.79, 26.06, 26.13, 26.49, 28.18, 28.85, 43.07, 59.59, 59.62, 76.91, 78.71, 127.12, 127.81, 128.19, 130.48, 138.36, 138.66, 155.73, 155.87, 166.82. 4.13.4 Asymmetric catalytic aziridination of imine (R)-129a (Procedure A) OTBS N (R)-VAPOL borate catalyst (5 mol%) O P + (R)-129a OEt N2 11 toluene, 25 ºC, 24 h OTBS N 136a OTBS P + COOEt N P COOEt 136b P = MEDAM (2S, 3R)-Ethyl 1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-((R)-((tertbutyldimethylsilyl)oxy) (cyclohexyl)methyl)aziridine-2-carboxylate 136b: To a 10 mL flame-dried home-made Schlenk flask, prepared from a single necked 25 mL pearshaped flask that had its 14/20 glass joint replaced with a high vacuum threaded Teflon valve, 243 flushed with argon was added (S)-VAPOL (14 mg, 0.025 mmol, 5 mol%) and B(OPh)3 (29 mg, 0.100 mmol, 20 mol%). Under an argon flow, dry toluene (2 mL) was added to dissolve the two reagents. The flask was sealed, and then placed in an 80 ºC for 1 h. After 1 hour, a vacuum (0.5 mm Hg) was applied carefully to remove the volatiles. The vacuum is maintained for a period of 30 min at a temperature of 80 ºC. The flask was then filled with argon and the catalyst mixture was cooled to room temperature. The solution of imine (R)-129a (0.5 mmol, crude) in dry toluene (1.0 mL) was then transferred to the flask containing the catalyst. The reaction mixture was stirred for 5 min at room temperature to give a light orange solution. To this solution was rapidly added EDA 11 (62 µL, 0.6 mmol, 1.2 equiv) and the resulting mixture was stirred for 24 h at room temperature. The reaction was diluted by addition of hexane (6 mL). The reaction mixture was then filtered through a silica gel plug to a 100 mL round bottom flask. The reaction flask was rinsed with EtOAc (20 mL × 3) and the rinse was filtered through the same silica gel plug. The resulting solution was then concentrated in vacuo followed by exposure to high vacuum (0.05 mm Hg) for 1 h to afford the crude aziridine as yellow colored viscous oil. Purification of the crude aziridine by neutral alumina chromatography (30 mm × 150 mm column, 4:2:0.1 hexanes/CH2Cl2/Et2O as eluent, gravity column) afforded inseparable mixture of aziridines 136b and 136a as a white solid (mp 48-50 ºC on > 99:1 dr material) in 80 % isolated yield (250 mg, 0.4 mmol). The diastereomeric ratio of 136b and 136a was determined to be 94.7:5.3 by HPLC analysis of crude reaction mixture (PIRKLE COVALENT (R, R) WHELK-O 1 column, 99.5:0.5 hexane/2-propanol at 222nm, flow-rate: 0.7 mL/min): retention times; Rt = 10.73 min (minor diastereomer, 136a) and Rt = 13.51 min (major diastereomer, 136b). 244 Imine (R)-129a was reacted according to the general Procedure A described above with (R)-VANOL as ligand to afford aziridines 136b and 136a with 8:1 diastereomeric ratio. Purification of the crude aziridine by neutral alumina chromatography (20 mm × 150 mm column, 4:2:0.1 hexanes/CH2Cl2/Et2O as eluent, gravity column) afforded inseparable mixture of aziridines 136a and 136b as a white solid in 85 % isolated yield (265 mg, 0.425 mmol). OTBS N (S)-VAPOL borate catalyst (10 mol%) O P + (R)-129a OEt N2 11 toluene, 25 ºC, 24 h OTBS N 136a OTBS P N + COOEt P COOEt 136b P = MEDAM Imine (R)-129a was reacted according to the general Procedure A described above with (S)VAPOL as ligand to afford aziridines 136a and 136b with 2:1 diastereomeric ratio. Purification of the crude aziridine by neutral alumina chromatography (20 mm × 150 mm column, 4:2:0.1 hexanes/CH2Cl2/Et2O as eluent, gravity column) afforded inseparable mixture of aziridines 136a and 136b as a viscous liquid in 30 % isolated yield (94 mg, 0.15 mmol). Imine (R)-129a was reacted according to the general Procedure A described above with (S)-VANOL as ligand to afford aziridines 136a and 136b with 2:1 diastereomeric ratio. Purification of the crude aziridine by neutral alumina chromatography (20 mm × 150 mm column, 4:2:0.1 hexanes/CH2Cl2/Et2O as eluent, gravity column) afforded inseparable mixture of aziridines 136a and 136b as a white solid in 40 % isolated yield (126 mg, 0.20 mmol). 245 4.13.5 Asymmetric catalytic multi-component aziridination reaction of aldehyde (R)-130a in presence of chiral catalyst (Procedure B) 4.13.5.1 Multi-component aziridination reaction of aldehyde (R)-130a and MEDAM amine 66 in presence of (R)-ligand (VAPOL/VANOL) 1) 4 Å MS 2) OTBS CHO (R)-VAPOL (10 mol%) MEDAM NH2 66 B(OPh)3 (30 mol%) toluene, 80 °C, 0.5 h OTBS (R)-130a (1.1 equiv) –10 ºC N 3) EDA (11) (1.2 equiv) OTBS MEDAM + N COOEt 136a MEDAM COOEt 136b (2S, 3R)-Ethyl 1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-((R)-((tertbutyldimethylsilyl)oxy) (cyclohexyl)methyl)aziridine-2-carboxylate 136b: To a 10 mL flame-dried home-made Schlenk flask, prepared from a singlenecked 25 mL pearshaped flask that had its 14/20 glass joint replaced with a high vacuum threaded Teflon valve, equipped with a stir bar and filled with argon was added (R)-VAPOL (11 mg, 0.02 mmol), B(OPh)3 (17 mg, 0.06 mmol) and amine 66 (60 mg, 0.2 mmol). Under an argon flow through the side arm of the Schlenk flask, dry toluene (0.5 mL) was added. The flask was sealed by closing the Teflon valve, and then placed in an oil bath (80 ºC) for 0.5 h. The flask was then allowed to cool to room temperature and open to argon through side arm of the Schlenk flask. To the flask containing the catalyst was added the 4Å Molecular Sieves (50 mg, freshly flamedried). The flask was then allowed to cool to –10 ºC and aldehyde (R)-130a (56.4 mg, 0.22 mmoL, 1.1 equiv) was added to the reaction mixture. To this solution was rapidly added ethyl 246 diazoacetate (EDA) 11 (25 µL, 0.24 mmoL, 1.2 equiv). The resulting mixture was stirred for 32 h at –10 ºC. The reaction was dilluted by addition of hexane (3 mL). The reaction mixture was then filtered through a silica gel plug to a 100 mL round bottom flask. The reaction flask was rinsed with EtOAc (10 mL × 3) and the rinse was filtered through the same silica gel plug. The resulting solution was then concentrated in vacuo followed by exposure to high vacuum (0.05 mm Hg) for 1 h to afford the crude aziridine as yellow colored viscous oil. Purification of the crude aziridine by neutral alumina chromatography (20 mm × 150 mm column, 4:2:0.1 hexanes/CH2Cl2/Et2O as eluent, gravity column) afforded inseparable mixture of aziridines 136b and 136a as a white solid (mp 48-50 ºC on 99:1 dr material) in 85 % isolated yield (106 mg, 0.17 mmol). The diastereomeric ratio of 136b and 136a was determined to be 94.7:5.3 by HPLC analysis of crude reaction mixture (PIRKLE COVALENT (R, R) WHELK-O 1 column, 99.5:0.5 hexane/2-propanol at 222nm, flow-rate: 0.7 mL/min): retention times; Rt = 10.73 min (minor diastereomer, 136a) and Rt = 13.51 min (major diastereomer, 136b). Aldehyde (R)-130a was reacted according to the general Procedure B described above with (R)-VANOL (9 mg, 0.02 mmol), as ligand to afford aziridines 136b and 136a with >99:1 diastereomeric ratio. Purification of the crude aziridine by neutral alumina chromatography (20 mm × 150 mm column, 4:2:0.1 hexanes/CH2Cl2/Et2O as eluent, gravity column) afforded inseparable mixture of aziridines 136b and 136a as a white solid in 80 % isolated yield (100 mg, 0.16 mmol). 1 Spectral data for 136b: Rf = 0.17 (4:1:0.2 hexanes/CH2Cl2/Et2O); H-NMR (300 MHz, CDCl3): 247 δ –0.30 (s, 3H), –0.03 (s, 3H), 0.72 (s, 9H), 0.98-1.18 (m, 6H), 1.28 (t, J = 7.1 Hz, 3H), 1.551.73 (m, 5H), 2.04 (d, J = 6.9 Hz, 1H), 2.21-2.25 (m, 13H), 3.52 (dd, J = 8.5, 3.8 Hz, 1H), 3.63 (s, 1H), 3.67 (s, 3H), 3.70 (s, 3H), 4.18 (qd, J = 7.1, 1.7 Hz, 2H), 6.92 (s, 2H), 6.96 (s, 2H); 13 C- NMR (151 MHz, CDCl3): δ –4.64, –4.40, 14.35, 16.16, 16.19, 17.96, 25.91, 26.57, 26.63, 26.65, 27.72, 28.78, 41.72, 44.05, 50.94, 59.39, 59.59, 60.63, 73.50, 76.97, 127.96, 129.05, 130.22, 130.34, 137.45, 137.63, 155.69, 156.04, 170.34; IR (thin film) 2930vs, 2855s, 1744s, 1483s, -1 + 1257s, 1221s, 1186vs, 1146vs, 1018vs cm ; HRMS (ESI-TOF) m/z 624.4054 [(M+H ); calcd. for C37H58NO5Si: 624.4084]; [α ]20 –90.4 (c 1.0, CH2Cl2) on >99:1 dr material (HPLC). D € 4.13.5.2 Multi-component aziridination reaction of aldehyde (R)-130a in presence of (S)-ligand (VAPOL/VANOL) 1) 4 Å MS 2) OTBS CHO (S)-VAPOL (10 mol%) MEDAM NH2 66 B(OPh)3 (30 mol%) toluene, 80 °C, 0.5 h OTBS (R)-130a (1.1 equiv) –10 ºC OTBS MEDAM N + 3) EDA (11) (1.2 equiv) –10 ºC N COOEt 136a MEDAM COOEt 136b Aldehyde (R)-130a was reacted according to the general Procedure B described above with (S)VAPOL as ligand to afford aziridines 136a and 136b with 1.1:1 diastereomeric ratio. Purification of the crude aziridine by neutral alumina chromatography (20 mm × 150 mm column, 4:2:0.1 hexanes/CH2Cl2/Et2O as eluent, gravity column) afforded inseparable mixture 248 of aziridines 136a and 136b as a white solid in 30 % isolated yield (37 mg, 0.06 mmol). Aldehyde (R)-130a was reacted according to the general Procedure B described above with (S)-VANOL as ligand to afford aziridines 136a and 136b with 1.5:1 diastereomeric ratio. Purification of the crude aziridine by neutral alumina chromatography (20 mm × 150 mm column, 4:2:0.1 hexanes/CH2Cl2/Et2O as eluent, gravity column) afforded inseparable mixture of aziridines 136a and 136b as a white solid in 15 % isolated yield (19 mg, 0.03 mmol). 1 Spectral data for 136a: Rf = 0.17 (4:1:0.2 hexanes/CH2Cl2/Et2O); H-NMR (300 MHz, CDCl3): δ –0.07 (s, 3H), –0.06 (s, 3H), 0.85 (s, 9H), 0.91-1.18 (m, 6H), 1.26 (t, J = 7.1 Hz, 3H), 1.571.86 (m, 5H), 2.14 (d, J = 6.4 Hz, 1H), 2.21-2.23 (m, 13H), 3.42 (s, 1H), 3.54 (d, J = 8.1 Hz, 1H), 3.67 (s, 3H), 3.68 (s, 3H), 4.05-4.31 (m, 2H), 7.03 (s, 4H); 13 C-NMR (126 MHz, CDCl3): δ –4.00, –3.50, 14.38, 16.17, 16.20, 18.03, 26.20, 26.62, 26.65, 27.65, 28.90, 29.57, 41.82, 44.09, 50.95, 59.38, 59.59, 60.66, 73.55, 77.02, 128.03, 129.05, 130.26, 130.38, 137.45, 137.65, 155.78, 156.09, 170.48. 4.13.5.3 Multi-component aziridination reaction of aldehyde (R)-130a and benzhydryl amine 137 in presence of (R)-VAPOL 1) 4 Å MS 2) OTBS Ph (R)-VAPOL (10 mol%) Ph NH2 137 B(OPh)3 (30 mol%) toluene, 80 °C, 0.5 h CHO (R)-130a (1.1 equiv) –10 ºC 3) EDA (11) (1.2 equiv) –10 ºC OTBS Ph N 249 N Ph + COOEt 136a' OTBS Ph Ph COOEt 136b' (2S, 3R)-Ethyl 1-benzhydryl-3-((R)-((tert-butyldimethylsilyl)oxy)(cyclohexyl)methyl) aziridine-2-carboxylate 136b': Aldehyde (R)-130a was reacted according to the general Procedure B described above with (R)VAPOL as ligand except the benzhydryl amine 137 (34.5 µL, 0.2 mmol) was used to afford aziridines 136b' and 136a' with >99:1 diastereomeric ratio. Purification of the crude aziridine by neutral alumina chromatography (20 mm × 150 mm column, 4:2:0.1 hexanes/CH2Cl2/Et2O as eluent, gravity column) afforded inseparable mixture of aziridines 136b' and 136a' as a white solid (mp 105-106 ºC on > 99:1 dr material) in 80 % isolated yield (81 mg, 0.16 mmol). 1 Spectral data for 136b': Rf = 0.32 (4:2:0.1 hexanes/CH2Cl2/Et2O); H-NMR (500 MHz, CDCl3): δ –0.21 (s, 3H), –0.02 (s, 3H), 0.75 (s, 9H), 0.99-1.18 (m, 5H), 1.26 (t, J = 7.1 Hz, 3H), 1.56-1.75 (m, 6H), 2.13 (d, J = 6.8 Hz, 1H), 2.28 (dd, J = 8.7, 6.8 Hz, 1H), 3.54 (dd, J = 8.7, 4.3 Hz, 1H), 4.03 (s, 1H), 4.11-4.24 (m, 2H), 7.17-7.37 (m, 10H); 13 C-NMR (126 MHz, CDCl3): δ –4.64, –4.03, 14.27, 18.11, 26.03, 26.55, 26.60, 26.64, 28.01, 28.46, 41.56, 44.08, 49.34, 60.69, 73.35, 76.61, 127.12, 127.18, 128.23, 128.26, 128.61, 141.36, 142.14, 170.05 (one Sp2 carbon -1 not located); IR (thin film) 2928vs, 2855s, 1745s, 1453s, 1190vs, 1065s cm ; HRMS (ESI-TOF) + m/z 508.3250 [(M+H ); calcd. for C31H46NO3Si: 508.3247]; [α ]20 –84.9 (c 1.0, CH2Cl2) on D >99:1 dr material (NMR). € 250 4.13.5.4 Multi-component aziridination reaction of aldehyde (R)-130a and benzhydryl amine 137 in presence of (S)-VAPOL 1) 4 Å MS 2) OTBS CHO Ph (S)-VAPOL (10 mol%) Ph (R)-130a (1.1 equiv) –10 ºC NH2 137 3) EDA (11) (1.2 equiv) –10 ºC, 32 h B(OPh)3 (30 mol%) toluene, 8 0 °C, 0.5 h OTBS N Ph Ph (R)-129a' unreacted imine Aldehyde (R)-130a was reacted according to the general Procedure B described above with (S)VAPOL as ligand except the benzhydryl amine 137 (34.5 µL, 0.2 mmol) was used. However, no aziridine was observed in this case. Instead, in situ formed imine (R)-129a' was observed. 1 Spectral data for (R)-129a': H-NMR (300MHz, CDCl3): δ –0.30 (3H, s), –0.16 (3H, s), 0.66 (9H, s), 0.82-1.12 (5H, m), 1.34-1.72 (6H, m), 3.83 (1H, t, J = 6.30 Hz), 5.24 (1H, s), 7.02 – 7.24 1 (10 H, m), 7.49 (1H, d, J = 6.30 Hz). ( H NMR data determined from the crude reaction mixture) 4.13.6 Asymmetric catalytic multi-component aziridination reaction of aldehyde (R)-130b in presence of chiral catalyst (Procedure B) 4.13.6.1 Multi-component aziridination reaction of aldehyde (R)-130b and MEDAM amine 66 in presence of (R)-ligand (VAPOL/VANOL) 251 1) 4 Å MS 2) OTBS CHO MEDAM NH2 66 (R)-VAPOL (10 mol%) B(OPh)3 (30 mol%) toluene, 80 °C, 0.5 h OTBS (R)-130b (1.1 equiv) –10 ºC N 3) EDA (11) (1.2 equiv) –10 ºC, 24 h OTBS MEDAM + N COOEt 138a MEDAM COOEt 138b (2S, 3R)-Ethyl 1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-((R)-((tertbutyldimethylsilyl) oxy)(phenyl)methyl)aziridine-2-carboxylate 138b: Aldehyde (R)-130b was reacted according to the general Procedure B described above with (R)VAPOL as ligand to afford aziridines 138b and 138a with 99:1 diastereomeric ratio. Purification of the crude aziridine by neutral alumina chromatography (20 mm × 150 mm column, 4:2:0.1 hexanes/CH2Cl2/Et2O as eluent, gravity column) afforded inseparable mixture of aziridines 138b and 138a as a white solid (mp 139-140 ºC on 99:1 dr material) in 90 % isolated yield (111 mg, 0.18 mmol). The diastereomeric ratio of 138b and 138a was determined to be 99:1 by HPLC analysis of crude reaction mixture (PIRKLE COVALENT (R, R) WHELK-O 1 column, 99:1 hexane/2propanol at 222nm, flow-rate: 0.7 mL/min): retention times; Rt = 8.49 min (minor diastereomer, 138a) and Rt = 17.92 min (major diastereomer, 138b). Aldehyde (R)-130b was reacted according to the general Procedure B described above 252 with (R)-VANOL (9 mg, 0.02 mmol), as ligand to afford aziridines 138b and 138a with 99:1 diastereomeric ratio. Purification of the crude aziridine by neutral alumina chromatography (20 mm × 150 mm column, 4:2:0.1 hexanes/CH2Cl2/Et2O as eluent, gravity column) afforded inseparable mixture of aziridines 138b and 138a as a white solid in 85 % isolated yield (105 mg, 0.17 mmol). 