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Chemical Synthesis of Peptides and Peptide Thioesters Indrajeet Sharma Wayne State University

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Chemical Synthesis of Peptides and Peptide Thioesters Indrajeet Sharma Wayne State University Wayne State University Wayne State University Dissertations 1-1-2011 Chemical Synthesis Of Peptides And Peptide Thioesters Indrajeet Sharma Wayne State University Follow this and additional works at: http://digitalcommons.wayne.edu/oa_dissertations Part of the Organic Chemistry Commons Recommended Citation Sharma, Indrajeet, "Chemical Synthesis Of Peptides And Peptide Thioesters" (2011). Wayne State University Dissertations. Paper 205. This Open Access Dissertation is brought to you for free and open access by DigitalCommons@WayneState. It has been accepted for inclusion in Wayne State University Dissertations by an authorized administrator of DigitalCommons@WayneState. CHEMICAL SYNTHESIS OF PEPTIDES AND PEPTIDE THIOESTERS by INDRAJEET SHARMA DISSERTATION Submitted to the Graduate School of Wayne State University, Detroit, Michigan in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY 2011 MAJOR: CHEMISTRY (Organic) Approved by: Advisor Date DEDICATION This dissertation is dedicated to my family for their endless love and support. ii ACKNOWLEDGEMENTS First and foremost, I would like to express my deepest gratitude to my graduate advisor Professor David Crich for his advice and mentoring through all the years of my research work in his laboratories at the University of Illinois at Chicago and at Wayne State University. This work would not have reached its zenith without his unwavering guidance. He has been really supportive of my work not only with his remarkable knowledge and painstaking guidance, but also with his valuable suggestions and constant encouragement. I wish to thank my committee members Professor Zhongwu Guo, Professor Ashok S. Bhagwat, and Professor Steven J. Sucheck for their valuable time and suggestions to this dissertation and defense. I would like to thank my undergraduate summer project advisor Professor H. M. Chawla for his inspiration during my very first entry to organic chemistry laboratory. With great respect, I would also like to record my sincere and heartiest thank to my undergraduate advisor Professor Dipakranjan Mal for his guidance throughout my undergraduate research. I want to acknowledge CIF staff from Wayne State University, especially to Dr. Bashar, Dr. Brian and Dr Lew for their help and support. I offer special thanks to Pat (UIC) and Melissa (WSU), who always helped with the paper work and smoothed the way to keep me on track. My special thanks are due to my elder brother Dr. Rupendra Sharma for his help and endless encouragement. I always found him standing beside me in every thick and thin. I owe more gratitude than I can express to my Uncle R. D iii Sharma. I would not have been able to reach at this pinnacle without his unflinching support. I feel short of words to express a deep sense of respect and gratitude for my friend and senior Dr. Venkat Krishnamurthy. In all my difficult moments, I always found him on my side to guide me in every way possible. I not only shared a good rapport with him but also find his criticism and suggestion fruitful in my graduate career. I would also like to thank my seniors Dr. Pallab, Dr. Sunil, Dr. Kaname, Dr. Linfeng, Dr. Sutapa, Dr. Annya and Dr. Bindu for their friendship and help. I would like to thank former and current members of the Crich group (Chandra, Md, Kasi, Myriame, Venkat, Feng, Abishek, Patel) for providing a friendly environment in which to work and study. I also owe thanks to my friends from Chemistry Cricket Club and Wayne State University. My special thanks are due to my wife Shailza for her moral support and incessant encouragements. I would also like to thank my friends Aditi, Shilpi, Shreya and Snigdha. I am really thankful to my mother for her unconditional love and sacrifice. I finally thanks to all of my family members for their endless love and support, which has made this dissertation possible iv TABLE OF CONTENTS Dedication ............................................................................................................. ii Acknowledgements .............................................................................................. iii List of Tables………………………………………………………………...……….....ix List of Figures ....................................................................................................... x List of Schemes…………………………………………………………. .................. xiv List of Abbreviations……….………………………………………………..………...xiii CHAPTER 1. INTRODUCTION ............................................................................ 1 1.1 Background and Significance ...................................................................... 