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Thiomaleic Anhydride: a Linchpin for Organic Synthesis and Structural Verification of a Nonprotein Antifreeze Oligosaccharide

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Thiomaleic Anhydride: a Linchpin for Organic Synthesis and Structural Verification of a Nonprotein Antifreeze Oligosaccharide Wayne State University Wayne State University Dissertations 1-1-2011 Thiomaleic anhydride: a linchpin for organic synthesis and structural verification of a nonprotein antifreeze oligosaccharide Md yeajur Rahaman Sardar Wayne State University, Follow this and additional works at: http://digitalcommons.wayne.edu/oa_dissertations Part of the Chemistry Commons Recommended Citation Sardar, Md yeajur Rahaman, "Thiomaleic anhydride: a linchpin for organic synthesis and structural verification of a nonprotein antifreeze oligosaccharide" (2011). Wayne State University Dissertations. Paper 394. 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. THIOMALEIC ANHYDRIDE: A LINCHPIN FOR ORGANIC SYNTHESIS AND STRUCTURAL VERIFICATION OF A NONPROTEIN ANTIFREEZE OLIGOSACCHARIDE by MD YEAJUR RAHAMAN SARDAR 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 grandfather and parents for their endless love and support. ii ACKNOWLEDGEMENTS I would like to express my sincere gratitude to my graduate advisor, Professor David Crich for his endless patience, guidance, encouragement and continuous support throughout my doctoral studies in his laboratory. He is a great teacher and an excellent mentor and without his help, this dissertation would not have been completed. I would like to thank my committee members Professor Jeremy Kodanko, Professor Claudio N. Verani, and Professor Jetze J. Tepe for their valuable time and suggestions for this dissertation and defense. I would like to thank my undergraduate professors S. Mondal, Dr. S. Sengupta, and Dr. F. A. Khan for their inspiration during my entry to chemistry. I would like to express my gratitude to Dr. Ksebati for the extensive help with NMR spectroscopy. I have had the privilege to work with an outstanding group of colleagues who have been a constant source of support and help; I would like to take this opportunity to thank all of them. In particular, thanks to Dr Sasaki, Dr Subramanian, and Dr Sana for teaching me proper laboratory techniques, intellectual discussions, and help. I also would like to thank Chandra, Myriame and Inder for the help and support. I would like to thank all my friends and cricket club members for making my stay in Detroit such an amazing one. I finally thank all of my family members for their endless love and support, which has made this dissertation possible. iii TABLE OF CONTENTS Dedication..............................................................................................................i Acknowledgements.............................................................................................. iii List of Figures ...................................................................................................... ix List of Schemes ................................................................................................... xi List of Tables ..................................................................................................... xvi List of Abbreviations .................................................................................................... xviii PART-I 1 CHAPTER 1- INTRODUCTION ............................................................................1 1.1 Importance of Thioacids ..............................................................................1 1.1.1.1 Native Chemical Ligation without Cysteine. ....................................... 4 1.1.1.2 Native Chemical Ligation with a Removable Auxiliary ...................... 4 1.1.2. Thioacid and Azide Coupling. ................................................................. 6 1.1.3 Coupling of Thioacids with Isocyanates and Isothiocyanates ............. 7 1.1.4 Amide Bond Formation by the Tomkinson Reaction ............................ 8 1.1.5 Coupling of thioacids and amines by Sanger’s and Mukaiyama’s reagent. ...................................................................................................... 9 1.1.6 Oxidative Coupling of Thioacids and Amines promoted by HOBT. 11 1.1.7 Amide Bond Formation via S-Nitrosothioacids .................................... 12 1.1.8 Application of Thioesters ......................................................................... 12 1.1.8.1 Thioester and Azide Coupling: the “Traceless” Staudinger Ligation ................................................................................................................... 14 1.2 Synthesis of Thioacids and Thioesters......................................................16 1.2.1 Direct Thiation of Carboxylic Acids ........................................................ 16 1.2.2. Nucleophilic Attack to Carbonyl Sulfide ............................................... 17 iv 1.2.3. Acylation of a Sulfur Source .................................................................. 17 1.2.4. Synthesis of Thioacids from Thioesters .............................................. 18 1.2.5. Solid Phase Synthesis of Peptidyl Thioacids and Thioesters .......... 19 1.2.5.1. Synthesis of C-Terminal Peptidyl Thioacids and Thioesters on Solid Support by Boc-chemistry Compatible Methods ..................... 20 1.2.5.2. Synthesis of C-Terminal Peptidyl Thioacids and Thioesters on Solid Support using Fmoc Chemistry .................................................. 24 1.3. Cyclic Thioanhydrides ..............................................................................27 1.3.1 Thiomaleic Anhydride .............................................................................. 30 1.3.1.1. Diels Alder Reaction ............................................................................ 30 1.3.1.2. Ene Reactions ...................................................................................... 31 1.3.1.3. Free-Radical Reactions ...................................................................... 31 1.3.1.4. Michael Addition Reactions ................................................................ 32 1.4. Objectives.................................................................................................33 CHAPTER 2- An exploration of thiomaleic anhydride as a central building block in multicomponent coupling reactions......................35 2.1. Background ..............................................................................................35 2.2. Synthesis of Thiomaleic Anhydride ..........................................................36 2.3. Multicomponent Coupling by Reaction of Thiomaleic Anhydride with Aminothiols and Subsequent Amide Bond Formation with Electron- Deficient Sulfonamides ............................................................................37 2.4. Multicomponent Coupling by Reaction of Thiomaleic Anhydride and Aminothiols and Subsequent Amide Bond Formation With Amines Promoted by Sanger’s Reagent. ..............................................................41 2.5. Heterocycle Synthesis Based on Diels-Alder Reaction. ...........................44 2.6. Synthesis of Radical Precursors...............................................................47 2.7. Radical Addition to Thiomaleic Anhydride ................................................49 v 2.8. Removal of the Boc Group, Cyclization and Subsequent Amide Bond Formation ..............................................................................................51 2.9. Deprtotection of Boc Group, Cyclization and Subsequent Thioester Formation ..............................................................................................57 2.10. Generation of Acyl Radical and Subsequent Capture ............................59 2.11. Conclusions............................................................................................62 CHAPTER 3- Multicomponent coupling reactions with thioitaconic anhydrides..............................................................................63 3.1 Background ...............................................................................................63 3.2 Synthesis of Dihydro-3-(triphenylphosphoranylidene)-2,5-thiophendione. 64 3.3 Synthesis of Monothioitaconic Anhydrides ................................................65 3.4. Multicomponent Coupling Reactions of Alkylidene Monothiosuccinic Anhydrides with Mercaptoamines and 2,4-Dinitrobenzenesulfonamides. ..............................................................................................................67 3.5. Free Radical Addition Reactions of Thioitaconic Anhydrides. ..................74 3.5.1. Heterocycle Synthesis from the Free Radical Adduct ....................... 75 3.6. Conclusions..............................................................................................77 CHAPTER 4- EXPERIMENTAL .........................................................................78 References 116 Part-II 126 CHAPTER 5- INTRODUCTION ........................................................................126 5.1. Antifreeze Substances. ..........................................................................126 5.2. Antifreeze Proteins and Glycoproteins ...................................................126 5.3.2.1. Mechanism of Thermal Hysteresis .................................................
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