1 Spectral data for 138b: Rf = 0.23 (4:1:0.2 hexanes/CH2Cl2/Et2O); H-NMR (500 MHz, CDCl3): δ –0.26 (s, 3H), –0.23 (s, 3H), 0.60 (s, 9H), 1.17 (t, J = 7.1 Hz, 3H), 1.99 (d, J = 7.0 Hz, 1H), 2.23 (s, 6H), 2.26 (s, 6H), 2.43 (t, J = 7.5 Hz, 1H), 3.49 (s, 1H), 3.68 (s, 3H), 3.70 (s, 3H), 4.06 (dq, J = 10.8, 7.1 Hz, 1H), 4.14 (dq, J = 10.8, 7.1 Hz, 1H), 4.70 (d, J = 7.9 Hz, 1H), 7.05 (s, 4H), 7.21-7.28 (m, 5H); 13 C-NMR (126 MHz, CDCl3): δ –5.12, –5.07, 14.12, 16.17, 16.24, 17.84, 25.55, 41.68, 55.25, 59.40, 59.54, 60.63, 73.40, 77.65, 126.54, 127.23, 127.47, 128.03, 128.63, 130.35, 130.44, 137.97, 138.20, 142.67, 155.64, 156.15, 169.78; IR (thin film) 2955vs, 2928vs, -1 + 1742vs, 1483s, 1221s, 1188vs, 1140s cm ; HRMS (ESI-TOF) m/z 618.3631 [(M+H ); calcd. for C37H52NO5Si: 618.3615]; [α ]20 –92.6 (c 1.0, CH2Cl2) on 99:1 dr material (HPLC). D € 253 4.13.6.2 Multi-component aziridination reaction of aldehyde (R)-130b and MEDAM amine 66 in presence of (S)-ligand (VAPOL/VANOL) 1) 4 Å MS 2) OTBS CHO MEDAM NH2 66 (S)-VAPOL (10 mol%) B(OPh)3 (30 mol%) toluene, 80 °C, 0.5 h OTBS (R)-130b (1.1 equiv) –10 ºC N 3) EDA (11) (1.2 equiv) –10 ºC, 24 h OTBS MEDAM + N COOEt 138a MEDAM COOEt 138b (2R, 3S)-Ethyl 1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-((R)-((tertbutyldimethylsilyl) oxy)(phenyl)methyl)aziridine-2-carboxylate 138a: Aldehyde (R)-130b was reacted according to the general Procedure B described above with (S)VAPOL as ligand to afford aziridines 138a and 138b with 98:2 diastereomeric ratio. Purification of the crude aziridine by neutral alumina chromatography (20 mm × 150 mm column, 4:2:0.1 hexanes/CH2Cl2/Et2O as eluent, gravity column) afforded inseparable mixture of aziridines 138a and 138b as a white solid (mp 49-50 ºC on >99:1 dr material) in 90 % isolated yield (111 mg, 0.18 mmol). The diastereomeric ratio of 138a and 138b was determined to be 98:2 by HPLC analysis of crude reaction mixture (PIRKLE COVALENT (R, R) WHELK-O 1 column, 99:1 hexane/2-propanol at 222nm, flow-rate: 0.7 mL/min): retention times; Rt = 8.30 min (major diastereomer, 138a) and Rt = 18.48 min (minor diastereomer, 138b). 254 Aldehyde (R)-130b was reacted according to the general Procedure B described above with (S)-VANOL (9 mg, 0.02 mmol), as ligand to afford aziridines 138a and 138b with 98:2 diastereomeric ratio. Purification of the crude aziridine by neutral alumina chromatography (20 mm × 150 mm column, 4:2:0.1 hexanes/CH2Cl2/Et2O as eluent, gravity column) afforded inseparable mixture of aziridines 138a and 138b as a white solid in 85 % isolated yield (105 mg, 0.17 mmol). 1 Spectral data for 138a: Rf = 0.23 (4:1:0.2 hexanes/CH2Cl2/Et2O); H-NMR (600 MHz, CDCl3): δ –0.33 (s, 3H), –0.09 (s, 3H), 1.31 (t, J = 7.1 Hz, 3H), 0.79 (s, 9H), 2.01 (s, 6H), 2.21 (s, 6H), 2.28 (d, J = 6.4 Hz, 1H), 2.40 (dd, J = 8.2, 6.4 Hz, 1H), 3.32 (s, 1H), 3.59 (s, 3H), 3.67 (s, 3H), 4.16 (dq, J = 10.8, 7.2 Hz, 1H), 4.29 (dq, J = 10.8, 7.1 Hz, 1H), 4.61 (d, J = 8.2 Hz, 1H), 6.51 (s, 2H), 6.99 (s, 2H), 7.00-7.01 (m, 3H), 7.11 (dd, J = 6.6, 2.9 Hz, 2H); 13 C-NMR (151 MHz, CDCl3): δ 14.18, 15.25, 16.03, 16.13, 17.92, 25.63, 25.63, 42.92, 54.13, 59.25, 59.55, 60.82, 65.82, 72.33, 126.49, 126.91, 127.14, 127.23, 128.07, 129.69, 130.39, 136.99, 137.66, 142.32, -1 155.61, 155.63, 169.56; IR(thin film) 2955vs, 2930vs, 1742s, 1483s, 1221s, 1188vs, 1147s cm ; + HRMS (ESI-TOF) m/z 618.3641 [(M+H ); calcd. for C37H52NO5Si: 618.3615]; [α ]20 +107.0 D (c 1.0, CH2Cl2) on 99:1 dr material (HPLC). € 4.13.6.3 Multi-component aziridination reaction of aldehyde (R)-130b and benzhydryl amine 137 in presence of (R)-VAPOL 255 1) 4 Å MS 2) OTBS Ph (R)-VAPOL (10 mol%) Ph NH2 137 B(OPh)3 (30 mol%) toluene, 80 °C, 0.5 h CHO (R)-130b (1.1 equiv) –10 ºC 3) EDA (11) (1.2 equiv) –10 ºC, 24 h OTBS Ph N OTBS Ph Ph + N COOEt 138a' Ph COOEt 138b' (2S, 3R)-Ethyl 1-benzhydryl-3-((R)-((tert-butyldimethylsilyl)oxy)(phenyl)methyl)aziridine2-carboxylate 138b': Aldehyde (R)-130a was reacted according to the general Procedure B described above with (R)VAPOL as ligand except the benzhydryl amine 137 (34.5 µL, 0.2 mmol) was used to afford aziridines 138b' and 138a' with 17:1 diastereomeric ratio. Purification of the crude aziridine by neutral alumina chromatography (20 mm × 150 mm column, 4:2:0.1 hexanes/CH2Cl2/Et2O as eluent, gravity column) afforded inseparable mixture of aziridines 138b' and 138a' as a white solid (mp 93-97 ºC on 17:1 dr material) in 65 % isolated yield (65 mg, 0.13 mmol). The diastereomeric ratio of 139b' and 139a' was determined to be 17:1 by HPLC analysis of crude reaction mixture (PIRKLE COVALENT (R, R) WHELK-O 1 column, 99.5:0.5 hexane/2propanol at 222nm, flow-rate: 0.7 mL/min): retention times; Rt = 6.43 min (minor diastereomer, 139a') and Rt = 11.47 min (major diastereomer, 139b'). 256 Spectral data for 138b': Rf = 0.20 (4:1:0.2 hexanes/CH2Cl2/Et2O); 1 H-NMR (500 MHz, CDCl3): δ –0.24 (s, 3H), –0.21 (s, 3H), 0.63 (s, 9H), 1.16 (t, J = 7.1 Hz, 3H), 2.09 (d, J = 7.0 Hz, 1H), 2.49 (dd, J = 8.0, 7.0 Hz, 1H), 3.79 (s, 1H), 4.14-4.07 (m, 2H), 4.74 (d, J = 8.0 Hz, 1H), 7.19-7.30 (m, 11H), 7.42-7.45 (m, 4H); 13 C-NMR (126 MHz, CDCl3): δ –4.95, –4.80, 14.07, 17.98, 25.76, 41.68, 54.57, 60.72, 73.31, 77.85, 126.51, 126.97, 127.29, 127.33, 127.54, 128.08, 128.29, 128.36, 128.40, 142.36, 142.57, 142.66, 169.59; IR (thin film) 2933vs, 1730vs, 1454s, -1 + 1256s, 1199vs cm ; HRMS (ESI-TOF) m/z 502.2765 [(M+H ); calcd. for C31H40NO3Si: 502.2777]; [α ]20 –70.5 (c 1.0, CH2Cl2) on 17:1 dr material (HPLC). D € 4.13.6.4 Multi-component aziridination reaction of aldehyde (R)-130b and benzhydryl amine 137 in presence of (S)-VAPOL 1) 4 Å MS 2) OTBS Ph (S)-VAPOL (10 mol%) Ph NH2 137 B(OPh)3 (30 mol%) toluene, 80 °C, 0.5 h CHO (R)-130b (1.1 equiv) –10 ºC 3) EDA (11) (1.2 equiv) –10 ºC, 24 h OTBS Ph N N Ph + COOEt 138a' OTBS Ph Ph COOEt 138b' (2R, 3S)-ethyl 1-benzhydryl-3-((R)-((tert-butyldimethylsilyl)oxy)(phenyl)methyl)aziridine-2carboxylate 138a': Aldehyde (R)-130a was reacted according to the general Procedure B described above with (S)VAPOL as ligand except the benzhydryl amine 137 (34.5 µL, 0.2 mmol) was used to afford 257 aziridines 138a' and 138b' with 99:1 diastereomeric ratio. Purification of the crude aziridine by neutral alumina chromatography (20 mm × 150 mm column, 4:2:0.1 hexanes/CH2Cl2/Et2O as eluent, gravity column) afforded inseparable mixture of aziridines 138a' and 138b' as a white solid (mp 126-131 ºC on 99:1 dr material) in 50 % isolated yield (50 mg, 0.10 mmol). The diastereomeric ratio of 139a' and 139b' was determined to be 99:1 by HPLC analysis of crude reaction mixture (PIRKLE COVALENT (R, R) WHELK-O 1 column, 99.5:0.5 hexane/2propanol at 222nm, flow-rate: 0.7 mL/min): retention times; Rt = 6.44 min (major diastereomer, 139a') and Rt = 11.76 min (minor diastereomer, 139b'). Spectral data for 138a': Rf = 0.20 (4:1:0.2 hexanes/CH2Cl2/Et2O); 1 H-NMR (300 MHz, CDCl3): δ –0.33 (s, 3H), –0.10 (s, 3H), 0.78 (s, 9H), 1.28 (t, J = 7.2 Hz, 3H), 2.35 (d, J = 6.4 Hz, 1H), 2.44 (t, J = 7.2 Hz, 1H), 3.58 (s, 1H), 4.12-4.28 (m, 2H), 4.62 (d, J = 7.9 Hz, 1H), 6.847.13 (m, 10H), 7.24 (t, J = 7.3 Hz, 3H), 7.36 (d, J = 7.4 Hz, 2H); 13 C-NMR (126 MHz, CDCl3): δ –5.10, –4.61, 14.11, 17.95, 25.66, 42.93, 53.86, 60.88, 72.22, 77.75, 126.64, 126.76, 126.89, 127.05, 127.12, 127.52, 127.74, 127.87, 128.28, 141.37, 142.35, 142.40, 169.37; IR (thin film) -1 + 2932vs, 1728vs, 1454s, 1252s, 1198vs cm ; HRMS (ESI-TOF) m/z 502.2761 [(M+H ); calcd. for C31H40NO3Si: 502.2777]; [α ]20 +105.3 (c 1.0, CH2Cl2) on 99:1 dr material (HPLC). D € 4.13.7 Asymmetric catalytic multi-component aziridination reaction of aldehyde (S)-130c in presence of chiral catalyst (Procedure B) 4.13.7.1 Multi-component aziridination reaction of aldehyde (S)-130c and MEDAM amine 66 in presence of (R)-ligand (VAPOL/VANOL) 258 1) 4 Å MS 2) (R)-VAPOL (10 mol%) MEDAM NH2 66 B(OPh)3 (30 mol%) toluene, 80 °C, 0.5 h OTBS CHO (S)-130c (1.1 equiv) –10 ºC OTBS OTBS MEDAM N + 3) EDA (11) (1.2 equiv) –10 ºC, 24 h COOEt 139a N MEDAM COOEt 139b (2S, 3R)-ethyl 1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-((S)-1-((tert-butyldimethyl silyl)oxy)ethyl)aziridine-2-carboxylate 139b: Aldehyde (S)-130c was reacted according to the general Procedure B described above with (R)VAPOL as ligand to afford aziridines 139b and 139a with 96:4 diastereomeric ratio. Purification of the crude aziridine by neutral alumina chromatography (20 mm × 150 mm column, 4:2:0.1 hexanes/CH2Cl2/Et2O as eluent, gravity column) afforded inseparable mixture of aziridines 139b and 139a as a sticky solid in 87 % isolated yield (97 mg, 0.174 mmol). The diastereomeric ratio of 139b and 139a was determined to be 96:4 by HPLC analysis of crude reaction mixture (PIRKLE COVALENT (R, R) WHELK-O 1 column, 99.5:0.5 hexane/2propanol at 222nm, flow-rate: 0.7 mL/min): retention times; Rt = 12.36 min (minor diastereomer, 139a) and Rt = 13.94 min (major diastereomer, 139b). Aldehyde (S)-130c was reacted according to the general Procedure B described above with (R)-VANOL (9 mg, 0.02 mmol), as ligand to afford aziridines 139b and 139a with 95:5 diastereomeric ratio. Purification of the crude aziridine by neutral alumina chromatography (20 259 mm × 150 mm column, 4:2:0.1 hexanes/CH2Cl2/Et2O as eluent, gravity column) afforded inseparable mixture of aziridines 139b and 139a as a sticky solid in 82 % isolated yield (91 mg, 0.164 mmol). 1 Spectral data for 139b: Rf = 0.37 (4:1:0.2 hexanes/CH2Cl2/Et2O); H-NMR (300 MHz, CDCl3): δ –0.06 (s, 3H), –0.04 (s, 3H), 0.71 (d, J = 6.2 Hz, 3H), 0.82 (s, 9H), 1.26 (t, J = 7.1 Hz, 3H), 2.06 (dd, J = 8.2, 6.5 Hz, 1H), 2.22-2.24 (m, 13H), 3.45 (s, 1H), 3.66 (s, 3H), 3.70 (s, 3H), 3.723.81 (m, 1H), 4.06-4.28 (m, 2H), 6.95 (s, 2H), 7.07 (s, 2H); 13 C-NMR (126 MHz, CDCl3): δ – 4.91, –4.34, 14.15, 16.05, 16.16, 17.84, 22.18, 25.70, 43.47, 53.01, 59.59, 59.64, 60.78, 66.12, (one sp3 carbon not located), 127.16, 128.66, 130.43, 130.53, 137.48, 137.76, 155.76, 156.42, -1 169.50; IR (thin film) 2957vs, 2930vs, 1744s, 1483s, 1221s, 1194vs cm ; HRMS (ESI-TOF) + m/z 556.3470 [(M+H ); calcd. for C32H50NO5Si: 556.3458]; [α ]20 –93.3 (c 0.6, CH2Cl2) on D 99:1 dr material (HPLC). € 4.13.7.2 Multi-component aziridination reaction of aldehyde (S)-130c and MEDAM amine 66 in presence of (S)-VAPOL 1) 4 Å MS 2) (S)-VAPOL (10 mol%) MEDAM NH2 66 B(OPh)3 (30 mol%) toluene, 80 °C, 0.5 h OTBS CHO (S)-130c (1.1 equiv) –10 ºC 3) EDA (11) (1.2 equiv) –10 ºC, 24 h 260 OTBS N OTBS MEDAM + COOEt 139a N MEDAM COOEt 139b (2R, 3S)-Ethyl 1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-((S)-1-((tert-butyldimethyl silyl)oxy)ethyl)aziridine-2-carboxylate 139a: Aldehyde (S)-130c was reacted according to the general Procedure B described above with (S)VAPOL as ligand to afford aziridines 139a and 139b with 91:9 diastereomeric ratio. Purification of the crude aziridine by neutral alumina chromatography (20 mm × 150 mm column, 4:2:0.1 hexanes/CH2Cl2/Et2O as eluent, gravity column) afforded inseparable mixture of aziridines 139a and 139b as a sticky solid in 85 % isolated yield (94 mg, 0.17 mmol). The diastereomeric ratio of 139b and 139a was determined to be 91:9 by HPLC analysis of crude reaction mixture (PIRKLE COVALENT (R, R) WHELK-O 1 column, 99.5:0.5 hexane/2propanol at 222nm, flow-rate: 0.7 mL/min): retention times; Rt = 11.63 min (major diastereomer, 139a) and Rt = 13.67 min (minor diastereomer, 139b). 1 Spectral data for 139a: Rf = 0.14 (4:1:0.2 hexanes/CH2Cl2/Et2O); H-NMR (300 MHz, CDCl3): δ –0.33 (s, 3H), –0.02 (s, 3H), 0.70 (s, 9H), 1.05 (d, J = 6.3 Hz, 3H), 1.27 (t, J = 7.1 Hz, 3H), 2.07 (d, J = 7.1 Hz, 1H), 2.14-2.19 (m, 1H), 2.22 (s, 6H), 2.23 (s, 6H), 3.42 (s, 1H), 3.66 (s, 3H), 3.68 (s, 3H), 3.75-3.84 (m, 1H), 4.11-4.26 (m, 2H), 6.96 (s, 2H), 7.04 (s, 2H); 13 C-NMR (126 MHz, CDCl3): δ –5.13, –5.00, 14.32, 16.18, 17.93, 21.52, 25.69, 41.53, 54.44, 59.38, 59.57, 60.71, 67.51, 77.78, (one sp3 carbon not located), 127.28, 128.76, 130.35, 130.40, 137.87, 138.15, 155.63, 156.14, 169.80; IR (thin film) 2928vs, 2956s, 1746s, 1484s, 1221s, 1188vs, -1 + 1097s cm ; HRMS (ESI-TOF) m/z 556.3475 [(M+H ); calcd. for C32H50NO5Si: 556.3458]; [α ]20 +69.8 (c 0.6, CH2Cl2) on 12:1 dr material (HPLC). D € 261 4.13.8 Asymmetric catalytic multi-component aziridination reaction of aldehyde (R)-140 in presence of chiral catalyst (Procedure B) 4.13.8.1 Multi-component aziridination reaction of aldehyde (R)-140 and MEDAM amine 66 in presence of (R)-VAPOL 1) 4 Å MS 2) O O (R)-VAPOL (10 mol%) MEDAM NH2 66 CHO (S)-140 (1.1 equiv) –10 ºC O O B(OPh)3 3) EDA (11) (1.2 equiv) (30 mol%) –10 ºC, 24 h toluene, 80 °C, 0.5 h O N MEDAM COOEt 141a O + N MEDAM COOEt 141b (2S, 3R)-Ethyl 1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-((S)-2,2-dimethyl-1,3dioxolan-4-yl)aziridine-2-carboxylate 141b: Aldehyde (R)-140 was reacted according to the general Procedure B described above with (R)VAPOL as ligand except before adding the aldehyde (R)-140 to the reaction mixture 0.5 mL dry toluene was added (0.2 M concentration) to afford aziridines 141b and 141a with 95.5:4.5 diastereomeric ratio. Purification of the crude aziridine by neutral alumina chromatography (20 mm × 150 mm column, 2:1 hexanes/Et2O as eluent, flash column) afforded inseparable mixture of aziridines 141b and 141a as a viscous liquid in 83 % isolated yield (83 mg, 0.166 mmol). The diastereomeric ratio of 141b and 141a was determined to be 95.5:4.5 by HPLC analysis of crude reaction mixture (PIRKLE COVALENT (R, R) WHELK-O 1 column, 98:2 hexane/2propanol at 222nm, flow-rate: 0.7 mL/min): retention times; Rt diastereomer, 141a) and Rt = 31.23 min (major diastereomer, 141b). 262 = 16.88 min (minor Aldehyde (R)-140 was reacted according to the general Procedure B described above with (R)-VAPOL at different concentration in toluene at –10 ºC. The results are represented in Table 4.5 (Chapter 4). 1 Spectral data for 141b: Rf = 0.25 (2:1 hexanes/Et2O); H-NMR (300 MHz, CDCl3): δ 1.22-1.26 (m, 6H), 1.28 (s, 3H), 2.13 (dd, J = 8.0, 7.0 Hz, 1H), 2.23-2.24 (m, 12H), 2.27 (d, J = 6.8 Hz, 1H), 3.58 (s, 1H), 3.65-3.70 (m, 7H), 3.92 (dd, J = 8.3, 6.5 Hz, 1H), 4.10-4.24 (m, 3H), 7.05 (s, 2H), 7.09 (s, 2H); 13 C-NMR (126 MHz, CDCl3): δ 14.16, 16.01, 16.11, 25.36, 26.59, 41.42, 48.13, 59.49, 59.51, 60.96, 66.97, 75.01, 76.26, 109.40, 127.79, 128.19, 130.13, 130.45, 137.05, 137.30, 155.94, 169.02, (one sp2 carbon not located); IR (thin film) 2986vs, 2938vs, 1744s, -1 1485s, 1221s, 1190vs, 1149s cm ; HRMS (ESI-TOF) m/z 498.2857 [(M+H+); calcd. for 1 C29H40NO6 : 498.2858]; [α ]20 –32.2 (c 1.0, CH2Cl2) on 20:1 dr material ( H NMR). D 4.13.8.2 Multi-component aziridination reaction of aldehyde (R)-140 and MEDAM amine 66 in presence of (S)-VAPOL € 1) 4 Å MS 2) O O (S)-VAPOL (10 mol%) MEDAM NH2 66 CHO (S)-140 (1.1 equiv) –10 ºC B(OPh)3 3) EDA (11) (1.2 equiv) (30 mol%) –10 ºC, 24 h toluene, 80 °C, 0.5 h O O O N MEDAM COOEt 141a O + N COOEt 141b (2R, 3S)-ethyl 1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-((S)-2,2-dimethyl-1,3dioxolan-4-yl)aziridine-2-carboxylate 141a: 263 MEDAM Aldehyde (R)-140 was reacted according to the general Procedure B described above with (S)VAPOL as ligand except before adding the aldehyde (R)-140 to the reaction mixture 0.5 mL dry toluene was added (0.2 M concentration) to afford aziridines 141a and 141b with 86:14 diastereomeric ratio. Purification of the crude aziridine by neutral alumina chromatography (20 mm × 150 mm column, 2:1 hexanes/Et2O as eluent, flash column) afforded inseparable mixture of aziridines 141b and 141a as a viscous liquid in 80 % isolated yield (80 mg, 0.16 mmol). The diastereomeric ratio of 141a and 141b was determined to be 86:14 by HPLC analysis of crude reaction mixture (PIRKLE COVALENT (R, R) WHELK-O 1 column, 98:2 hexane/2propanol at 222nm, flow-rate: 0.7 mL/min): retention times; Rt = 16.64 min (major diastereomer, 141a) and Rt = 30.26 min (minor diastereomer, 141b). Aldehyde (R)-140 was reacted according to the general Procedure B described above with (S)VAPOL at different concentration in toluene at –10 ºC. The results are represented in Table 4.5 (Chapter 4). 