The Utilization of Sulfinimines (N-Sulfinyl Imines) in The
Total Page：16
File Type：pdf, Size：1020Kb
THE UTILIZATION OF SULFINIMINES (N-SULFINYL IMINES) IN THE ASYMMETRIC SYNTHESIS OF SUBSTITUTED PYRROLIDINES A Dissertation Submitted to the Temple University Graduate Board In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY By Kerisha Andrea Bowen May 2009 ABSTRACT The Utilization of Sulfinimines (N-Sulfinyl Imines) Towards the Sythesis of Nitrogen Containing Compounds By Kerisha A. Bowen Doctor of Philosophy Temple University, 2009 Doctoral Advisory Committee Chair: Professor Franklin A. Davis, Ph.D. The objective of this research was the development of new methods for the asymmetric synthesis of nitrogen containing compounds. As one part of this goal, 3,4- dihydroxyprolines and their derivatives were prepared from sulfinimines (N-sulfinyl imines). During this project new methods were developed for asymmetric hydroxylation and decarboxylation of 3-oxo-2-carboxylate pyrroldines. The application of this new methodology was realized by the total synthesis of the α- and β-glycosidases inhibitor (+)-lentginosine. It was also found that electrophiles regioselectively add to the 4-position of 3-oxo-2- carboxylate-5-substituted pyrrolidines. The addition is accomplished through lithium diisopropyl amide generation of the pyrrolidine dianion. This addition was also compatible with 3-oxo-2-phosophono-5-substituted pyrroldines. Furthermore air oxidation of these pyrrolidines give the corresponding pyrroles. This procedure represents the first general preparation procedure for 2-phonopyrroles, which have been examined as HIV protease inhibitors. ii A range of β-amino carbonyl compounds were prepared from N-sulfinyl β-amino Weinreb amides in a concise and efficient procedure. A general method for the preparation of a variety of β-amino carbonyl compounds arose from the addition of an assortment of organometallic reagents to the Weinreb amides. The N-sulfinl β-amino Weinreb amides are prepared by reaction of the potassium enolate of N-methoxy-N- methylacetamide with sulfinimines or lithium N,O-dimethylhydroxylamine with N- sulfinyl β-amino esters. iii ACKNOWLEDGEMENTS I have so many people to thank for all of my successes at Temple University. While there are many that I want to mention by name, please know that there are countless people who have helped and supported me in my studies. Although it would be impossible for me to mention everyone by name, I would like to express my gratitude to all of them. First, I would like to thank my “Father in Chemistry” my research advisor Dr. Franklin A. Davis. His help and guidance in my life has gone beyond just the traditional role of professor and has truly stepped into the realm of fatherhood. From my first year at Temple, Dr. Davis took time out of his busy schedule to help me with my classes and made sure that I understood the theory of Organic mechanisms. As the years past, Dr. Davis became a friend and confidante. As a true father would, he challenged me to be best person that I could possibly be. Although, I may have questioned his methods along the way, the person that I am now appreciates who he was then. I would also like to thank my graduate committee members Dr. John R. Williams, Dr. Scott Sieburth, and Dr. Madeleine Joullié. All of whom have supported along the way. Dr. Joullié who I have known the longest, has been a great mentor and role model. She is an inspiration, and I am blessed to have worked with her. Dr. Williams, who also served as one of my instructors, taught me the importance of mechanisms and I have adopted his grading methods in my own personal teaching career. Finally, Dr. Sieburth, who not only served as an excellent instructor, but also a much needed comic relief. I have not only enjoyed the conversations that we have had, but also the many posters iv outside of his office. Although, he may not get the recognition that he deserves for all that he does behind the scenes, I would like to say that I am thankful for him. Other faculty that should be recognized include Dr. Alfred Findeisen for his dedicated service as the Organic chemistry class coordinator and Dr. Charles DeBrosse, without whom Organic synthesis would not be credible at Temple University. My gratitude also goes to Dr. Grant Krow, Dr. David Dalton, and Dr. Rodrigo Andrade for their continued support. The Temple University chemistry department staff also deserve much thanks because without them the building would not function. Regina Shapiro, the departments trusted business manager, who was there to help solve most of my dilemmas. Bobbi Johnson, who year after year, arranged my teaching schedule. Jeanette Ford, the department’s purchasing administer, who made sure I had all of the reagents and materials that I need to complete my reactions and who was