1 1.2 Chemical Synthesis ..................................................................................... 2 1.3 Native Chemical Ligation ............................................................................. 7 1.4 Native Chemical Ligation without Cysteine ................................................. 9 1.4.1 Assistance from Nα-Linked Auxiliaries .................................................. 9 1.4.2 Side Chain Linked Auxiliaries ............................................................. 12 1.4.3 NCL-Desulfurization Combination ....................................................... 13 1.4.4 Met Ligation: Alkylation of Hcy ............................................................ 15 1.4.5 Ser Ligation ......................................................................................... 16 1.5 Other Ligation Methods ............................................................................. 16 1.5.1 His Ligation ......................................................................................... 16 1.5.2 The Staudinger Ligation ...................................................................... 17 1.5.3 Chemoselective Decarboxylative Amide Ligation ............................... 19 1.5.4 Non-conventional Peptide Synthesis .................................................. 20 v 1.6 Thioacid Chemistry .................................................................................... 20 1.6.1 Cysteine Acyl Hydrosulfide Strategy ................................................... 20 1.6.2 Thioacid/Azide Amidation ................................................................... 21 1.6.3 Coupling of Thioacids with Isocyanates and Isothiocyanates ............. 22 1.6.4 Thioacid/Aziridine Ligation .................................................................. 22 1.7 Convergent Strategies for Multiple Fragment Ligations ............................. 24 1.8 Synthesis of C-Terminal Peptidyl Thioesters ............................................. 26 1.8.1 Synthesis of C-Terminal Peptidyl Thioesters on Solid Support using Boc Chemistry ............................................................................................. 27 1.8.2 Synthesis of C-Terminal Peptidyl Thioesters on a Solid Support using Fmoc Chemistry ........................................................................................... 30 1.8.2.1 O→S Acyl Transfer ...................................................................... 37 1.8.2.2 N →S Acyl Shift ............................................................................. 38 1.9 Goals of This Thesis .................................................................................. 41 CHAPTER 2. BLOCK SYNTHESIS OF PEPTIDES FROM THIOACIDS AND AMINES WITH THE SANGER AND MUKAIYAMA REAGENTS....................... 43 2.1 Introduction ................................................................................................ 43 2.2 Amide Bond Formation by the Sanger’s Reagent ..................................... 43 2.3 Synthesis of Peptidyl Thioesters ............................................................... 45 2.4 Peptide Synthesis using the Sanger and Mukaiyama Reagents ............... 50 2.5. Summary .................................................................................................. 74 vi CHAPTER 3. CONVERGENT SYNTHESIS OF PEPTIDES AND PEPTIDE THIOESTERS WITH REACTIVITY-DIFFERINTIATED SULFONAMIDES AND PEPTIDYL THIOACIDS ...................................................................................... 75 3.1 Introduction ................................................................................................ 75 3.2 Convergent Synthesis of Peptides ............................................................ 75 3.3 Preparation of Sulfonyl Chlorides .............................................................. 76 3.4. Screening of N-Arenesulfonylphenylalanine Derivatives for Reaction with Thioacetic Acid ................................................................................................ 77 3.5 Synthesis of Thioacids .............................................................................. 79 3.6 Synthesis of the ENS and the CNS Protected Peptidyl Thioesters ........... 80 3.7 Synthesis of the DNS Peptides ................................................................. 81 3.8 Triply Convergent Synthesis...................................................................... 88 3.9 Verification of the Extent of Epimerization in the DNS Coupling................ 96 3.10 Synthesis of the FNS Protected Peptidyl Thioesters ............................... 98 3.11 The Left to Right Strategy using the FNS group ...................................... 99 3.14 Synthesis of the Schiff Bases ................................................................ 108 3.15 Synthesis of Thioesters ........................................................................
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