1 Spectral data for 141a: Rf = 0.25 (2:1 hexanes/Et2O); H-NMR (300 MHz, CDCl3): δ 1.24-1.29 (m, 6H), 1.34 (s, 3H), 2.05-2.10 (m, 1H), 2.23-2.24 (m, 12H), 2.38 (d, J = 6.5 Hz, 1H), 3.05 (dd, J = 8.5, 6.1 Hz, 1H), 3.48 (s, 1H), 3.67 (s, 3H), 3.68 (s, 3H), 3.80 (dd, J = 8.4, 6.3 Hz, 1H), 4.134.06 (m, 1H), 4.22 (q, J = 7.1 Hz, 2H), 6.97 (s, 2H), 7.06 (s, 2H); 13 C-NMR (151 MHz, CDCl3): δ 14.20, 16.11, 16.18, 25.20, 26.68, 42.71, 47.60, 59.58, 59.68, 61.01, 68.09, 73.28, 76.70, 109.30, 127.08, 127.93, 130.65, 130.78, 137.23, 137.74, 155.93, 156.47, 168.89; IR (thin film) -1 2988vs, 2938vs, 1746s, 1485s, 1220s, 1194vs, 1149s cm ; HRMS (ESI-TOF) m/z 498.2856 264 [(M+H+); calcd. for C29H40NO6 : 498.2858]; [α ]20 +62.3 (c 1.0, CH2Cl2) on >99:1 dr material D 1 ( H NMR). € 4.13.9 Asymmetric catalytic multi-component aziridination reaction of aldehyde (S)-147 in presence of chiral catalyst (Procedure B) 4.13.9.1 Multi-component aziridination reaction of aldehyde (S)-147 and MEDAM amine 66 in presence of (R)-VAPOL 1) 4 Å MS 2) N Boc O (R)-VAPOL (10 mol%) MEDAM NH2 66 CHO (S)-147 (1.1 equiv) –10 ºC N O Boc N B(OPh)3 3) EDA (11) (1.2 equiv) (30 mol%) –10 ºC, 24 h toluene, 80 °C, 0.5 h N MEDAM O + COOEt 143a Boc N MEDAM COOEt 143b (R)-tert-Butyl 4-((2S, 3S)-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-(ethoxycarbonyl) aziridin-2-yl)-2,2-dimethyloxazolidine-3-carboxylate 143b: Aldehyde (S)-147 was reacted according to the general Procedure B described above with (R)VAPOL as ligand to afford aziridines 143b and 143a with >99:1 diastereomeric ratio. Purification of the crude aziridine by neutral alumina chromatography (20 mm × 150 mm column, 2:1 hexanes/Et2O as eluent, flash column) afforded inseparable mixture of aziridines 143b and 143a as a viscous liquid in 60 % isolated yield (72 mg, 0.12 mmol). 1 Spectral data for 143b: Rf = 0.29 (2:1 hexane/Et2O); H-NMR (500 MHz, CDCl3): δ 1.24-1.27 (m, 5H), 1.35-1.34 (m, 4H), 1.41 (s, 9H), 2.14 (t, J = 6.9 Hz, 1H), 2.21 (s, 13H), 3.45 (s, 1H), 3.65-3.68 (s, 8H), 3.88 (td, J = 6.6, 2.2 Hz, 1H), 4.26-4.16 (m, 2H), 6.93 (s, 2H), 7.02 (s, 2H); 265 13 C-NMR (126 MHz, CDCl3): δ 14.17, 16.08, 16.18, 28.41, 43.91, 48.59, 54.65, 59.60, 59.65, 60.72, 66.66, 79.81, 93.45, 102.86, 127.27, 128.49, 130.53, 130.70, 137.25, 137.73, 151.96, 155.81, 156.52, 169.18(one Sp3 carbon not located); IR (thin film) 2979s, 2932s, 1742s, 1699vs, -1 + 1484s, 1387vs, 1223vs, 1190s cm ; HRMS (ESI-TOF) m/z 597.4229 [(M+H ); calcd. for C34H49N2O7: 597.4230]; [α ]20 –90.5 (c 1.0, CH2Cl2) on >99:1 dr material D € 4.13.9.2 Multi-component aziridination reaction of aldehyde (R)-147 and MEDAM amine 66 in presence of (S)-VAPOL 1) 4 Å MS 2) N Boc O (S)-VAPOL (10 mol%) MEDAM NH2 66 CHO (S)-147 (1.1 equiv) –10 ºC B(OPh)3 3) EDA (11) (1.2 equiv) (30 mol%) –10 ºC, 24 h toluene, 80 °C, 0.5 h N O Boc N N MEDAM O + COOEt 143a Boc N MEDAM COOEt 143b (R)-tert-Butyl 4-((2R, 3R)-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-(ethoxycarbonyl) aziridin-2-yl)-2,2-dimethyloxazolidine-3-carboxylate 143a: Aldehyde (S)-147 was reacted according to the general Procedure B described above with (S)VAPOL as ligand to afford aziridines 143a and 143b with >99:1 diastereomeric ratio. Purification of the crude aziridine by neutral alumina chromatography (20 mm × 150 mm column, 2:1 hexanes/Et2O as eluent, flash column) afforded inseparable mixture of aziridines 143a and 143b as a sticky solid in 70 % isolated yield (83 mg, 0.14 mmol). 266 The diastereomeric ratio of 143a and 143b was determined to be 99.4:0.6 by HPLC analysis of crude reaction mixture (PIRKLE COVALENT (R, R) WHELK-O 1 column, 98:2 hexane/2propanol at 222nm, flow-rate: 0.7 mL/min): retention times; Rt = 16.26 min (major diastereomer, 143a) and Rt = 18.98 min (minor diastereomer, 143b). 1 Spectral data for 143a: Rf = 0.29 (2:1 hexanes / Et2O); H-NMR (500 MHz, CDCl3): δ 1.261.23 (m, 4H), 1.30 (s, 2H), 1.41 (brs, 12H), 2.16-2.15 (m, 1H), 2.20 (s, 7H), 2.23 (s, 6H), 3.63 (s, 3H), 3.67 (s, 4H), 3.70 (dd, J = 9.2, 5.8 Hz, 1H), 4.08-4.03 (m, 1H), 4.15 (qd, J = 7.1, 1.5 Hz, 2H), 6.90 (s, 2H), 7.12 (s, 2H). 13 C-NMR (126 MHz, CDCl3): δ 14.16, 16.07, 16.18, 28.35, 28.47, 43.52, 47.00, 56.38, 59.46, 59.55, 60.77, 64.85, 79.61, 93.89, 127.65, 128.15, 130.40, 130.62, 137.12, 137.85, 155.82, 168.75. (two Sp2 and one Sp3 carbon not located); IR (thin film) -1 2980s, 2936s, 1748s, 1698vs, 1484s, 1383vs, 1221vs, 1184vs cm ; HRMS (ESI-TOF) m/z + 597.4225 [(M+H ); calcd. for C34H49N2O7: 597.4230]; [α ]20 +70.3 (c 1.0, CH2Cl2) on >99:1 D dr material. € 267 4.13.10Asymmetric catalytic multi-component aziridination reaction of aldehyde 148 in presence of chiral catalyst (Procedure B) 4.13.10.1 Multi-component aziridination reaction of aldehyde 148 and MEDAM amine 66 in presence of (R)-VAPOL 1) 4 Å MS 2) MEDAM N (R)-VAPOL (10 mol%) MEDAM NH2 66 B(OPh)3 (30 mol%) toluene, 80 °C, 0.5 h CHO 148 (1.1 equiv) –10 ºC 3) EDA (11) (1.2 equiv) –10 ºC, 24 h P N n-Pr P N N 149a P + n-Pr COOEt N 149b P COOEt P = MEDAM (2S, 2'S, 3S, 3'S)-Ethyl 1,1'-bis(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3'-propyl-[2,2'biaziridine]-3-carboxylate 149b: Aldehyde 148 was reacted according to the general Procedure B described above with (R)VAPOL as ligand to afford aziridines 149b and 149a with >99:1 diastereomeric ratio. Purification of the crude aziridine by neutral alumina chromatography (20 mm × 150 mm column, 4:2:0.1 hexanes/CH2Cl2/Et2O as eluent, gravity column) afforded inseparable mixture of aziridines 149b and 149a as a white solid (mp 79-82 ºC on > 99:1 dr material) in 80 % isolated yield (122 mg, 0.16 mmol). The diastereomeric ratio of 149b and 149a was determined to be 99.5:0.5 by HPLC analysis of crude reaction mixture (PIRKLE COVALENT (R, R) WHELK-O 1 column, 99.7:0.3 hexane/2-propanol at 222nm, flow-rate: 0.7 mL/min): retention times; Rt = 16.30 min (minor 268 diastereomer, 149a) and Rt = 19.75 min (major diastereomer, 149b). 1 Spectral data for 149b: Rf = 0.29 (2:1 hexanes/Et2O); H-NMR (300 MHz, CDCl3): δ 0.49 (t, J = 6.5 Hz, 2H), 0.55-0.64 (m, 2H), 0.68-0.77 (m, 2H), 1.00 (t, J = 7.1 Hz, 3H), 1.50-1.56 (m, 1H), 1.80 (dd, J = 8.7, 6.7 Hz, 1H), 2.01-2.06 (m, 1H), 2.20-2.28 (m, 26H), 3.28 (s, 1H), 3.45 (s, 1H), 3.64 (brs, 6H), 3.66-3.67 (m, 6H), 3.69-3.84 (m, 2H), 6.87 (s, 2H), 6.97 (s, 4H), 7.04 (s, 2H); 13 C-NMR (75 MHz, CDCl3): δ 13.69, 13.87, 15.99, 16.04, 16.05, 16.10, 20.39, 29.84, 41.35, 42.78, 43.31, 45.42, 59.43, 59.46, 59.50, 59.52, 60.47, 77.21, 77.36, 127.09, 127.11, 128.12, 128.38, 130.04, 130.20, 130.45, 137.52, 137.58, 138.04, 138.97, 155.37, 155.72, 155.88, 156.29, 168.92 (one sp2 carbon not located); IR (thin film) 2955vs, 1736s, 1483s, 1221s, 1190vs, 1138s -1 + cm ; HRMS (ESI-TOF) m/z 763.4703 [(M+H ); calcd. for C48H63N2O6: 763.4686]; [α ]20 – D 62.8 (c 1.0, CH2Cl2) on >99:1 dr material (HPLC). € 4.13.10.2 Multi-component aziridination reaction of aldehyde 148 and MEDAM amine 66 in presence of (S)-VAPOL 1) 4 Å MS 2) MEDAM N (S)-VAPOL (10 mol%) MEDAM NH2 66 B(OPh)3 (30 mol%) toluene, 80 °C, 0.5 h CHO 148 (1.1 equiv) –10 ºC 3) EDA (11) (1.2 equiv) –10 ºC, 24 h P N P N PH2 + N n-Pr n-Pr 149a COOEt N 149b P = MEDAM 269 P COOEt (2R, 2'S, 3R, 3'S)-ethyl 1,1'-bis(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3'-propyl-[2,2'biaziridine]-3-carboxylate 149a: Aldehyde 148 was reacted according to the general Procedure B described above with (S)VAPOL as ligand to afford aziridines 149a and 149b with >99:1 diastereomeric ratio. Purification of the crude aziridine by neutral alumina chromatography (20 mm × 150 mm column, 4:2:0.1 hexanes/CH2Cl2/Et2O as eluent, gravity column) afforded inseparable mixture of aziridines 149a and 149b as a white solid (mp 67-70 ºC on >99:1 dr material) in 84 % isolated yield (129 mg, 0.164 mmol). 1 Spectral data for 149a: Rf = 0.29 (2:1 hexanes/Et2O); H-NMR (300 MHz, CDCl3): δ 0.61 (t, J = 7.2 Hz, 3H), 0.75-1.02 (m, 2H), 1.07-1.28 (m, 5H), 1.50-1.57 (m, 1H), 2.01 (dd, J = 6.5, 5.3 Hz, 1H), 2.05 (s, 12H), 2.11-2.15 (m, 1H), 2.21-2.26 (m, 13H), 3.45 (s, 1H), 3.63 (s, 3H), 3.64 (s, 3H), 3.65 (s, 3H), 3.67 (s, 3H), 3.82 (s, 1H), 4.14 (q, J = 7.1 Hz, 2H), 6.85 (s, 2H), 6.91 (s, 2H), 6.95 (s, 4H); 13 C-NMR (75 MHz, CDCl3): δ 13.67, 14.22, 15.92, 16.03, 16.13, 20.36, 31.22, 40.43, 41.67, 43.75, 45.57, 59.44, 59.46, 59.50, 59.56, 60.62, 75.06, 77.17, (one Sp2 carbon not located), 127.10, 127.12, 128.19, 128.48, 129.92, 130.17, 130.19, 130.42, 137.17, 137.20, 137.87, 139.12, 155.34, 155.63, 155.89, 155.91, 169.78; IR (thin film) 2955vs, 1743s, -1 + 1483s, 1221s, 1186vs, 1140s cm ; HRMS (ESI-TOF) m/z 763.4706 [(M+H ); calcd. for C48H63N2O6: 763.4686]; [α ]20 –97.6 (c 1.0, CH2Cl2) on >99:1 dr material (NMR). D € 4.13.11Asymmetric catalytic multi-component aziridination reaction of aldehyde (S)-150 in presence of chiral catalyst (Procedure C) 270 4.13.11.1 Multi-component aziridination reaction of aldehyde (S)-150 and MEDAM amine 66 in presence of (S)-VAPOL 1) 4 Å MS (S)-VAPOL (10 mol%) 2) EDA (11) (4.0 equiv) –10 ºC MEDAM NH2 66 B(OPh)3 (30 mol%) toluene, 80 °C, 0.5 h N N MEDAM + COOEt 151a + 3) CHO (S)-150 (1.1 equiv) –10 ºC, 24 h N MEDAM + COOEt ent-151b N MEDAM COOEt 151b N MEDAM COOEt ent-151a MEDAM (S)-152 Intermediate imine To a 25 mL flame-dried home-made Schlenk flask, equipped with a stir bar and filled with argon was added (S)-VAPOL (11 mg, 0.02 mmol), B(OPh)3 (17 mg, 0.06 mmol) and amine 66 (60 mg, 0.2 mmol). Under an argon flow through the side arm of the Schlenk flask, dry toluene (0.5 mL) was added. The flask was sealed by closing the Teflon valve, and then placed in an oil bath (80 ºC) for 0.5 h. The flask was then allowed to cool to room temperature and open to argon through side arm of the Schlenk flask. To the flask containing the catalyst was added the 4Å Molecular Sieves (50 mg, freshly flame-dried). The flask was then allowed to cool to –10 ºC and 4.5 mL dry toluene was added to the flask. To the resulting reaction mixture was added ethyl diazoacetate (EDA) 11 (83 µL, 0.80 mmoL, 4.0 equiv). To this solution was rapidly added 271 aldehyde (S)-150 (29.5 mg, 0.22 mmoL, 1.1 equiv). The resulting mixture was stirred for 24 h at –10 ºC. The reaction was dilluted by addition of hexane (3 mL). The reaction mixture was then filtered through a silica gel plug to a 100 mL round bottom flask. The reaction flask was rinsed with EtOAc (10 mL × 3) and the rinse was filtered through the same silica gel plug. The resulting solution was then concentrated in vacuo followed by exposure to high vacuum (0.05 mm Hg) for 1 h to afford the crude aziridine as yellow colored viscous oil. Purification of the crude aziridine by neutral alumina chromatography (20 mm × 150 mm column, 6:2:0.1 hexanes/CH2Cl2/Et2O as eluent, gravity column) afforded inseparable mixture of aziridines 151b, 151a, ent-151b and ent-151a as a white solid (mp 46-51 ºC on 23:1 dr material) in 92% isolated yield (92 mg, 0.184 mmol). The ratio of 151b, 151a, ent-151b and ent-151a was determined to be 0.37: 95.40: 3.49 :0.74 by HPLC analysis of crude reaction mixture (PIRKLE COVALENT (R, R) WHELK-O 1 column, 99:1 hexane/2-propanol at 226nm, flow-rate: 0.7 mL/min): retention times; Rt = 14.90 min (ent-151b ), Rt = 15.79 min (151a), Rt = 21.82 min (151b), Rt = 26.25 min (ent-151a). Comparing the HPLC data following results were determined: dr = 24:1 [(151a + ent-151a) : (151b + ent-151b)]; % ee 151a = 99% ee; % ee ent-151b = 80% ee ; %ee imine (S)-152 = 91.4%ee Although, there was no imine 152 left unreacted in the reaction mixture the % ee of (S)152 was determined from the ratio [(151a + 151b) : (ent-151b + ent-151b)]. Aldehyde (S)-150 was reacted according to the general Procedure C described above with (S)-VAPOL at different concentration in toluene at –10 ºC. The results are represented in Table 4.8 (Chapter 4). Aldehyde (R)-150 was reacted according to the general Procedure C described above with (S)- 272 VAPOL except the concentration of the reaction was 0.4 M in amine 66 at –10 ºC. The results are represented in Table 4.8, entry 8 (Chapter 4). Purification of the crude aziridine by neutral alumina chromatography (20 mm × 150 mm column, 6:2:0.1 hexanes/CH2Cl2/Et2O as eluent, gravity column) afforded inseparable mixture of aziridines 151b, 151a, ent-151b and ent-151a as a sticky solid in 92% isolated yield (92 mg, 0.184 mmol). The ratio of 151b, 151a, ent-151b and ent-151a was determined to be 7.88: 2.02: 0.71: 89.38 by HPLC analysis of crude reaction mixture (PIRKLE COVALENT (R, R) WHELK-O 1 column, 99:1 hexane/2-propanol at 226nm, flow-rate: 0.7 mL/min): retention times; Rt = 15.52 min (ent-151b), Rt = 16.90 min (151a), Rt = 22.56 min (151b), Rt = 26.65 min (ent-151a). Comparing the HPLC data following results were determined: dr = 11:1 [(151a + ent-151a) : (151b + ent-151b)]; % ee 151b = 83% ee ; % ee of ent-151a = 95.6% ee; % ee imine (S)-152 = 80% ee. Although, there was no imine 152 left unreacted in the reaction mixture the % ee of (S)152 was determined from the ratio [(151a + 151b) : (ent-151b + ent-151b)]. 