able to figure out the chaotic solvent system maintenance forms. Jason Pfeffer and Regee Neely the graduate secretaries who were in charge of my graduate file and contracts. I would like to thank, Reverend George McCurdy for his inspirational words and friendship throughout the years. I would like to take time to thank the late Mr. Warren Muir, who was responsible for the department’s stockroom. Warren was a great friend and mentor, and the department has not been the same since he left. I have a lot of respect and gratitude to my colleagues. Particularly, Dr. Ramachandar Tokalo and Dr. Junyi Zhang who served as postdoctoral fellows in the Davis research group and who mentored my laboratory training. My friends in the Davis group Dr. Yongzhong Wu, Dr. Bin Yang, Dr. Jeffrey Melamed, Dr. He Xu, Dr. Minsoo Song, Dr. Jianghe Deng, Mr. Yinxing Li, Ms. Danyang Li, Mr. Yanfeng Zhang, Mr. Hui Qiu, Mr. v Paul Gaspari, Mr. Naresh Theddu, Mr. Venkata Velvadapu, Mr. Narendra Gaddiraja, and Mr. Peng Xu. I would want to especially recognize my lab mate Ms. Jing Chai, who has become a valued friend. Also, I would like to thank my many friends throughout the chemistry department. A large amount of my thanks and gratitude go to my friend and undergraduate lab partner Mr. GorDan Tyson Reeves for his friendship and in particular his assistance with my mass spectra data collection; your help is very much appreciated. To the people who have watched me grow up, I am forever grateful. My church family at Shiloh Baptist church, who have supported me throughout the years both spiritually and financially, thank you. My friends, who have grown with me, your companionship is very much appreciated. I have a lot of love to give to my large but close family. I have lost some of them on this journey, but I will always remember them in my heart. To my brother, Keville Bowen, who has put up with me since birth, thank you for everything that you have done. Finally, my mother, Marjorie Bowen, you are an inspiration, and you have set a perfect example of what people can accomplish if they focus. I realize that the road that we traveled to get to this point in life was rough, but we did it together, and as you always say “no one can take away your education.” vi TABLE OF CONTENTS Page ABSTRACT……………………………………………………………………………...ii ACKNOWLEDGEMENTS…………………………………………………………….iv LIST OF TABLES………………………………………………………………………xi LIST OF FIGURES……………………………………………………………………xiii LIST OF ABBREVIATIONS........................................................................................xiv CHAPTER 1. SYNTHESIS OF 3-OXO-2-CARBOXYLATE-PYRROLIDINES AND PYRROLIDINE DERIVATIVES 1.1 Introduction……………………………………………………………………...1 1.2 Functionalization of Pyrrolidines………………………………………………..2 1.2.1 Introduction of an Ester into a Pyrrolidine Ring……….....……………2 1.2.2 C-3 Oxidations of Pyrrolidines……………...…...…………………….3 1.3 Cyclization of Vicinal Tricarbonyls………………………………..……………6 1.4 Dieckmann Condensation of 3-[(Carbonyl)methylamino]propanoates……..…14 1.5 Metal Catalyzed NH Insertion Reactions of α-Diazo-β-ketoesters……………18 1.5.1 Copper Catalyzed Cyclizations……………………………………….19 1.5.2 Rhodium Catalyzed Reactions………………………………………..22 2. SYNTHESIS AND UTILIZATION OF SULFINIMINES (N-SULFINYL IMINES) AS CHIRAL IMINE BUILIDING BLOCKS vii 2.1 Introduction………………………………………………………………….…25 2.2 Present Study…………………………………………………………………...33 2.2.1 Previous Syntheses of 3,4-Dihydroxyprolines………………………..34 2.2.2 Synthesis of (2R)-3,4-Dihydroxyproline Isomers……………….........36 2.2.2.1 Decarboxylation of 3-Oxo-2-carboxylate Pyrrolidines………….38 2.2.2.2 Additions to C-2 of 2-Phenyl-4-oxo Pyrrolidine………...…...….43 2.2.3 Synthesis of (+)-Lentiginosine……………………….……………….50 2.2.3.1 Previous Syntheses of (+)-Lentiginosine……...…………………51 2.2.3.2 Total Synthesis of (+)-Lentiginosine...……………….………….53 2.2.4 Conclusion............................................................................................58 3. SYNTHESIS OF POLYSUBSTITUTED PYRROLES FROM SULFINIMINES (N-SULFINYL IMINES) 3.1 Introduction.........................................................................................................59 3.2 Present Study.......................................................................................................63 3.2.1 Synthesis of Racemic 2-Carboxy and 2-Phosphonopyrrolidines..........64 3.2.2 Synthesis of 4-Substituted-3-oxo-2,5-disubstituted Pyrolidines...........67 3.2.3 Aromatization of 3-Oxo Pyrrolidines to Pyrroles.................................71 3.2.4 Conclusion.............................................................................................76 4. ASYMMETRIC SYNTHESIS OF β-AMINO CARBONYL COMPOUNDS WITH N-SULFINYL β-AMINO WEINREB AMIDES 4.1 Introduction.........................................................................................................77