1 Spectral data for 151a: Rf = 0.11 (4:1:0.2 hexanes/CH2Cl2/Et2O); H-NMR (500 MHz, CDCl3): δ 0.90 (d, J = 7.0 Hz, 3H), 1.10 (t, J = 7.1 Hz, 3H), 2.14 (dd, J = 9.4, 6.8 Hz, 1H), 2.20 (d, J = 6.8 Hz, 1H), 2.26 (s, 6H), 2.28 (s, 6H), 2.81-2.87 (m, 1H), 3.47 (s, 1H), 3.69 (s, 3H), 3.70 (s, 3H), 4.07 (q, J = 7.1 Hz, 2H), 7.07 (s, 2H), 7.10 (dd, J = 8.2, 1.2 Hz, 2H), 7.14 (s, 2H), 7.16-7.19 (m, 1H), 7.23-7.27 (m, 2H); 13 C-NMR (126 MHz, CDCl3): δ 14.06, 16.10, 16.17, 19.96, 38.14, 44.02, 52.85, 59.56, 59.65, 60.60, 77.44, 126.29, 127.00, 127.23, 128.29, 128.53, 130.49, 130.53, 137.51, 138.10, 144.11, 155.78, 156.37, 169.47; IR (thin film) 2932vs, 1742s, 1485s, 1221s, -1 + 1188vs, 1148s cm ; HRMS (ESI-TOF) m/z 502.2978 [(M+H ); calcd. for C32H40NO4: 273 502.2957]; [α ]20 +108.9 (c 0.6, CH2Cl2) on 23:1 dr material (NMR, entry 5, Table 4.8, Chapter D 4). € 4.13.11.2 Multi-component aziridination reaction of aldehyde (S)-150 and MEDAM amine 66 in presence of (R)-VAPOL 1) 4 Å MS (R)-VAPOL (10 mol%) MEDAM NH2 66 B(OPh)3 (30 mol%) toluene, 80 °C, 0.5 h 2) EDA (11) (4.0 equiv) –10 ºC N MEDAM + COOEt 151a + 3) CHO (S)-150 (1.1 equiv) –10 ºC, 24 h N MEDAM + COOEt ent-151b N MEDAM COOEt 151b N MEDAM COOEt ent-151a Aldehyde (S)-150 was reacted according to the general Procedure C described above with (R)VAPOL at –10 ºC. The results are represented in Table 4.8, entry7 (Chapter 4). Purification of the crude aziridine by neutral alumina chromatography (20 mm × 150 mm column, 6:2:0.1 hexanes/CH2Cl2/Et2O as eluent, gravity column) afforded inseparable mixture of aziridines 151b, 151a, ent-151b and ent-151a as a sticky solid in 90% isolated yield (90 mg, 0.18 mmol). The ratio of 151b, 151a, ent-151b and ent-151a was determined to be 83.16: 10.71: 0.05: 6.07 by HPLC analysis of crude reaction mixture (PIRKLE COVALENT (R, R) WHELK-O 1 column, 99:1 hexane/2-propanol at 226nm, flow-rate: 0.7 mL/min). Comparing the HPLC data following results were determined: dr = 1:5 [(151a + ent-151a) : (151b + ent-151b)]; % ee ent151b = 99.9% ee ; % ee of 151a = 43% ee; % ee imine (S)-152 = 93% ee. Although, there was no imine 152 left unreacted in the reaction mixture the % ee of (S)-152 was determined from the ratio [(151a + 151b) : (ent-151b + ent-151b)]. 274 1 Spectral data for 151b: Rf = 0.11 (4:1:0.2 hexanes/CH2Cl2/Et2O); H-NMR (500 MHz, CDCl3): δ 1.15 (d, J = 7.2 Hz, 3H), 1.31 (t, J = 7.1 Hz, 3H), 2.02 (s, 6H), 2.19 (dd, J = 6.4, 3.1 Hz, 1H), 2.22 (s, 6H), 2.26 (d, J = 6.8 Hz, 1H), 2.80-2.86 (m, 1H), 3.33 (s, 1H), 3.61 (s, 3H), 3.67 (s, 3H), 4.23-4.30 (m, 2H), 6.63 (s, 2H), 6.96-7.00 (m, 5H), 7.04 (s, 2H).; 13 C-NMR (126 MHz, CDCl3): δ 14.37, 16.02, 16.15, 19.21, 38.37, 42.99, 53.46, 59.32, 59.55, 60.77, 77.52, 125.78, 126.93, 127.22, 127.60, 127.99, 129.84, 130.40, 137.46, 137.78, 143.95, 155.70, 169.70 (one sp2 carbon -1 not located); IR (thin film) 2932vs, 1741s, 1483s, 1221s, 1186vs, 1148s cm ; HRMS (ESI-TOF) + m/z 502.2976 [(M+H ); calcd. for C32H40NO4: 502.2957]; [α ]20 –73.9 (c 0.6, CH2Cl2) on 4:1 D dr material (NMR, entry 6, Table 4.8, Chapter 4). € 4.13.12 Asymmetric catalytic multi-component aziridination reaction of aldehyde (S)-155 in presence of chiral catalyst (Procedure B) 4.13.12.1 Multi-component aziridination reaction of aldehyde (S)-155 and MEDAM amine 66 in presence of (S)-VAPOL 1) 4 Å MS 2) (S)-VAPOL (10 mol%) MEDAM NH2 66 CHO Ph (S)-155 (1.1 equiv) –10 ºC 3) EDA (11) B(OPh)3 (1.2 equiv) (30 mol%) –10 ºC, 24 h toluene, 80 °C, 0.5 h N Ph MEDAM + COOEt 156a N MEDAM Ph COOEt 156b (2R, 3R)-Ethyl 1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-((S)-2-phenylpropyl) aziridine-2-carboxylate 156a: 275 Aldehyde (S)-155 was reacted according to the general Procedure B described above with (S)VAPOL as ligand to afford aziridines 156a and 156b with 94:6 diastereomeric ratio. Purification of the crude aziridine by neutral alumina chromatography (20 mm × 150 mm column, 4:2:0.1 hexanes/CH2Cl2/Et2O as eluent, gravity column) afforded inseparable mixture of aziridines 156a and 156b as a sticky solid in 80 % isolated yield (82 mg, 0.16 mmol). The diastereomeric ratio of 156a and 156b was determined to be 94:6 by HPLC analysis of crude reaction mixture (PIRKLE COVALENT (R, R) WHELK-O 1 column, 99:1 hexane/2propanol at 222nm, flow-rate: 0.7 mL/min): retention times; Rt = 17.68 min (major diastereomer, 156a) and Rt = 32.01 min (minor diastereomer, 156b). 1 Spectral data for 156a: Rf = 0.10 (4:1:0.2 hexanes/CH2Cl2/Et2O); H-NMR (300 MHz, CDCl3): δ 1.14 (d, J = 7.0 Hz, 3H), 1.25 (t, J = 7.1 Hz, 3H), 1.73-1.83 (m, 2H), 2.07 (d, J = 6.3 Hz, 1H), 2.22-2.25 (m, 7H), 2.31 (s, 6H), 2.43-2.53 (m, 1H), 3.30 (s, 1H), 3.67 (s, 3H), 3.73 (s, 3H), 4.134.20 (m, 2H), 6.68 (dd, J = 7.7, 1.7 Hz, 2H), 7.06 (s, 2H), 7.07 (s, 2H), 7.12-7.20 (m, 3H); 13 C- NMR (75 MHz, CDCl3): δ 14.28, 16.15, 23.17, 36.39, 38.40, 43.13, 45.44, 59.54, 59.65, 60.72, 77.25, (one sp3 carbon not located) 125.83, 127.08, 128.06, 128.18, 130.48, 130.61, 137.91, 138.44, 146.09, 155.68, 156.24, 169.66 (one sp2 carbon not located); IR (thin film) 2957vs, -1 + 2930vs, 1742s, 1483s, 1221s, 1186vs cm ; HRMS (ESI-TOF) m/z 516.3119 [(M+H ); calcd. for C33H42NO4: 516.3114]; [α ]20 +70.6 (c 1.0, CH2Cl2) on 94:6 dr material (HPLC). D € 4.13.12.2 Multi-component aziridination reaction of aldehyde (S)-155 and MEDAM amine 66 in presence of (R)-VAPOL 276 1) 4 Å MS 2) (R)-VAPOL (10 mol%) MEDAM NH2 66 CHO Ph (S)-155 (1.1 equiv) –10 ºC 3) EDA (11) B(OPh)3 (1.2 equiv) (30 mol%) –10 ºC, 24 h toluene, 80 °C, 0.5 h N Ph MEDAM + COOEt 156a N MEDAM Ph COOEt 156b (2S, 3S)-Ethyl 1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-((S)-2-phenylpropyl) aziridine-2-carboxylate 156b: Aldehyde (S)-155 was reacted according to the general Procedure B described above with (R)VAPOL as ligand to afford aziridines 156b and 156a with >99:1 diastereomeric ratio. Purification of the crude aziridine by neutral alumina chromatography (20 mm × 150 mm column, 4:2:0.1 hexanes/CH2Cl2/Et2O as eluent, gravity column) afforded inseparable mixture of aziridines 156b and 156a as a white solid (mp 101-102 ºC on 99:1 dr material) in 85 % isolated yield (88 mg, 0.17 mmol). The diastereomeric ratio of 156b and 156a was determined to be 99.4:0.6 by HPLC analysis of crude reaction mixture (PIRKLE COVALENT (R, R) WHELK-O 1 column, 99:1 hexane/2-propanol at 222nm, flow-rate: 0.7 mL/min): retention times; Rt = 18.49 min (minor diastereomer, 156a) and Rt = 31.04 min (major diastereomer, 156b). 1 Spectral data for 156b: Rf = 0.10 (4:1:0.2 hexanes/CH2Cl2/Et2O); H-NMR (300 MHz, CDCl3): δ 1.02 (d, J = 6.9 Hz, 3H), 1.27 (t, J = 7.1 Hz, 3H), 1.71-1.81 (m, 1H), 1.85-1.97 (m, 2H), 2.222.54 (m, 13H), 2.45-2.55 (m, 1H), 3.40 (s, 1H), 3.68 (s, 3H), 3.69 (s, 3H), 4.20 (qd, J = 7.1, 2.3 Hz, 2H), 7.02 (s, 2H), 7.08 (s, 2H), 7.10-7.28 (m, 5H); 277 13 C-NMR (75 MHz, CDCl3): δ 14.34, 16.13, 16.17, 21.29, 35.73, 37.96, 43.44, 45.49, 59.56, 59.60, 60.72, 77.07, 125.93, 126.78, 127.32, 127.95, 128.31, 130.49, 137.66, 138.17, 146.99, 155.76, 156.09, 169.65 (one sp2 carbon -1 not located); IR (thin film) 2959vs, 2930vs, 1744s, 1483s, 1221s, 1183vs cm ; HRMS (ESI+ TOF) m/z 516.3120 [(M+H ); calcd. for C33H42NO4: 516.3114]; [α ]20 –20.0 (c 1.0, CH2Cl2) D on 99:1 dr material (HPLC). € 4.13.13 Asymmetric catalytic multi-component aziridination reaction of aldehyde (R)-159 in presence of chiral catalyst (Procedure B) 4.13.13.1 Multi-component aziridination reaction of aldehyde (R)-159 and MEDAM amine 66 in presence of (S)-VAPOL 1) 4 Å MS 2) (S)-VAPOL (10 mol%) MEDAM NH2 66 CHO OTBS (R)-159 (1.1 equiv) –10 ºC 3) EDA (11) B(OPh)3 (1.2 equiv) (30 mol%) –10 ºC, 24 h toluene, 80 °C, 0.5 h N OTBS MEDAM + N MEDAM OTBS COOEt 160a COOEt 160b (2R, 3R)-ethyl 1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-((R)-2-((tertbutyldimethylsilyl)oxy)propyl)aziridine-2-carboxylate 160a: Aldehyde (R)-159 was reacted according to the general Procedure B described above with (S)VAPOL as ligand to afford aziridines 160a and 160b with 98:2 diastereomeric ratio. Purification of the crude aziridine by neutral alumina chromatography (20 mm × 150 mm column, 4:2:0.1 hexanes/CH2Cl2/Et2O as eluent, gravity column) afforded inseparable mixture 278 of aziridines 160a and 160b as a viscous liquid in 83 % isolated yield (94 mg, 0.16 mmol). The diastereomeric ratio of 160a and 160b was determined to be 98:2 by HPLC analysis of crude reaction mixture (PIRKLE COVALENT (R, R) WHELK-O 1 column, 99.5:0.5 hexane/2-propanol at 222nm, flow-rate: 0.7 mL/min): retention times; Rt = 20.28 min (major diastereomer, 160a) and Rt = 29.15 min (minor diastereomer, 160b). 1 Spectral data for 160a: Rf = 0.13 (4:1:0.2 hexanes/CH2Cl2/Et2O); H-NMR (300 MHz, CDCl3): δ 0.00 (s, 3H), 0.02 (s, 3H), 0.86 (s, 9H), 0.88 (d, J = 6.1 Hz, 3H), 1.26 (t, J = 7.1 Hz, 3H), 1.56 (ddd, J = 13.6, 6.7, 6.7 Hz, 1H), 1.78 (ddd, J = 13.6, 6.7, 6.7 Hz, 1H), 2.07 (q, J = 6.5 Hz, 1H), 2.19 (d, J = 6.8 Hz, 1H), 2.24 (s, 12H), 3.42 (s, 1H), 3.56 (q, J = 6.3 Hz, 1H), 3.68 (s, 3H), 3.69 (s, 3H), 4.25-4.13 (m, 2H), 6.99 (s, 2H), 7.08 (s, 2H); 13 C-NMR (75 MHz, CDCl3): δ –4.81, – 4.55, 14.33, 16.16, 16.19, 18.05, 23.22, 25.84, 37.72, 43.12, 44.14, 59.57, 60.65, 67.15, 77.26, (one sp3 carbon not located), 127.36, 128.03, 130.47, 130.50, 137.72, 138.06, 155.77, 156.12, -1 169.62; IR (thin film) 2957vs, 2930vs, 1746s, 1483s, 1223s, 1184vs, 1145s cm ; HRMS (ESI+ TOF) m/z 570.3634 [(M+H ); calcd. for C33H52NO5Si: 570.3615]; [α ]20 +38.5 (c 1.0, CH2Cl2) D on 97:3 dr material (HPLC). € 279 4.13.13.2 Multi-component aziridination reaction of aldehyde (R)-159 and MEDAM amine 66 in presence of (R)-VAPOL 1) 4 Å MS 2) (R)-VAPOL (10 mol%) MEDAM NH2 66 CHO OTBS (R)-159 (1.1 equiv) –10 ºC 3) EDA (11) B(OPh)3 (1.2 equiv) (30 mol%) –10 ºC, 24 h toluene, 80 °C, 0.5 h N OTBS MEDAM + N MEDAM OTBS COOEt 160a COOEt 160b (2S, 3S)-ethyl 1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-((R)-2-((tertbutyldimethylsilyl)oxy)propyl)aziridine-2-carboxylate 160b: Aldehyde (R)-159 was reacted according to the general Procedure B described above with (S)VAPOL as ligand to afford aziridines 160b and 160a with 99:1 diastereomeric ratio. Purification of the crude aziridine by neutral alumina chromatography (20 mm × 150 mm column, 4:2:0.1 hexanes/CH2Cl2/Et2O as eluent, gravity column) afforded inseparable mixture of aziridines 160b and 160a as a viscous liquid in 85 % isolated yield (97 mg, 0.17 mmol). The diastereomeric ratio of 160b and 160a was determined to be 99:1 by HPLC analysis of crude reaction mixture (PIRKLE COVALENT (R, R) WHELK-O 1 column, 99.5:0.5 hexane/2-propanol at 222nm, flow-rate: 0.7 mL/min): retention times; Rt = 20.83 min (minor diastereomer, 160a) and Rt = 28.04 min (major diastereomer, 160b). 1 Spectral data for 160b: Rf = 0.13 (4:1:0.2 hexanes/CH2Cl2/Et2O); H-NMR (300 MHz, CDCl3): δ –0.21 (s, 3H), –0.10 (s, 3H), 0.80 (s, 9H), 1.04 (d, J = 6.2 Hz, 3H), 1.24 (t, J = 7.1 Hz, 3H), 1.77-1.59 (m, 2H), 2.16-2.24 (m, 14H), 3.43 (s, 1H), 3.68 (s, 6H), 3.70-3.76 (m, 1H), 4.17 (q, J = 280 7.1 Hz, 2H), 7.07 (s, 2H), 7.08 (s, 2H); 13 C-NMR (75 MHz, CDCl3): δ –5.21, –4.64, 14.29, 16.11, 16.16, 17.92, 23.75, 25.78, 37.63, 43.10, 44.34, 59.51, 59.54, 60.66, 67.11, 77.34, 127.23, 127.72, 130.48, 130.50, 138.03, 138.23, 155.75, 155.99, 169.71; IR (thin film) 2955vs, 2930vs, 1 + 2856s, 1746s, 1483s, 1221s, 1183vs, 1140s cm- ; HRMS (ESI-TOF) m/z 570.3632 [(M+H ); calcd. for C33H52NO5Si : 570.3615]; [α ]20 –33.5 (c 1.0, CH2Cl2) on 99:1 dr material (HPLC). D € 281 REFERENCES 282 REFERENCES (1) (a) Joly, G. D.; Jacobsen, E. N. Org Lett 2002, 4, 1795; (b) Akashi, M.; Arai, N.; Inoue, T.; Ohkuma, T. Adv Synth Catal 2011, 353, 1955; (c) Robles-MachiÃÅn, R.; GonzaÃÅlezEsguevillas, M.; Adrio, J.; Carretero, J. C. J. Org. Chem. 2009, 75, 233; (d) Chavez, D. E.; Jacobsen, E. N. Org Lett 2003, 5, 2563; (e) Doyle, M. P.; Kalinin, A. V.; Ene, D. G. J. Am. Chem. Soc. 1996, 118, 8837; (f) Kobayashi, S.; Ohtsubo, A.; Mukaiyama, T. Chem Lett 1991, 20, 831. (2) (a) Zhang, Y.; Lu, Z. J.; Wulff, W. D. Synlett 2009, 2715; (b) Mukherjee, M.; Gupta, A. K.; Lu, Z.; Zhang, Y.; Wulff, W. D. J. Org. Chem. 2010, 75, 5643; (c) Desai, A. A.; Wulff, W. D. J. Am. Chem. Soc. 2010, 132, 13100; (d) Zhang, Y.; Lu, Z.; Desai, A.; Wulff, W. D. Org Lett 2008, 10, 5429; (e) Zhang, Y.; Desai, A.; Lu, Z. J.; Hu, G.; Ding, Z. S.; Wulff, W. D. Chem-Eur J 2008, 14, 3785. (3) (a) Cherest, M.; Felkin, H.; Prudent, N. Tetrahedron Letters 1968, 2199; (b) Anh, N. T. Top. Curr. 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Org Biomol Chem 2004, 2, 2220. 284 CHAPTER 5   STUDIES TOWARDS THE ASYMMETRIC SYNTHESIS OF PHYTOSPHINGOSINES 5.1 Introduction Recent findings have shown that the Wulff’s catalytic asymmetric aziridination reaction is primarily a catalyst-controlled process in the case of chiral aldehydes, leading to an easy access to complex organic molecules with multiple chiral centers (Chapter 4). These finding inspired us to plan a synthesis of all four diasereomers of phytosphingosine 75 starting from the αoxygenated chiral aldehyde 192 (Scheme 5.6) using the Wulff catalytic asymmetric aziridination reaction as the key step. 5.2 Biological activity and previous syntheses of phytosphingosines The most abundant naturally occurring isomer of phytosphingosine is the D-ribo isomer 75a (Figure 5.1). The phytosphingosines 75 are one of the major ‘long-chain base’ components 1 of glycosphingolipids and were isolated from mushrooms in 1911. It is widely distributed as one of the molecular species of sphingolipids in microorganisms, in plants, and in many 2 3 4 5 6 mammalian tissues such as brain, hair, kidney, skin, liver, uterus, and intestine, and in blood plasma. 7 285 Figure 5.1 Family of phytosphingosines 75 OH 12 OH OH OH 12 NH2 75a D-ribo- phytosphingosine OH OH OH NH2 75b L-arabino- phytosphingosine 12 OH OH NH2 75c D-xylo- phytosphingosine OH 12 OH OH NH2 75d L- lyxo-phytosphingosine A great deal of effort has been made by the scientific community towards the synthesis of phytosphingosines for their use in biochemical, biophysical, and pharmacological studies. 8 Inspired by the fact that various unnatural isomers of sphinganines and sphingosines have different vital biological properties, scientists have been attracted towards the synthesis and biological testing of all eight isomers of phytosphingosines 75. Recently, there are two reports describing the synthesis of ceramide library that includes the synthesis of all eight isomers of 9 phytosphingosines. Most common approaches towards the synthesis of phytosphingosines involve nature’s chiral pool such as amino acids or carbohydrates as the source of chirality. 8,10 Until now, there are very few syntheses of phytosphingosine that involve asymmetric catalytic reactions as the key step. In 2003, the synthesis of isomers of xylo-phytosphingosine acetates was reported using double stereodifferentiation in Sharpless asymmetric dihydroxylation reaction (Scheme 5.1). 11 The key substrates 163 and 164 were each made in 99% ee via the 286 Sharpless asymmetric dihydroxylation of a trans-α,β- unsaturated ester. The enantiomers 163 and 164 were each subjected to Sharpless asymmetric dihydroxylation with both (DHQD)2AQN and (DHQ)2PHAL based catalyst but strong catalyst control was not observed preventing clean access to four of eight stereoisomers of phytosphingosines. The reaction of 163 with (DHQD)2AQN catalyst provided 165a with 6:1 selectivity, and after separation, a route to Lxylo-phytosphingosine. Similarly, the reaction of 164 provided 166a as a 5.5:1 mixture of diastereomers, and after separation, a route to D-xylo-phytosphingosine. Scheme 5.1 Synthesis of xylo-phytosphingosine derivative via Sharpless asymmetric dihydroxylation 7 steps 12 OH 11 162 O O O or 11 163 O O 164 HO Ligand, OsO4, K3Fe(CN)6, K2CO3 11 O HO OH + t-BuOH:H2O (1:1), 0 ºC, 24 h 11 O O 11 165a 163 OH O O 165b Ligand 165a:165b % yield (DHQ)2PHAL 1:2 89 (DHQD)2PHAL 5:1 92 HO 165a + 165b separation OH 11 O O 6 steps OAc OAc 11 OAc NHAc 167 tetraacetate of L-xylo-phytosphingosine 165a 287 Scheme 5.1 (cont’d) HO Ligand, OsO4, K3Fe(CN)6, K2CO3 11 O O t-BuOH:H2O (1:1), 0 ºC, 24 h 11 O OH O 11 166a 164 Ligand (DHQD)2PHAL HO separation OH 11 O O O 166b 166a:166b (DHQ)2PHAL 166a + 166b HO OH + % yield 5.5:1 70 1:2 92 6 steps OAc O 11 OAc OAc NHAc 168 tetraacetate of D-xylo-phytosphingosine 166a There is a separate report where Sharpless asymmetric epoxidation has been used as the 12 key step for the synthesis of D-lyxo-phytosphingosine (Scheme 5.2A). isomers of phytosphingosine were not described in this report. The synthesis of other Further, L-arabino- phytosphingosine has been prepared using Sharpless’s kinetic resolution of allylic alcohols as the key step (Scheme 5.2B). 13 A synthesis of L-xylo-phytosphingosine was also achieved from the allylic alcohol (S)-171. 288 Scheme 5.2 Synthesis of phytosphingosines ent-75d and its derivative 173 via (A) Sharpless asymmetric epoxidation (B) Sharpless kinetic resolution (A) Sharpless AE BnO OH BnO 169 OH 11 steps O 12 CO2Me 170 OH OH NH2 ent-75d D- lyxo-phytosphingosine (B) (–)-DIPT, Ti(OiPr)4, TBHP OH CH2Cl2, 3Å MS, –20 ºC, 4 d 13 rac-171 OH OH OH + 13 O 172 96:4 (erythro:threo) 49% yield 13 (S)-171 46% yield OAc 8 steps 12 13 O 172 OAc OAc NHAc 173 tetraacetate of L-arabino- phytosphingosine The organocatalytic asymmetric synthesis of D-arabino- and L-ribo-phytosphingosine was reported by Enders et. al employing (S)-proline-catalyzed diastereo and enantioselective aldol reaction of 2,2-dimethyl-1,3-dioxan-5-one 174 and pentadecanal 175 as the key step 289 14 (Scheme 5.3). This approach should allow access to only four of the eight stereoisomers of the phytosphingosines since the aldol reaction will give only the anti adduct. Scheme 5.3 Synthesis of phytosphingosines ent-75d and its derivative 177 and 178 via organocatalytic aldol reaction + O O 174 O CHCl3 13 O 175 NH2 OH O O H OH O 13 176 60% yield >90% de, 95% ee O 5 steps 13 O (S)-proline (30 mol%) O O Bn OH 2 steps 13 O O 176 177 protected L-ribophytosphingosine >99% de, 95% ee NH OTBS O 13 178 protected D-arabinophytosphingosine >99% de, 95% ee 3 steps OH HO NH2 OH 12 ent-75b D-arabino- phytosphingosine Bittman and coworkers employed a combination of Trost asymmetric alkynylation reaction and then optical purity enhancement by partial kinetic resolution via Sharpless 15 asymmetric epoxidation for an asymmetric synthesis of D-ribo-phytosphingosine 75a. The stereochemistry determining steps involve the prophenol (R,R)-183 catalyzed alkynylation of 290 unsaturated aldehyde 180 resulting in the allylic propargylic alcohol (S)-181 in 60% ee. This was followed by the Shapless asymmetric epoxidation to afford epoxy alcohol anti-182 in 93% de. The synthesis of other isomers of phytosphingosine was not reported. Scheme 5.4 Synthesis of D-ribo-phytosphingosine 75a via Trost asymmetric alkynylation reaction and Sharpless asymmetric epoxidation C12H25 179 HO Ph + OPMP O OH Me2Zn, PhMe, 4 ºC, 4 d Ph N OH N Ph OH Ph OPMP C12H25 180 (–)-DIPT, Ti(OiPr)4 Me2C(Ph)OOH CH2Cl2, 4Å MS –20 ºC, 4 d (R, R)-183 (10 mol%) OH 12 181 86% yield 60% ee OH 3 steps OPMP OH OH NH2 75a D-ribo- phytosphingosine C12H25 O 182 68% yield 93% de Llaveria et. al made the chiral synthon 185 for the synthesis of D-ribo-phytosphingosine 75a by a palladium-catalyzed dynamic kinetic asymmetric transformation (DYKAT) from the 16 racemic butadiene monoepoxide 184 (Scheme 5.5). 291 Scheme 5.5 Synthesis of D-ribo-phytosphingosine 75a via palladium-catalyzed dynamic kinetic asymmetric transformation from the racemic epoxide 184 phthalimide, Na2CO3 5 steps (!3-C3H5PdCl)2 O O 184 O N H HN PPh2 Ph2P N O O HO O O N C14H29 HO 185 99% yield 99% ee O 187 O S O O 6 steps OH 12 OH OH NH2 75a D-ribo- phytosphingosine All of the previous approaches are limited to the synthesis of certain diastereomers only. In all cases, the previous methods were unable to cleanly provide all diastereomers of the phytosphingosines with high selectivity. The aim of the present work is to devise a common protocol for the synthesis of four diastereomers of the phytosphingosines. To attain the objective, we envisioned to utilize the catalyst controlled aziridination reaction starting from aldehyde 192 (Scheme 5.6). 5.3 Retro-synthetic analysis of phytosphingosines A retro-synthetic analysis of the phytosphingosines is presented in Scheme 5.6. The synthesis of D-xylo-phytosphingosine 75c and L-lyxo-phytosphingosine 75d is projected via ring 292 opening of the corresponding diastereomers of the cis-aziridines 188 and 189, respectively, with an oxygen nucleophile. Scheme 5.6 Retro-synthetic analysis: D-ribo-phytosphingosine 75a, D-xylo-phytosphingosine 75b, L-arabino-phytosphingosine 75c and L-lyxo-phytosphingosine75d O OH NH O OH OH NH2 75a D-ribo-phytosphingosine 12 12 OP 191 CO2Et ring expansion (P' = Boc) ring opening with 'O' nucleophile and reduction OH N OH 12 OH NH2 75c D-xylo-phytosphingosine 12 OP 188 catalyst-controlled MCAZ O P' OH NH2 12 OP 189 OH CO2Et O OH O OH NH2 75b L-arabino-phytosphingosine 12 OP 190 293 OP 192 catalyst-controlled MCAZ ring expansion (P' = Boc) 12 H N OH 75d L-lyxo-phytosphingosine CO2Et 12 ring opening with 'O' nucleophile and reduction OH 12 P' NH CO2Et The synthesis of D-ribo-phytosphingosine 75a could be achieved via the ring expansion of N-Boc (P' = Boc) protected aziridine 188 with retention of configuration to the oxazolidinone 191. A similar approach was demonstrated for the synthesis of erythro-sphinganines 74a and 74d in the Chapter 3. Subsequent hydrolysis of the oxazolidinone 191 and the reduction of the corresponding ester would give the D-ribo-phytosphingosine 75a. In a similar fashion, the Larabino- phytosphingosine 75b could be possible via the ring expansion of N-Boc (P' = Boc) protected aziridine 189 to oxazolidinone 190. A multi-component aziridination reaction (MCAZ) of chiral aldehyde 192 would yield aziridines 188 and 189 in the presence of the (S)VAPOL catalyst and the (R)-VAPOL catalyst respectively, assuming the reaction would behave in a catalyst-controlled manner as was demonstrated for related chiral aldehydes (see Chapter 4). 5.4 Synthesis of chiral aldehyde (R)-192 via hydrolytic kinetic resolution of rac-epoxide The chiral aldehyde (R)-192a and (R)-192b were synthesized starting from 1-hexadecene following the synthetic route shown in Schemes 5.7 and 5.8. Scheme 5.7 Synthesis of optically pure 1,2- diol (R)-195 by hydrolytic kinetic resolution 1) N t-Bu N Co O t-Bu 193 DCM, 16h t-Bu t-Bu (1S, 2S)-196 (0.5 mol%) HOAc (0.5 mol%) m-CPBA 12 O 12 O 2) 194 90% yield H2O (0.55 equiv) 12 OH OH (R)-195 40% yield 294 The reaction of 1-hexadecene 193 with mCPBA afforded the corresponding epoxide 194 in 90% yield. The hydrolytic kinetic resolution of the racemic epoxide 194 resulted in optically pure (> 99% ee) (R)-hexadecane-1,2-diol (R)-195 in 40% yield (Scheme 5.7). Stepwise protection of the terminal hydroxyl group as trityl and the internal hydroxyl group as tertbutyldimethylsilyl afforded the bis-protected alcohol (R)-197a in 90% yield over two steps. Similarly, the stepwise protection of the terminal hydroxyl group as trityl and internal hydroxyl group as benzyl afforded the bis-protected alcohol (R)-197b that was used for the next step without further purification (Scheme 5.8). Scheme 5.8 Synthesis of optically pure aldehydes (R)-192a and (R)-192b 1) TrCl pyridine rt, 24h 2) TBSCl Imidazole DMF, rt, 32h 12 OTr OTBS TFA, Et3SiH (5 equiv) CH2Cl2, 0 ºC (R)-197a 95% yield OH OTBS (R)-198a 85% yield 12 DMP, DCM rt, 30 min O 12 OH 12 OH OP (R)-192a, P= TBS, 85% yield (R)-192b, P= Bn, 90% yield (R)-195 1) TrCl pyridine rt, 24h 2) BnBr, NaH DMF, rt, 12h H 12 OTr OBn TFA, Et3SiH (5 equiv) CH2Cl2, 0 ºC (R)-197b 92% yield 295 DMP, DCM rt, 30 min OH OBn (R)-198b 85% yield 12 Subsequent mono deprotection of the terminal trityl ether under reductive conditions resulted in the mono protected alcohol (R)-198a and (R)-198b from alcohols (R)-197a and (R)197b, respectively, in high yields. The aldehydes (R)-192a and (R)-192b was obtained via the oxidation of the alcohols (R)-198a and (R)-198b, respectively, with Dess-Martin periodinane and used immediately after purification by column chromatography. 5.5 Synthesis of aziridine precursor via multi-component catalytic asymmetric aziridination reaction of chiral aldehyde (R)-192. As expected from the previous studies presented in Chapter 4, the catalytic asymmetric aziridination reaction with the aldehyde (R)-192 proceeds under a catalyst-controlled process. Table 5.1 Multi-component aziridination reaction of chiral aldehyde (R)-192 in the presence of a chiral boroxinate catalyst a 1) O 12 Ar Ar NH2 66 OP (R)-192a, P= TBS (R)-192b, P= Bn (1.1 equiv) Ligand (x mol%) B(OPh)3 (3x mol%) toluene 80 °C, 0.5 h H Ar Ar Ar N 4 Å MS, temp Ar N + 2) EDA (11) (2 equiv) temp, 24 h 12 OP CO2Et 12 OP CO2Et 199a, P= TBS 199a', P= Bn Ar = 3,5-Me2-4-OMe-C6H2 199b, P= TBS 199b', P= Bn Ar 12 TBSO N Ar H (R)-200 (in situ formed imine) 296 Table 5.1 (cont’d) entry P temp (ºC) ligand Catalyst loading dr (199a:199b) c % yield b (199a + 199b) (x mol%) d –10 (S)-VAPOL 10 82:18(82:18) 90 –10 (R)-VAPOL 10 <1:>99(<1:>99) 95 3 –10 (S)-VAPOL 10 90:10(90:10) 85 4 –10 (S)-VAPOL 5 90:10(90:10) 88 5 –10 (R)-VAPOL 10 <1:>99(<1:>99) 92 6 –10 (R)-VAPOL 5 <1:>99(<1:>99) 94 –10 (S)-VANOL 5 88:12(90:10) 80 8 –10 (R)-VANOL 5 1:99(1:99) 85 9 0 (S)-VAPOL 5 89:11(90:10) 80 10 0 (R)-VAPOL 5 <1:>99(<1:>99) 94 e –30 (S)-VAPOL 10 nd nd f –30 (R)-VAPOL 5 <1:>99(<1:>99) 90 1 d 2 7 TBS 11 12 a Bn Unless otherwise specified, all reactions were performed with 0.2 mmol amine 66 (0.2 M in toluene) and 1.1 equiv of (R)-192 and 2.0 equiv EDA 11 and went to 100% completion. Prior to the addition of the aldehyde and the EDA 11, a solution of amine 66 with x mol% ligand and 3x 297 Table 5.1 (cont’d) mol% commercial B(OPh)3 was stirred for 30 min at 80 °C under nitrogen. nd = not determined. All reactions with 5 mol% catalyst loading are performed with 0.5 mmol 66 (0.2 M in toluene). b c Isolated combined yield of 199a and 199b after chromatography on silica gel. Determined on a sample prepared by passing the crude reaction mixture through a silica plug. Determined by using PIRKLE COVALENT (R, R) WHELK-O1 column. Diastereomeric ratio in parentheses is for the purified inseparable mixture of 199a and 199b and was deterimined by HPLC on PIRKLE COVALENT (R, R) WHELK-O1 column. 199b'. e d The product aziridines are 199a' and 1 Reaction was incomplete even after 48 h based on the crude HNMR analysis. The ratio of major diastereomer and unreacted in situ formed imine (R)-200 is 1.0:2.5. f 1.2 equiv EDA used. The aziridination reaction of the (R)-192b (P = CH2Ph), with a benzyl ether at the αposition, in the presence of 10 mol% (S)-VAPOL boroxinate catalyst at –10 ºC resulted in cisaziridines 199a' and 199b' with an 82:18 diastereomeric ratio and in 90% yield (Table 5.1, entry 1). The aziridination reaction of (R)-192b in the presence of 10 mol% (R)-VAPOL boroxinate catalyst at –10 ºC gave aziridine 199b' as major the diastereomer with a 1:99 diastereomeric ratio in 95% yield (Table 5.1, entry 2). In order to see the effect of the protecting group on the diastereomeric ratio of the product, the hydroxyl protecting group at the α- position in aldehyde was changed to tert-butyldimethylsilyl group. The aziridination reaction of the (R)-192a (P = TBS) in the presence of 10 mol% (S)-VAPOL boroxinate catalyst at –10 ºC resulted in cisaziridines 199a and 199b in a 90:10 diastereomeric ratio (Table 5.1, entry 3). The reaction with 298 10 mol% (R)-VAPOL boroxinate catalyst at –10 ºC resulted in cis-aziridines 199a and 199b with an <1:>99 diastereomeric ratio and in 92% yield (Table 5.1, entry 5). It was important to find that the catalyst loading could be decreased to 5 mol% without any detrimental effect on the yield or the diastereomeric ratio (entries 4 and 6). The aziridination reaction of (R)-192a (P = TBS) in the presence of 5 mol% (S)-VANOL boroxinate catalyst at –10 ºC resulted in cisaziridines 199a and 199b with an 88:12 diastereomeric ratio and in 80% yield (Table 5.1, entry 7). Similarly, with 5 mol% (R)-VANOL boroxinate catalyst at –10 ºC, cis-aziridines 199a and 199b were obtained in a 1:99 diastereomeric ratio and in 85% yield (Table 5.1, entry 8). An increase in the temperature of the reaction to 0 ºC does not show any significant effect either on the yield or the diastereoselectivity of the aziridination reaction (Table 5.1, entries 9 and 10). In the case of the aziridination reaction of aldehyde (R)-192a with 5 mol% (R)-VAPOL boroxinate catalyst, no effect on the yield or the diastereomeric ratio was observed when the reaction temperature was decreased to –30 ºC. The reaction resulted in cis-aziridine 199a and 199b with a <1:>99 diastereomeric ratio and in 90% yield (entry 12). Interestingly, the reaction of aldehyde (R)-192a in the presence of 10 mol% of (S)-VAPOL boroxinate catalyst at –30 ºC was not completed even after 48 h (entry 11). A substantial amount of unreacted imine (R)-200 could 1 be observed in the crude reaction mixture by H NMR analysis. This observation suggests that there is a significant rate difference between the aziridination reactions of aldehyde (R)-192a with the (R)-VAPOL and (S)-VAPOL derived boroxinate catalysts at –30 ºC. This suggests that there might be a possibility of a kinetic resolution of racemic aldehyde 192a. Encouraged by this observation, the aziridination reaction of the aldehyde rac-192a was performed in the presence of the (R)-VAPOL boroxinate catalyst (Scheme 5.9). 299 Scheme 5.9 Aziridination reaction with rac-168a in the presence of the (R)-VAPOL catalyst 1) O H OTBS rac-192a (1.1 equiv) 12 Ar Ar NH2 66 Ligand (5 mol%) B(OPh)3 (15 mol%) toluene 80 °C, 0.5 h Ar Ar Ar N 4 Å MS, temp Ar N + CO2Et OTBS 12 2) EDA (11) (0.45 equiv) –30 ºC, 24 h CO2Et OTBS 12 199b 199a (99% ee) Ar = 3,5-Me2-4-OMe-C6H2 Ar Ar Ar N Ar N + CO2Et OTBS 12 ent-199b CO2Et OTBS 12 ent-199a 85% yield 1:27 dr [(199a+ent-199a):(199b+ent-199b)] The aziridination reaction of the aldehyde rac-192a with MEDAM amine 66 and EDA 11 (0.45 equiv) in the presence of 5 mol% (R)-VAPOL boroxinate catalyst resulted in cis-aziridine 199b as the major diastereomer. The reaction resulted in cis-aziridines 199a and 199b with a 1:27 diastereomeric ratio and in 35% combined yield. The asymmetric induction of 199a was determined to be 99% ee. It must be noted that the ee was determined by the integration of the peaks having same UV absorption pattern in the chiral HPLC. However, the ee could not confirmed due to the unavailability of the authentic sample of ent-199a. This observation provides an opportunity to synthesize complex molecules such as Myriocin via aziridination of the racemic aldehyde 202 (Scheme 5.10), where the synthesis of the chiral aldehyde might be otherwise troublesome. 300 Scheme 5.10 Proposed synthesis of Myriocin via aziridination of rac-202 in the presence of the (R)-VAPOL catalyst. O OH 3 COOH OH OH NH2 6 P' N O 3 6 Myriocin OP CO2Et 201 (optically pure) MCAZ (R)-VAPOL H O 3 6 O OP rac-202 5.6 Studies towards the synthesis of phytosphingosines 75 We have shown previously (Chapter 3) that the ring opening of the aziridine ent-37l was achieved in high yield using TFA (Scheme 5.11). However, the ring opening of aziridine 199b in the presence of TFA resulted complex mixture of unidentified products, which were no separated or characterized. Scheme 5.11 Ring opening of aziridine ent-37l with TFA Ar Ar 1) TFA DCM, reflux, 12 h N CO2Et 12 OH 12 2) NaOH ent-37l CO2Et NHCHAr2 ent-103 75% yield Ar = 3,5-Me2-4-OMe-C6H2 Ar2CH = MEDAM 301 In the planned synthesis of the L-lyxo-phytosphingosine 75d, it was thought to activate the aziridine by replacing the N-MEDAM group with an electron withdrawing N-Boc group. Surprisingly, the acid catalyzed deprotection of the N-MEDAM group in anisole resulted in the formation of the γ-lactone fused aziridine 203 (Scheme 5.12). The formation of the γ-lactone might be facilitated by the deprotection of the TBS group in acidic medium, as lactone ring formation is expected to be entropically favorable over the ring opened γ- hydroxy ester form. The aziridine 203 was not purified but instead directly treated with Boc anhydride under basic condition to afford Boc-protected aziridine 204 in 65% yield. Scheme 5.12 Deprotection of N-MEDAM group and subsequent protection with Boc2O. Ar H Ar N CO2Et OTBS 12 N TfOH (5 equiv) anisole, rt, 5 min 199b Ar = 3,5-Me2-4-OMe-C6H2 Ar2CH = MEDAM Boc O N Boc2O, NaHCO3 O 12 203 (not purified) THF, H2O, rt, 12h O O 12 204 65 % yield (over 2 steps, from 199b ) During the synthesis of threo-sphinganines 74b and 74c (Chapter 3), the reaction of the N-Boc aziridines 100 and ent-100 with formic acid resulted in the ring-opened products 101 and ent-101, respectively, in quantitative yields (Scheme 5.13). 302 Scheme 5.13 Ring opening of N-Boc aziridines 101 and ent-101 with formic acid Boc N OH HCO2H (88%) CO2Et 25 ºC, 1 h 12 12 99 CO2Et NHCHO 101 98% yield Boc N OH HCO2H (88%) CO2Et 25 ºC, 1 h 12 ent-99 12 CO2Et NHCHO ent-101 99% yield However, no ring-opened product was observed when the same protocol was applied to the lactone fused N-Boc aziridine 204. Instead, a very small amount of N-H aziridine 203 was observed after 1 h (Scheme 5.13). The reason for the failure of the ring opening of 204 using formic acid is not known yet. However, there are examples of the ring opening of lactone fused aziridines using alcohol as the nucleophile. 17 Therefore, the N-Boc aziridine 204 was subjected to the ring opening conditions in presence of benzyl alcohol and BF3•OEt2 in CHCl3 at 25 ºC. Unfortunately, the reaction resulted in a complex mixture of unknown products, which was not further pursued. 303 Scheme 5.14 Reaction of N-Boc aziridine 204 with formic acid H Boc N O N HCO2H (88%) O Boc N + 25 ºC, 1 h O O 12 12 204 203 7% (NMR yield) BnOH, BF3•OEt2 CHCl3, rt, 3 h O O 12 unreacted 204 90% (NMR yield) complex mixture of unknown products In 1995, Dodd and coworkers demonstrated that in the presence of BF3•OEt2, ring 17 opening of N-Cbz protected 2,3-aziridino--lactones by alcohols occurs regioselectively at C-3. Hence, it was thought to replace the Boc group with a Cbz group to affect the ring opening reaction. The N-Cbz aziridine 205 was synthesized by reacting the crude N-H aziridine 203 in presence of N-(benzyloxycarbonyloxy)succinimide 206 under basic condition (Scheme 5.15). The ring opening reaction of N-Cbz aziridine 205 with benzyl alcohol in presence of BF3•OEt2 resulted in the corresponding lactone 207 with 45% yield (Scheme 5.15). 18 The difference in the reactions of 204 and 205 with benzyl alcohol and is BF3•OEt2 quite unexpected. 304 Scheme 5.15 Cbz protection and subsequent ring opening O Ar H Ar N TfOH (5 equiv) N CO2Et OTBS 12 Cbz anisole, rt, 5 min Ar = 3,5-Me2-4-OMe-C6H2 Ar2CH = MEDAM O Cbz 206 N NaHCO3 THF, H2O rt, 24h O O 12 199b N O O 12 205 80 % yield (over 2 steps, from 199b ) 203 (not purified) BnOH BF3•OEt2 CHCl3, rt, 3 h NHCbz BnO O O O 12 207 45% yield Although, the aziridine 207 was obtained in 45% yield, it may be possible to improve the yield by employing different Lewis acids and oxygen nucleophiles although this has not yet been explored. Nonetheless, the lactone 207 is likely to provide a direct access to the synthesis of Llyxo-phytosphingosine 75d by reduction followed by hydrogenolytic cleavage of the ‘N’ and ‘O’ protecting groups (Scheme 5.16). Scheme 5.16 Proposed synthesis of L-lyxo-phytosphingosine 75d from lactone 207 NHCbz BnO O 12 O OH 1) reduction 2) hydrogenolysis 207 12 OH OH NH2 75d L-lyxo-phytosphingosine 305 In an effort to develop a synthesis of L-arabino-phytosphingosine 75b, the N-Boc aziridine 204 was subjected to ring expansion conditions in the presence of Lewis acids (see Chapter 3, Table 3.6). To our surprise, the ring expansion in the presence of either scandium triflate or tin (II) triflate resulted in the undesired regioisomer of the lactone-fused oxazolidinone 204 as the major product (Scheme 5.17A). However, it must be remembered that the ring expansion of the aziridines without pre-installed lactone functionality resulted in the desired C3N bond cleavage of the aziridine ring. 19 Scheme 5.17 (A) Ring expansion of N-Boc aziridine 204 to oxazolidinones 208 and 209. (B) possible rational for the formation of 208 A Boc N O O O Lewis acid (0.2 equiv) HN H O CH2Cl2, rt, 48 h + H O H O O 204 208 Lewis acid 209 208:209 combined yield (%) Sc(OTf)3 10:1 65 Sn(OTf)2 7:1 60 B O H O O HN H M N C3 R C2 O C1 R O1 R= 12 M = Lewis acid 306 O 12 12 12 NH H O O O H O 208 O This reversal in the regioselectivity in the ring-expansion of 204 might be due to the 1 coordination of the Lewis acid with the O oxygen in the lactone ring, which facilitates the cleavage of the C2-N bond instead of the C3-N bond resulting in the regio-isomer 208 (Scheme 5.17B). Presently, this project is on hold due to time constraints. However, if the explanation for the reversal in regioselectivity is correct and if N-Boc aziridine 210 can be accessed by some means, then subsequent Lewis acid mediated ring expansion to 211 may be possible following a protocol reported for a similar aziridine. 20 The synthesis of the L-arabino-phytosphingosine 75b could be possible via reduction of ester functionality and hydrolysis of the oxazolidinone ring in 211 (Scheme 5.18). Scheme 5.18 Possible solution to synthesize the required regio-isomer of oxazolidinone 211 by ring expansion of the N-Boc aziridine 210 Boc N O Lewis acid CO2Et OTBS 12 210 O NH OH 1) reduction CO2Et 2) hydrolysis OTBS 12 211 12 OH OH NH2 75b L-arabino-phytosphingosine Following similar strategies as discussed above, D-ribo-phytosphingosine 75a could be synthesized via ring opening of the N-Cbz aziridine 212. The synthesis of D-xylo- phytosphingosine 75c could be possible via the ring expansion of the N-Boc aziridine 214 to oxazolidinone 215 (Scheme 5.19). 307 Scheme 5.19 Possible synthetic route to (A) D-ribo-phytosphingonine and (B) D-xylophytosphingonine from aziridine 199a. A Ar Ar Cbz N N 1) TfOH, anisole CO2Et 12 OTBS 2) O 199a Cbz Ar = OMe N O O O 12 ring opening NHCbz BnO O O 12 212 O 213 206 NaHCO3 THF, H2O 1) reduction 2) hydrogenolysis OH OH OH NH2 75c D-xylo-phytosphingosine 12 B Ar Ar 1) deprotection N CO2Et OTBS 12 199a Ar = O Boc 2) Boc protection ring expansion N CO2Et OTBS 12 214 O CO2Et OTBS 12 215 1) reduction 2) hydrogenolysis OMe OH 12 OH OH NH2 75a D-ribo-phytosphingosine 308 NH 5.7 Conclusions This chapter describes a study directed to the application of the Wulff catalytic asymmetric aziridination reaction to phytosphingosines. The syntheses of all four diastereomers of phytosphingosine were attempted using the aziridination reaction as the key step. Although, the asymmetric syntheses are not completed, the key premise has been established with the demonstration that the aziridination of the chiral aldehyde (R)-192 is catalyst-controlled giving high absolute stereocontrol with either (R)- or (S)-VAPOL or VANOL catalysts. Thus, these initial efforts have defined direct and stereoselective route to all four diastereomers. Hopefully, based on the advances made in this project, these targets can be realized in the near future. 309 APPENDIX 310 5.8 5.8.1 Experimental procedure General information Same as Chapter 2. 1-hexadecene 193, 3-chloroperoxybenzoic acid was obtained from Alfa Aesar and used as received. The catalyst (1S, 2S)-196 was was obtained from Strem Chemicals and used as received. 5.8.2 Synthesis of chiral aldehyde (R)-192 5.8.2.1 Epoxidation of 1-hexadecene mCPBA 12 CH2Cl2, 16h, rt 193 12 O 194 90% yield 2-Tetradecyloxirane 194: To an oven dried 500 mL round bottom flask was added 1hexadecene 193 (14.3 mL, 50 mmol) and freshly distilled dichloromethane (250 mL). The solution was cooled to 0 °C. To the solution was added 3-Chloroperoxybenzoic acid (77%, remainder 3-chlorobenzoic acid and water), (15.0 g, 65 mmol, 1.3 equiv) was added in one portion. After 10 min, the resulting suspension was warmed to room temperature and was stirred at that temperature for 16 h. The reaction mixture was then diluted with hexanes (600 mL) and filtered through a Celite pad to a 1L round bottom flask, in order to remove undissolved 3chlorobenzoic acid from the reaction mixture. The filtrate was washed sequentially with saturated aqueous sodium bicarbonate solution (1 × 800 mL), saturated aqueous sodium bisulfite solution (1 × 800 mL), saturated aqueous sodium bicarbonate solution (1 × 800 mL) and brine (1 311 × 800 mL). The organic layer was then isolated, dried over MgSO4, concentrated under reduced pressure to afford crude epoxide 194 as colorless oil. The epoxide 194 was purified by simple distillation under reduced pressure (bp 93 ºC at 0.1 Hg) to afford 194 as colorless oil in 90% yield (10.82 g, 45 mmol). Spectral data for 194: 1 H-NMR (500 MHz, CDCl3): δ 0.88 (t, J = 7.0 Hz, 3H), 1.30-1.33 (m, 26H), 2.46 (dd, J = 5.1, 2.8 Hz, 1H), 2.74 (dd, J = 5.0, 4.0 Hz, 1H), 2.90 (tdd, J = 5.5, 3.9, 2.7 Hz, 1H); 13 C-NMR (151 MHz, CDCl3): δ 14.11, 22.69, 25.97, 29.36, 29.45, 29.56, 29.64, 29.65, 29.67, 29.68, 29.70, 31.93, 32.50, 47.13, 52.41 (one sp3 carbon not located). The spectral data matched with those for the reported compound. 21 5.8.2.2 Hydrolytic kinetic resolution of 2-tetradecyloxirane 194 1) (1S, 2S)- 172 (0.5 mol%) HOAc (0.5 mol%) 12 O 12 2) H2O (0.55 equiv) OH OH (R)-195 40% yield 194 N t-Bu N Co O t-Bu O t-Bu t-Bu (1S, 2S)- 196 (R)-Hexadecane-1,2-diol (R)-195: To a 50 mL round bottom flask (1S, 2S)-196 (151 mg, 0.25 mmol), toluene (1.3 mL), and acetic acid (28.8 µL, 0.50 mmol, 2.0 equiv to catalyst) was added. 312 The mixture was stirred while open to the air for 1 h at room temperature. The solvent was removed by rotary evaporation, and the brown residue was dried under vacuum (0.05 mm Hg) for 2h. To the reaction flask, 2-tetradecyloxirane (12.02 g, 50.0 mmol) was added in one portion, and the stirred mixture was cooled in an ice-water bath. Water (495.5 µL, 27.5 mmol, 0.55 equiv) was slowly added to the reaction mixture. Thereafter, the ice-water bath was removed and the reaction mixture was vigorously stirred at room temperature for 12 h. Hexanes (10 mL) were added to the thick slurry and the mixture was filtered through a sintered glass funnel under mild vacuum. The solid precipitate was washed with ice-cold hexanes (4 × 20 mL). The hexanes washing removes the left over chiral epoxide 194. The light reddish white solid (R)-195 was crystallized from EtOAc/hexanes (1:3) mixture. The first crop was collected with 35% yield (4.52 g, 17.5 mmol) of (R)-195 as an off-white flaky solid (mp 83-84 ºC). The mother liquor was concentrated and again crystallized from EtOAc/hexanes (1:3) mixture. The second crop was collected with 5% yield (646 mg, 2.5 mmol) of (R)-195 (mp 83-84 ºC). Spectral data for (R)-195: 1 H-NMR (300 MHz, CDCl3): δ 0.88 (t, J = 6.7 Hz, 3H), 1.30-1.26 (m, 24H), 1.41-1.43 (m, 2H), 1.80 (t, J = 5.7 Hz, 1H), 1.94 (d, J = 4.3 Hz, 1H), 3.44 (ddd, J = 10.9, 7.5, 5.0 Hz, 1H), 3.75-3.63 (m, 2H).; 13 C-NMR (151 MHz, CDCl3): δ 14.10, 22.68, 25.55, 29.35, 29.55, 29.59, 29.65, 29.66, 29.68, 29.69, 31.91, 33.19, 66.82, 72.34 (two sp3 carbon not located). [α ]20 +9.5 (c 1.0 EtOH). D € 313 5.8.2.3 Bis-protection of (R)-hexadecane-1,2-diol (R)-195 12 OH OH (R)-195 1) TrCl, pyridine 24h, rt 2) TBSCl, Imidazole DMF, rt, 32h OTr OTBS (R)-197a 12 (R)-tert-Butyldimethyl((1-(trityloxy)hexadecan-2-yl)oxy)silane (R)-197a: To an oven dried 100 mL round bottom flask equipped with a stir bar and a rubber septum with a nitrogen balloon at the top, was added 1,2-diol (R)-195 (1.03 g, 4.0 mmol) and pyridine (22 mL). The mixture was stirred at room temperature to get a clear solution. Thereafter, the flask was transferred to an ice water bath and stirred for another 10 min at 0 ºC. To the reaction mixture was added triphenylmethyl chloride (2.34 g, 8.4 mmol, 2.1 equiv) at 0 ºC. The reaction mixture was warmed to room temperature and stirred for 24 h at room temperature under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to afford a pale yellow solid. The crude solid was dissolved in freshly distilled DMF (10 ml) under nitrogen atmosphere. To the clear solution was added imidazole (544 mg, 8.0 mmol, 2.0 equiv) and TBSCl (1.2 g, 8.0 mmol, 2.0 equiv). The reaction mixture was stirred at room temperature for 32 h under nitrogen atmosphere. Upon completion, the reaction mixture was diluted with hexanes (30 mL) and brine (50 mL) was added to the flask. The organic layer was separated and the aqueous layer was extracted with ether (4 × 20 mL). The combined organic layer was dried with MgSO4 and concentrated under reduced pressure to afford the crude reaction mixture. Purification of the crude by silica gel chromatography with a rubber septum and a nitrogen balloon at the top (30 mm×300 mm column, 50:1 hexanes/Et2O as eluent) afforded pure (R)197a as a colorless liquid in 95 % isolated yield (2.34 g, 3.8 mmol) over two steps from (R)-195. 314 1 Spectral data for (R)-197a: Rf = 0.70 (1:16 Et2O / hexanes) H-NMR (300 MHz, CDCl3): δ – 0.03 (s, 3H), –0.01 (s, 3H), 0.84-0.89 (m, 12H), 1.18-1.33 (m, 24H), 1.39-1.45 (m, 1H), 1.601.67 (m, 1H), 2.96 (dd, J = 9.2, 5.8 Hz, 1H), 3.05 (dd, J = 9.2, 5.2 Hz, 1H), 3.76 (quintet, J = 5.7 Hz, 1H), 7.19-7.32 (m, 9H), 7.46 (dd, J = 8.3, 1.4 Hz, 6H). 13 C-NMR (151 MHz, CDCl3): δ – 4.75, –4.39, 14.12, 18.12, 22.70, 24.96, 25.89, 29.37, 29.60, 29.67, 29.69, 29.70, 29.79, 31.93, 34.97, 67.66, 71.77, 86.37, (three sp3 carbon not located), 126.82, 127.66, 128.78, 144.31; IR -1 (thin film) 2926vs, 2855s, 1464s, 1448s, 1257s, 1076 s cm ; HRMS (ESI-TOF) m/z 615.4603 + [(M+H ); calcd. for C41H63O2Si: 615.4597]; [α ]20 +9.0 (c 1.0, CH2Cl2). D OH OH (R)-195 12 1) TrCl, pyridine 24h, rt € 2) BnBr, NaH, TBAI DMF, rt, 12h OTr OBn (R)-197b 12 (R)-(((2-(Benzyloxy)hexadecyl)oxy)methanetriyl)tribenzene (R)-197b: To an oven dried 100 mL round bottom flask equipped with a stir bar and a rubber septum with a nitrogen balloon at the top, was added 1,2-diol (R)-195 (517 mg, 2.0 mmol) and pyridine (11 mL). The mixture was stirred at room temperature to get a clear solution. Thereafter, the flask was transferred to an ice water bath and stirred for another 10 min at 0 ºC. To the reaction mixture was added triphenylmethyl chloride (1.17 g, 4.2 mmol, 2.1 equiv) at 0 ºC. The reaction mixture was warmed to room temperature and stirred for 24 h at room temperature under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to afford pale yellow solid. The crude solid was dissolved in freshly distilled DMF (10 ml) under nitrogen 315 atmosphere. The reaction mixture was cooled to 0 ºC. To the clear solution was added sodium hydride (160 mg, 4.0 mmol, 2.0 equiv) and the resulting suspension was stirred at 0 ºC for 10 min. Thereafter, to the reaction flask was added benzyl bromide (475 µL, 4.0 mmol, 2.0 equiv) and TBAI (74 mg, 0.2 mmol, 0.1 equiv). The reaction mixture was warmed to room temperature and stirred at room temperature for 16 h under nitrogen atmosphere. Upon completion, the reaction mixture was cooled to 0 ºC and diluted with hexanes (20 mL) and brine (50 mL) was added to the flask. The organic layer was separated and the aqueous layer was extracted with ether (4 × 20 mL). The combined organic layer was washed with water (1 × 20 mL) and brine (1 × 20 mL). The resulting organic layer was dried with MgSO4 and concentrated under reduced pressure to afford the crude reaction mixture. The crude was dissolved in ether (5 mL) and the solution was filtered through a silica gel plug. The silica gel plug was washed with hexanes (3 × 50 mL). The resulting solution was concentrated under reduced pressure and the mixture was used for the next step without further purification. Spectral data for (R)-197b: 1 H-NMR (300 MHz, CDCl3): δ 0.88 (t, J = 6.7 Hz, 4H), 1.18-1.30 (m, 24H), 1.50-1.56 (m, 2H), 3.14 (dd, J = 9.9, 4.1 Hz, 1H), 3.22 (dd, J = 9.9, 5.7 Hz, 1H), 3.573.52 (m, 1H), 4.54 (d, J = 11.7 Hz, 1H), 4.71 (d, J = 11.7 Hz, 1H), 7.38-7.23 (m, 20H). The 1 spectral data was extracted from the crude H NMR of (R)-197b. 5.8.2.4 De-protection of trityl ether in (R)-197 OTr OTBS (R)-197a 12 TFA, Et3SiH (5 equiv) CH2Cl2, 0 ºC 316 OH OTBS (R)-198a 12 (R)-2-((tert-Butyldimethylsilyl)oxy)hexadecan-1-ol (R)-198a: To a flame dried 100 mL round bottom flask flush with nitrogen and equipped with a stir bar was added the trityl ether (R)-197a (615 mg, 1.0 mmol) and freshly distilled CH2Cl2 (10 mL). The resulting clear solution was cooled to 0 °C. Triethylsilane (581 mg, 5.0 mmol) was added and the solution was stirred for 10 min after which TFA (153µL, 2.0 mmol) was added dropwise at 0 °C until the yellow color stopped reappearing. The reaction mixture was quenched immediately by the addition of sat. aq. NaHCO3-solution (30 mL) at 0 ºC. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (4 × 50 mL). The combined organic layers were dried over MgSO4 and the solvents were removed in vacuo. Purification of the crude by silica gel chromatography with a rubber septum and a nitrogen balloon at the top of the column (30 mm×150 mm column, 20:1 hexanes/Et2O as eluent) afforded pure (R)-198a as a colorless liquid in 85 % isolated yield (317 mg, 0.85 mmol). 1 Spectral data for (R)-198a: Rf = 0.12 (16:1 hexanes / Et2O); H-NMR (300 MHz, CDCl3): δ 0.08 (s, 6H), 0.86-0.91 (m, 12H), 1.30-1.21 (m, 24H), 1.44-1.51 (m, 2H), 1.85 (t, J = 6.3 Hz, 1H), 3.40-3.49 (m, 1H), 3.56 (ddd, J = 11.0, 6.3, 3.6 Hz, 1H), 3.72 (qd, J = 5.9, 3.6 Hz, 1H); 13 C-NMR (126 MHz, CDCl3): δ –4.56, –4.43, 14.11, 22.69, 25.34, 25.86, 29.35, 29.56, 29.57, 29.65, 29.67, 29.69, 29.78, 31.93, 33.98, 66.30, 72.96, (three sp3 carbon not located); IR (thin -1 film) 3400 br, 2926vs, 2855s, 1464s, 1255s, 1109 s cm ; HRMS (ESI-TOF) m/z 373.3499 + [(M+H ); calcd. for C22H49O2Si: 373.3502]; [α ]20 –6.5 (c 1.0, CH2Cl2). D € 317 OTr OBn (R)-197b 12 TFA, Et3SiH (5 equiv) OH OBn (R)-198b 12 CH2Cl2, 0 ºC (R)-2-(Benzyloxy)hexadecan-1-ol (R)-198b: The (R)-198b was synthesized from trityl ether (R)-197b (709 mg, 1.2 mmol) following the procedure described above for the synthesis of (R)198a. Purification of the crude by silica gel chromatography with a rubber septum and a nitrogen balloon at the top of the column (30 mm×150 mm column, 20:1 hexanes/Et2O as eluent) afforded pure (R)-198b as a colorless solid (mp 35-36 ºC) in 80 % isolated yield (335 mg, 0.96 mmol). 1 Spectral data for (R)-198b: Rf = 0.12 (10:1 hexanes / EtOAc); H-NMR (300 MHz, CDCl3): δ 0.88 (t, J = 6.7 Hz, 3H), 1.26-1.36 (m, 24H), 1.46-1.67 (m, 2H), 1.90-1.94 (m, 1H), 3.47-3.57 (m, 2H), 3.66-3.73 (m, 1H), 4.55 (d, J = 11.5 Hz, 1H), 4.63 (d, J = 11.5 Hz, 1H), 7.27-7.37 (m, 5H); 13 C-NMR (126 MHz, CDCl3): δ 14.10, 22.67, 25.37, 29.35, 29.53, 29.58, 29.64, 29.66, 29.67, 29.78, 30.78, 31.91 (2 sp3 carbon not located), 64.27, 71.48, 79.81, 127.70, 127.75, -1 128.43, 138.47; IR (thin film) 3422 br, 2926vs, 2855 vs, 1466s, 1350s cm ; HRMS (ESI-TOF) + m/z 371.2925 [(M+Na ); calcd. for C23H40O2Na: 371.2926]; [α ]20 –11.8 (c 1.0, CH2Cl2). D 5.8.2.5 Oxidation of alcohol (R)-198 to aldehyde (R)-192 € H OH OTBS (R)-198a 12 DMP (1.2 equiv) CH2Cl2 rt, 30 min 318 O OTBS (R)-192a 12 (R)-2-((tert-Butyldimethylsilyl)oxy)hexadecanal (R)-192a: To a flame dried 25 mL round bottom flask flush with nitrogen and equipped with a stir bar was added the (R)-198a (410 mg, 1.1 mmol) and freshly distilled CH2Cl2 (5.5 mL). To the resulting clear solution was added Dess-Martin periodinane (560 mg, 1.32 mmol, 1.2 equiv). The turbid reaction mixture was stirred for 30 min at room temperature under nitrogen atmosphere. Thereafter, a buffer solution made from dissolving NaH2PO4 (262 mg) and Na2HPO4 (366 mg) in 2.5 mL water, was added to the reaction mixture. The resulting mixture was stirred for 5 min at room temperature. The turbid mixture was filtered through a Celite pad to a 100 mL round bottom flask. The reaction flask was washed with CH2Cl2 (3 × 10 mL) and passed through the same Celite pad. The resulting organic layer was washed with sat. aq. NaHCO3 (2× 10 mL) and then with brine (2 × 10 mL). The organic layer was dried over MgSO4 and the solvents were removed in vacuo. Purification of the crude by silica gel chromatography (20 mm×150 mm column, 10:1 hexanes/Et2O as eluent, flash column) afforded pure (R)-192a as a colorless liquid in 85 % isolated yield (346 mg, 0.935 mmol). 1 Spectral data for (R)-192a: Rf = 0.50 (16:1 hexanes / Et2O); H-NMR (300 MHz, CDCl3): δ 0.07 (s, 3H), 0.08 (s, 3H), 0.88 (t, J = 6.8 Hz, 3H), 0.92 (s, 9H), 1.22-1.41 (m, 24H), 1.57-1.65 (m, 2H), 3.96 (ddd, J = 6.9, 5.6, 1.5 Hz, 1H), 9.59 (d, J = 1.8 Hz, 1H); 13 C-NMR (126 MHz, CDCl3): δ –4.93, –4.62, 14.10, 18.20, 22.69, 25.75, 29.36, 29.43, 29.45, 29.53, 29.62, 29.66, 319 29.68, 29.69, 31.93, 32.64, 77.71, (two sp3 carbon not located), 204.32; IR (thin film) 2928 vs, -1 + 2855 vs, 1738s, 1464s, 1253s cm ; HRMS (ESI-TOF) m/z 371.3346 [(M+H ); calcd. for C22H49O2Si: 371.3345]; [α ]20 +18.6 (c 1.0, CH2Cl2). D € H OH OBn (R)-198b 12 DMP (1.2 equiv) O OBn (R)-192b 12 CH2Cl2 rt, 30 min (R)-2-(Benzyloxy)hexadecanal (R)-192b: The (R)-192b was synthesized from (R)-198b (348 mg, 1.0 mmol) following the procedure described above for the synthesis of (R)-192a. Purification of the crude by silica gel chromatography (30 mm×150 mm column, 20:1 hexanes/Et2O as eluent, flash column) afforded pure (R)-192b as a colorless liquid in 90 % isolated yield (312 mg, 0.90 mmol). 1 Spectral data for (R)-192b: Rf = 0.26 (10:1 hexanes / Et2O); H-NMR (500 MHz, CDCl3): δ 0.88 (t, J = 7.0 Hz, 3H), 1.28-1.30 (m, 22H), 1.35-1.46 (m, 2H), 1.65-1.70 (m, 2H), 3.75 (td, J = 6.4, 2.1 Hz, 1H), 4.54 (d, J = 11.7 Hz, 1H), 4.67 (d, J = 11.7 Hz, 1H), 7.30-7.36 (m, 5H), 9.65 (d, J = 2.2 Hz, 1H). 320 5.8.3 Multi-component asymmetric aziridination reaction of aldehyde (R)-192 5.8.3.1 Multi-component asymmetric aziridination reaction of aldehyde (R)-192a 1) 4 Å MS H 2) MEDAM NH2 66 O OTBS (R)-192a (1.1 equiv) –10 ºC 12 (R)-VAPOL (5 mol%) B(OPh) (15 mol%) 3) EDA (11) (2.0 equiv) 3 –10 ºC, 24 h toluene, 80 °C, 0.5 h MEDAM N CO2Et OTBS 12 199a MEDAM + N CO2Et OTBS 12 199b (2S,3R)-Ethyl 1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-((R)-1((tertbutyldimethylsilyl) oxy)pentadecyl)aziridine-2-carboxylate 199b: To a 10 mL flame-dried home-made Schlenk flask, prepared from a singlenecked 25 mL pearshaped flask that had its 14/20 glass joint replaced with a high vacuum threaded Teflon valve, equipped with a stir bar and filled with argon was added (R)-VAPOL (14 mg, 0.025 mmol, 5 mol%), B(OPh)3 (22 mg, 0.075 mmol, 15 mol%) and amine 66 (149 mg, 0.5 mmol). Under an argon flow through the side arm of the Schlenk flask, dry toluene (1.0 mL) was added. The flask was sealed by closing the Teflon valve, and then placed in an oil bath (80 ºC) for 0.5 h. The flask was then allowed to cool to room temperature and open to argon through side arm of the Schlenk flask. To the flask containing the catalyst was added the 4Å Molecular Sieves (120 mg, freshly flame-dried) and dry toluene (1.5 mL). The flask was then allowed to cool to –10 ºC and aldehyde (R)-192a (204 mg, 0.55 mmoL, 1.1 equiv) was added to the reaction mixture. To this solution was rapidly added ethyl diazoacetate (EDA) 11 (68 µL, 0.6 mmoL, 1.2 equiv). The 321 resulting mixture was stirred for 24 h at –10 ºC. The reaction was dilluted by addition of hexane (3 mL). The reaction mixture was then filtered through a silica gel plug to a 250 mL round bottom flask. The reaction flask was rinsed with EtOAc (20 mL × 3) and the rinse was filtered through the same silica gel plug. The resulting solution was then concentrated in vacuo followed by exposure to high vacuum (0.05 mm Hg) for 1 h to afford the crude aziridine as yellow colored viscous oil. Purification of the crude aziridine by neutral alumina chromatography (30 mm × 150 mm column, 4:2:0.1 hexanes/CH2Cl2/Et2O as eluent, gravity column) afforded inseparable mixture of aziridines 199b and 199a as colorless oil in 94 % isolated yield (347 mg, 0.47 mmol). The diastereomeric ratio of 199b and 199a was determined to be >99:1 by HPLC analysis of crude reaction mixture (PIRKLE COVALENT (R, R) WHELK-O 1 column, 99:1 hexane/2propanol at 226nm, flow-rate: 0.7 mL/min): retention times; Rt = 9.26 min (major diastereomer, 199b) and Rt = 12.52 min (minor diastereomer, 199a). Aldehyde (R)-192a was reacted, according to the multi-component aziridination protocol described above, with (R)-VANOL (11 mg, 0.025 mmol, 5 mol%), as ligand to afford aziridines 199b and 199a with 99:1 diastereomeric ratio. Purification of the crude aziridine by neutral alumina chromatography (30 mm × 150 mm column, 4:2:0.1 hexanes/CH2Cl2/Et2O as eluent, gravity column) afforded inseparable mixture of aziridines 199b and 199a as a colorless liquid in 85 % isolated yield (314 mg, 0.425 mmol). 1 Spectral data for 198b: Rf = 0.65 (2:1 hexanes/Et2O); H-NMR (300 MHz, CDCl3): δ –0.35 (s, 322 3H), –0.02 (s, 3H), 0.88 (t, J = 6.7 Hz, 3H), 0.70 (s, 9H), 1.21-1.37 (m, 29H), 2.05 (d, J = 7.0 Hz, 1H), 2.16-2.18 (m, 1H), 2.21 (s, 6H), 2.22 (s, 6H), 3.48 (s, 1H), 3.66-3.73 (m, 7H), 4.22-4.11 (m, 2H), 6.95 (s, 2H), 7.00 (s, 2H); 13 C-NMR (126 MHz, CDCl3): δ –4.91, –4.82, 14.10, 14.32, 16.17, 16.19, 17.94, 22.68, 24.17, 25.79, 29.35, 29.51, 29.57, 29.64, 29.67, 29.68, 30.03, 31.92, 36.24, 41.59, 53.23, 59.38, 59.58, 60.68, 70.44, 77.61, (one sp3 carbon not located), 127.51, 128.86, 130.33, 130.39, 137.81, 138.01, 155.66, 156.11, 170.05; IR (thin film) 2928vs, 2855vs, -1 + 1747s, 1485s, 1221s, 1184vs cm ; HRMS (ESI-TOF) m/z 738.5476 [(M+H ); calcd. for C45H76NO5Si: 738.5493]. 1) 4 Å MS H 2) MEDAM NH2 66 O OTBS (R)-192a (1.1 equiv) –10 ºC 12 (S)-VAPOL (5 mol%) B(OPh) (15 mol%) 3) EDA (11) (2.0 equiv) 3 –10 ºC, 24 h toluene, 80 °C, 0.5 h MEDAM N CO2Et OTBS 12 199a MEDAM + N CO2Et 12 OTBS 199b (2R,3S)-ethyl 1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-((R)-1((tertbutyldimethylsilyl)oxy)pentadecyl)aziridine-2-carboxylate 198a: Aldehyde (R)-192a (204 mg, 0.55 mmoL, 1.1 equiv) was reacted according to the multicomponent aziridination protocol described above, with (S)-VAPOL (14 mg, 0.025 mmol, 5 mol%) as ligand to afford aziridines 199a and 199b with 90:10 diastereomeric ratio. Purification of the crude aziridine by neutral alumina chromatography (30 mm × 150 mm column, 4:2:0.1 hexanes/CH2Cl2/Et2O as eluent, gravity column) afforded inseparable mixture of aziridines 199a 323 and 199b as colorless oil in 88 % isolated yield (325 mg, 0.44 mmol). Aldehyde (R)-192a (204 mg, 0.55 mmoL, 1.1 equiv) was reacted according to the multicomponent aziridination protocol described above with (S)-VANOL (11 mg, 0.025 mmol, 5 mol%), as ligand to afford 199a and 199b with 88:12 diastereomeric ratio. Purification of the crude aziridine by neutral alumina chromatography (20 mm × 150 mm column, 4:2:0.1 hexanes/CH2Cl2/Et2O as eluent, gravity column) afforded inseparable mixture of aziridines 199a and 199b as colorless liquid in 80 % isolated yield (295 mg, 0.4 mmol). 1 Spectral data for 199a: Rf = 0.65 (2:1 hexanes/Et2O); H-NMR (500 MHz, CDCl3): δ –0.05 (s, 3H), –0.03 (s, 3H), 0.85 (s, 9H), 0.90 (t, J = 7.0 Hz, 3H), 1.22-1.30 (m, 29H), 2.13-2.15 (m, 1H), 2.21-2.24 (m, 13H), 3.44 (s, 1H), 3.67 (s, 3H), 3.69 (s, 3H), 3.71-3.74 (m, 1H), 4.09-4.28 (m, 2H), 6.99 (s, 2H), 7.07 (s, 2H); 13 C-NMR (126 MHz, CDCl3): δ –4.65, –4.56, 14.08, 14.14, 16.08, 16.13, 18.00, 22.67, 23.74, 25.77, 25.78, 29.34, 29.58, 29.60, 29.63, 29.65, 29.68, 29.94, 31.91, 35.90, 43.34, 51.96, 59.47, 59.54, 60.74, 69.01, 77.73, (one sp3 carbon not located), 127.01, 128.55, 130.41, 130.50, 137.69, 137.77, 155.71, 156.43, 169.70; IR (thin film) 2928vs, -1 + 2855vs, 1744s, 1483s, 1221s, 1186vs cm ; HRMS (ESI-TOF) m/z 738.5490 [(M+H ); calcd. for C45H76NO5Si: 738.5493]; [α ]20 +36.0 (c 1.0, CH2Cl2). D € 324 5.8.3.2 Multi-component asymmetric aziridination reaction of aldehyde (R)-192b 1) 4 Å MS H 2) MEDAM NH2 66 O OBn (R)-192b (1.1 equiv) –10 ºC 12 MEDAM N (R)-VAPOL (10 mol%) B(OPh) (15 mol%) 3) EDA (11) (2.0 equiv) 3 –10 ºC, 24 h toluene, 80 °C, 0.5 h CO2Et OBn 12 199a' MEDAM + N CO2Et OBn 12 199b' (2S,3R)-Ethyl 3-((R)-1-(benzyloxy)pentadecyl)-1-(bis(4-methoxy-3,5-dimethylphenyl) methyl)aziridine-2-carboxylate 198b': Aldehyde (R)-192b (76 mg, 0.22 mmoL, 1.1 equiv) was reacted according to the multicomponent aziridination protocol described above, with (R)-VAPOL (11 mg, 0.02 mmol, 10 mol%) as ligand to afford aziridines 199b' and 199a' with >99:1 diastereomeric ratio. Purification of the crude aziridine by neutral alumina chromatography (20 mm × 150 mm column, 1:1:0.1 hexanes/CH2Cl2/Et2O as eluent, gravity column) afforded inseparable mixture of aziridines 199b' and 199a' as colorless oil in 95 % isolated yield (136 mg, 0.19 mmol). The diastereomeric ratio of 199b' and 199a' was determined to be >99:1 by HPLC analysis of crude reaction mixture (PIRKLE COVALENT (R, R) WHELK-O 1 column, 99:1 hexane/2propanol at 226nm, flow-rate: 0.7 mL/min): retention times; Rt = 6.25 min (major diastereomer, 199b') and Rt = 14.62 min (minor diastereomer, 199a'). 1 Spectral data for 199b': Rf = 0.25 (1:1 hexanes/CH2Cl2); H-NMR (500 MHz, CDCl3): δ 0.88 (t, J = 7.0 Hz, 3H), 1.20-1.29 (m, 27H), 1.35-1.41 (m, 1H), 1.47-1.54 (m, 1H), 2.14 (d, J = 7.1 Hz, 325 1H), 2.17 (s, 6H), 2.24-2.29 (m, 7H), 3.45 (td, J = 8.8, 2.3 Hz, 1H), 3.49 (s, 1H), 3.51 (s, 3H), 3.70 (s, 3H), 3.96 (d, J = 11.6 Hz, 1H), 4.08 (d, J = 11.6 Hz, 1H), 4.23-4.16 (m, 2H), 6.98-6.97 (m, 2H), 7.06 (s, 2H), 7.11 (s, 2H), 7.24-7.16 (m, 3H); 13 C-NMR (126 MHz, CDCl3): δ 14.06, 14.28, 16.10, 16.15, 22.63, 25.17, 29.30, 29.34, 29.44, 29.54, 29.60, 29.62, 29.63, 29.64, 31.87, 33.44, 40.76, 51.62, 59.33, 59.52, 60.83, 71.33, 77.37, 77.74, (one sp3 carbon not located), 126.95, 127.17, 127.33, 127.90, 128.67, 130.52, 130.67, 137.49, 137.82, 139.13, 155.73, 156.47, -1 169.46; IR (thin film) 2926vs, 2855vs, 1746s, 1484s, 1223s, 1188vs cm ; HRMS (ESI-TOF) + m/z 714.5110 [(M+H ); calcd. for C46H68NO5 : 714.5097]; [α ]20 –52.6 (c 1.0, CH2Cl2). D 1) 4 Å MS H 2) MEDAM NH2 66 € O OBn (R)-192b (1.1 equiv) –10 ºC 12 (S)-VAPOL (10 mol%) B(OPh) (15 mol%) 3) EDA (11) (2.0 equiv) 3 –10 ºC, 24 h toluene, 80 °C, 0.5 h MEDAM N CO2Et OBn 12 199a' MEDAM + N CO2Et OBn 12 199b' (2R,3S)-Ethyl 3-((R)-1-(benzyloxy)pentadecyl)-1-(bis(4-methoxy-3,5-dimethylphenyl) methyl)aziridine-2-carboxylate 199a': Aldehyde (R)-192b (76 mg, 0.22 mmoL, 1.1 equiv) was reacted according to the multicomponent aziridination protocol described above in presence of (S)-VAPOL (11 mg, 0.02 mmol, 10 mol%) as ligand to afford aziridines 199a' and 199b' with 82:18 diastereomeric ratio. Purification of the crude aziridine by neutral alumina chromatography (20 mm × 150 mm 326 column, 1:1:0.1 hexanes/CH2Cl2/Et2O as eluent, gravity column) afforded inseparable mixture of aziridines 199a' and 199b' as colorless oil in 90 % isolated yield (128 mg, 0.18 mmol). 1 Spectral data for 199a': Rf = 0.25 (1:1 hexanes/CH2Cl2); H-NMR (500 MHz, CDCl3): δ 0.89 (t, J = 6.9 Hz, 3H), 1.18-1.30 (m, 29H), 2.13-2.15 (m, 1H), 2.23 (s, 6H), 2.25 (s, 6H), 2.36 (d, J = 6.5 Hz, 1H), 3.40 (td, J = 8.0, 2.6 Hz, 1H), 3.47 (s, 1H), 3.66 (s, 3H), 3.70 (s, 3H), 4.17 (q, J = 7.1 Hz, 2H), 4.28 (d, J = 11.2 Hz, 1H), 4.44 (d, J = 11.2 Hz, 1H), 6.96 (s, 2H), 7.09 (s, 2H), 7.327.23 (m, 5H); 13 C-NMR (126 MHz, CDCl3): δ 14.09, 14.28, 16.09, 16.17, 22.67, 24.63, 29.33, 29.35, 29.53, 29.62, 29.64, 29.65, 29.69, 29.88, 31.90, 31.91, 33.18, 43.81, 49.50, 59.54, 59.58, 60.89, 71.21, 76.39, 77.44, 127.16, 127.41, 127.46, 128.23, 128.63, 130.50, 130.55, 137.39, 137.58, 138.68, 155.81, 156.52, 169.68; IR (thin film) 2926vs, 2855vs, 1741s, 1483s, 1223s, -1 + 1188vs cm ; HRMS (ESI-TOF) m/z 714.5094 [(M+H ); calcd. for C46H68NO5 : 714.5097]; [α ]20 +36.9 (c 1.0, CH2Cl2). D € 5.8.4 Synthesis of racemic aldehyde rac-192a 5.8.4.1 Bis-protection of 1,2-diol rac-195 OH OH rac-195 12 1) TrCl, pyridine 24h, rt 2) TBSCl, Imidazole DMF, rt, 32h OTr OTBS rac-197a 12 tert-Butyldimethyl((1-(trityloxy)hexadecan-2-yl)oxy)silane rac-197a: Bis protected 1,2-diol rac-197a was synthesized from 1,2-diol rac-195 following the procedure described above for the synthesis of (R)-197a. Purification of the crude by silica gel chromatography with a rubber 327 septum and a nitrogen balloon at the top (30 mm×300 mm column, 50:1 hexanes/Et2O as eluent) afforded pure rac-197a as a colorless liquid in 90 % isolated yield (2.21 g, 3.6 mmol) over two steps from rac-195. Spectral data was identical to (R)-195. 5.8.4.2 Synthesis of rac-198a via mono de-protection of rac-197a OTr OTBS rac-197a TFA, Et3SiH (5 equiv) 12 CH2Cl2, 0 ºC OH OTBS rac-198a 12 2-((tert-butyldimethylsilyl)oxy)hexadecan-1-ol rac-198a: The rac-198a was synthesized from trityl ether rac-197a (615 mg, 1.0 mmol) following the mono deprotection procedure described above for the synthesis of (R)-198a. Purification of the crude by silica gel chromatography with a rubber septum and a nitrogen balloon at the top of the column (30 mm×150 mm column, 20:1 hexanes/Et2O as eluent) afforded pure rac-198a as a colorless liquid in 80 % isolated yield (298 mg, 0.80 mmol). Spectral data was identical to (R)-198a. 5.8.4.3 Oxidation of rac-198a to aldehyde rac-192a H OH OTBS rac-198a 12 DMP (1.2 equiv) CH2Cl2, rt, 30 min 328 O OTBS rac-192a 12 2-((tert-butyldimethylsilyl)oxy)hexadecanal rac-192a: The aldehyde rac-192a was synthesized from rac-198a (261 mg, 0.7 mmol) following the procedure described above for the synthesis of (R)-192a. Purification of the crude by silica gel chromatography (30 mm×150 mm column, 10:1 hexanes/Et2O as eluent, flash column) afforded pure rac-192b as a colorless liquid in 90 % isolated yield (233 mg, 0.63 mmol). Spectral data was identical to (R)-192a. 5.8.5 Multi-component asymmetric aziridination of racemic aldehyde rac-192a 1) 4 Å MS MEDAM H 2) O OTBS rac-192a (1.1 equiv) –10 ºC 12 MEDAM NH2 66 (R)-VAPOL (5 mol%) B(OPh) (15 mol%) 3) EDA (11) (0.45 equiv) 3 –10 ºC, 24 h toluene, 80 °C, 0.5 h N MEDAM + CO2Et OTBS 12 199a + CO2Et 12 OTBS ent-199b CO2Et 12 OTBS 199b MEDAM MEDAM N N + N CO2Et 12 OTBS ent-199a Aldehyde rac-192a (204 mg, 0.55 mmoL, 1.1 equiv) was reacted according to the multicomponent aziridination protocol described above, with (S)-VAPOL (14 mg, 0.025 mmol, 5 mol%) as ligand to afford aziridines 199a, 199b, ent-199a and ent-199b. The diastereomeric 1 ratio determined form crude H NMR was 27:1 (199b+ent-199b:199a+ent-199a). Purification of the crude aziridine by neutral alumina chromatography (30 mm × 150 mm column, 4:2:0.1 329 hexanes/CH2Cl2/Et2O as eluent, gravity column) afforded inseparable mixture of aziridines 199a and 199b and their enantiomers as colorless oil in 35 % isolated yield (129 mg, 0.175 mmol). The enantiomeric excess of either 199a or 199b was not confirmed, due to unavailability of authenticate sample of ent-199a or ent-199b. The diastereomeric ratio of 199b and 199a was determined to be 96.6:3.4 by HPLC analysis of crude reaction mixture (PIRKLE COVALENT (R, R) WHELK-O 1 column, 99:1 hexane/2propanol at 226nm, flow-rate: 0.7 mL/min): retention times; Rt = 9.26 min (major diastereomer, 199b) and Rt = 12.52 min (minor diastereomer, 199a). [α ]20 –68.3 (c 1.0, CH2Cl2). D 5.8.6 Synthesis of N-Boc aziridine 204 € H MEDAM N N TfOH (5 equiv) CO2Et anisole, rt, 5 min OTBS 12 199b Boc O N Boc2O, NaHCO3 O THF, H2O, rt, 12h 12 203 not purified O 12 O 204 (1S,4R,5R)-tert-Butyl 2-oxo-4-tetradecyl-3-oxa-6-azabicyclo[3.1.0]hexane-6-carboxylate 204: To a 50 mL flame-dried round bottom flask flushed with nitrogen and equipped with a stir bar was added aziridine 199b (700 mg, 0.95 mmol, > 99:1 dr material). Dry anisole (9.5 mL) was added to dissolve 199b. Thereafter, triflic acid (420 µL, 4.75 mmol, 5 equiv) was added slowly to the reaction flask. The reaction mixture was stirred for 5 min under nitrogen atmosphere at room temperature. Upon completion, the gel like reaction mixture was place on ice bath and saturated aq. Na2CO3 (20 mL) and ether (10 mL) was added to the reaction flask. The mixture 330 was stirred for 5 min at room temperature. The organic layer was separated and the water layer was extracted with ethyl acetate (4 × 25 mL). The resulting organic layer was dried with MgSO4 and concentrated under reduced pressure to afford the crude reaction mixture as white solid. To the solution of the crude reaction mixture in THF (9.5 mL) solid NaHCO3 (199 mg, 2.37 mmol, 2.5 equiv), Boc2O (415 mg, 1.90 mmol, 2.0 equiv) and water (1.9 mL, 1:5 v/v H2O / THF) was added. The resulting reaction mixture was stirred for 12 h at room temperature under nitrogen atmosphere. The reaction mixture was diluted with diethyl ether (40 mL) and the organic layer was washed with brine (1 × 10 mL). The resulting organic layer was dried with MgSO4 and concentrated under reduced pressure to afford the crude reaction mixture as white solid. Purification of the crude lactone fused N-Boc aziridine 204 by silica gel chromatography (30 mm×300 mm column, 5:1 to 1:1 hexanes/Et2O as eluent, flash column) afforded pure 204 as a white solid (mp 79-80 ºC) in 65% isolated yield over two steps (244 mg, 0.617 mmol) from 199b. 1 Spectral data for 204: Rf = 0.46 (1:2 EtOAc / hexanes) H-NMR (300 MHz, CDCl3): δ 0.88 (t, J = 6.7 Hz, 3H), 1.23-1.32 (m, 24H), 1.47 (s, 9H), 1.89-1.76 (m, 2H), 3.46 (d, J = 4.4 Hz, 1H), 3.58 (dd, J = 4.4, 2.7 Hz, 1H), 4.47 (td, J = 7.1, 2.7 Hz, 1H); 13 C-NMR (151 MHz, CDCl3): δ 14.11, 22.68, 25.05, 27.78, 29.33, 29.35, 29.43, 29.50, 29.62, 29.65, 29.67, 29.69, 30.26, 31.92, 38.72, 42.60, 79.80, 83.20, (one sp3 carbon not located), 158.73, 169.59; IR (thin film) 2920vs, -1 + 2851vs, 1788vs, 1724vs, 1468s, 1294s, 1197vs cm ; HRMS (ESI-TOF) m/z 396.3096 [(M+H ); calcd. for C23H42NO4: 396.3114]; [α ]20 –34.2 (c 1.0, CH2Cl2). D € 331 5.8.7 Lewis acid catalyzed ring expansion of N-Boc aziridine 204 O Boc N O 12 Sc(OTf)3 (0.2 equiv) O HN H CH2Cl2, rt, 48 h O O O 12 204 NH H O H + H O O O 12 208 209 To a 10 mL flame-dried round bottom flask equipped with a stir bar and a rubber septum with a nitrogen balloon at the top, was added N-Boc aziridine 204 (40 mg, 0.1 mmol) and dry CH2Cl2 (1 mL). To the resulting solution was added Sc(OTf)3(10 mg, 0.02 mmol, 0.2 equiv). The reaction mixture was stirred at room temperature for 48 h under nitrogen atmosphere. Thereafter, the reaction mixture was filtered through a silica gel plug on a sintered glass funnel. The silica plug was washed with ethyl acetate (3 × 10 mL). The filtrate was concentrated under reduced pressure to afford crude product as white solid. Purification of the crude by silica gel chromatography (20 mm × 150 mm column, 1:1 hexanes/EtOAc as eluent, flash column) 1 afforded mixture of oxazolidinone 208 and 209 (10:1 mixture from HNMR) as a white solid in 65% combined yield (22 mg, 0.065 mmol). The N-Boc aziridine 204 was reacted with Sn(OTf)2 (8 mg, 0.02 mmol, 0.2 equiv) according the procedure described above. Purification of the crude by silica gel chromatography (20 mm × 150 mm column, 1:1 hexanes/EtOAc as eluent, flash column) afforded mixture of oxazolidinone 208 and 209 (7:1) as a white solid in 60% combined yield (20 mg, 0.060 mmol). 1 Spectral data for 208: Rf = 0.11 (1:1 EtOAc / hexanes); H-NMR (500 MHz, CDCl3): δ 0.88 (t, 332 J = 7.0 Hz, 3H), 1.26-1.39 (m, 24H), 1.61-1.67 (m, 1H), 1.84-1.91 (m, 1H), 4.49 (ddd, J = 8.6, 5.2, 4.4 Hz, 1H), 4.61 (ddd, J = 7.6, 4.3, 1.6 Hz, 1H), 5.15 (d, J = 7.6 Hz, 1H), 5.97 (br s, 1H). 1 Spectral data for 209: H-NMR (500 MHz, CDCl3): δ 4.45 (dd, J = 7.4, 0.7 Hz, 1H), 4.67-4.64 (m, 1H), 5.21 (dd, J = 7.4, 4.4 Hz, 1H), 5.84 (s, 1H) (other sp3 H’s are not located due to overlap the major regio-isomer 208 H’s peaks). 5.8.8 Synthesis of N-Cbz aziridine 205 MEDAM N CO2Et OTBS 12 199b O H anisole, rt, 5 min O O Cbz Cbz 206 (1.5 eqiv) N TfOH (5 equiv) N O O 12 203 not purified N NaHCO3, THF, H2O, rt 24 h O 12 O 205 (1S,4R,5R)-benzyl 2-oxo-4-tetradecyl-3-oxa-6-azabicyclo[3.1.0]hexane-6-carboxylate 205: To a 50 mL flame-dried round bottom flask flushed with nitrogen and equipped with a stir bar was added aziridine 199b (143 mg, 0.2 mmol, > 99:1 dr material). Dry anisole (3.0 mL) was added to dissolve 199b. Thereafter, triflic acid (88 µL, 1.0 mmol, 5 equiv) was added slowly to the reaction flask. The reaction mixture was stirred for 5 min under nitrogen atmosphere at room temperature. Upon completion, the gel like reaction mixture was place on ice bath and saturated aq. Na2CO3 (10 mL) and ether (10 mL) was added to the reaction flask. The mixture was stirred for 5 min at room temperature. The organic layer was separated and the water layer was extracted with ethyl acetate (4 × 10 mL). The resulting organic layer was dried with MgSO4 and concentrated under reduced pressure to afford the crude reaction mixture as white solid. To the 333 solution of the crude reaction mixture in THF (2.0 mL) solid NaHCO3 (42 mg, 0.5 mmol, 2.5 equiv), Cbz-OSu 206 (374 mg, 0.3 mmol, 1.5 equiv) and water (0.4 mL, 1:5 v/v H2O / THF) was added. The resulting reaction mixture was stirred for 24 h at room temperature under nitrogen atmosphere. The reaction mixture was diluted with diethyl ether (20 mL) and the organic layer was washed with brine (1 × 5 mL). The resulting organic layer was dried with MgSO4 and concentrated under reduced pressure to afford the crude reaction mixture as white solid. Purification of the crude lactone fused N-Cbz aziridine 205 by silica gel chromatography (30 mm×300 mm column, 5:1 to 1:2 hexanes/Et2O as eluent, flash column) afforded pure 205 as a white solid (mp 67-68 ºC) in 80% isolated yield over two steps (69 mg, 0.16 mmol) from 199b. 1 Spectral data for 205 Rf = 0.36 (1:2 EtOAc / hexanes) H-NMR (300 MHz, CDCl3): δ 0.88 (t, J = 6.7 Hz, 3H), 1.26-1.38 (m, 22H), 1.41-1.50 (m, 2H), 1.73-1.90 (m, 2H), 3.55 (d, J = 4.4 Hz, 1H), 3.65 (dd, J = 4.4, 2.8 Hz, 1H), 4.48 (td, J = 7.0, 2.7 Hz, 1H), 5.16 (s, 2H), 7.39-7.34 (m, 5H); 13 C-NMR (126 MHz, CDCl3): δ 14.08, 22.65, 25.02, 29.28, 29.32, 29.37, 29.46, 29.58, 29.62, 29.65, 29.66, 30.32, 31.89, 38.77, 42.87, 69.16, 79.67, (one sp3 carbon not located), 128.26, 128.64, 128.66, 134.83, 159.84, 169.09; IR (thin film) 2920vs, 2851s, 1780s, 1720s, + 1469s, 1273s cm-1; HRMS (ESI-TOF) m/z 430.2860 [(M+H ); calcd. for C26H40NO4 : 430.2957]; [α ]20 –26.8 (c 1.0, CH2Cl2). 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