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Dechalcogenative Allylic Selenosulfide and Disulfide Rearrangements for Cysteine Modification and Glycoligation Venkataraman Subramanian Wayne State University

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Dechalcogenative Allylic Selenosulfide and Disulfide Rearrangements for Cysteine Modification and Glycoligation Venkataraman Subramanian Wayne State University Wayne State University Wayne State University Dissertations 1-1-2010 Dechalcogenative Allylic Selenosulfide And Disulfide Rearrangements For Cysteine Modification And Glycoligation Venkataraman Subramanian Wayne State University Follow this and additional works at: http://digitalcommons.wayne.edu/oa_dissertations Part of the Organic Chemistry Commons Recommended Citation Subramanian, Venkataraman, "Dechalcogenative Allylic Selenosulfide And Disulfide Rearrangements For Cysteine Modification And Glycoligation" (2010). Wayne State University Dissertations. Paper 31. 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. DECHALCOGENATIVE ALLYLIC SELENOSULFIDE AND DISULFIDE REARRANGEMENTS FOR CYSTEINE MODIFICATION AND GLYCOLIGATION by VENKATARAMAN SUBRAMANIAN 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 2010 MAJOR: CHEMISTRY (Organic) Approved by: Advisor Date DEDICATION To my beloved parents for their endless love and support ii ACKNOWLEDGEMENTS I owe my deepest gratitude to my advisor Professor David Crich for his endless patience, brilliant guidance, continuous encouragement and constant support throughout the years of my Ph.D study at University of Illinois at Chicago and at Wayne State University. Without his continuous help and guidance this dissertation would not have been possible. I wish to thank my dissertation committee members Professor Jin K Cha, Professor Andrew Feig and Professor Xuefei Huang for their time, valuable suggestions and assistance. I would like to thank my previous mentors Dr. Bipul Baruah and Dr. Manojit Pal for their encouragement and guidance. I extend my thanks to the past Crich group members especially Dr. Jayalath, Dr. Brebion, Dr. Karatholuvhu, Dr. Krishnamurthy and Dr. Yang for their intellectual discussions, help and support. My sincere thanks to the current Crich group members Dr Sasaki, Kasinath, Chandra, Inder, Mohammed and Myriame for their help and encouragement. I take pleasure in thanking my friends Karthik, Bala, Kavitha, Balaji, Guru and Sudhakar for their help and support. I truly thank my friends Dr. Dakshnamurthy, Raja, Rama and Venkatesh here at Wayne State University. I want to acknowledge the departments of Chemistry at UIC and WSU for their support. iii I especially thank my parents and my brother for their endless love and constant encouragement in all my endeavors. Finally, I would like to thank my wife for her love and support. iv TABLE OF CONTENTS Dedication .............................................................................................................ii Acknowledgements .............................................................................................. iii Table of Contents..................................................................................................v List of Figures...................................................................................................... iix List of Tables.........................................................................................................x List of Schemes....................................................................................................xi List of Abbreviations........................................................................................... xvi CHAPTER I. Introduction................................................................................... 1 1.1 Chemoselective ligations............................................................................ 1 1.1.1 Acyl-transfer ligations........................................................................... 2 1.1.2 Prior thiol capture................................................................................. 2 1.1.3 Pseudo proline ligation......................................................................... 3 1.1.4 Native chemical ligation ....................................................................... 4 1.1.5 Staundinger ligation ............................................................................. 5 1.2 Non-native ligations .................................................................................... 6 1.2.1 Cycloadditions...................................................................................... 6 1.2.2 Oxime formation................................................................................. 10 1.3 Thiol nucleophiles..................................................................................... 11 1.3.1 Thioesterification based chemoselective ligations.............................. 11 1.3.2 Thioetherification based chemoselective ligations ............................. 13 1.3.3 Synthesis of S-lipidated peptides ....................................................... 14 1.3.4 Synthesis of S-linked glycosyl amino acids and glycopeptides.......... 15 1.3.4.1 Alkylation of anomeric thiol ............................................................. 15 1.3.5 Michael Additions............................................................................... 16 v 1.4 Radical addition to form thioethers ........................................................... 17 1.5 Synthesis of S-linked glycoprotein mimics................................................ 18 1.5.1 Ligation via disulfide linkage .............................................................. 18 1.6 From Disulfides to thioether linked chemoselective ligations.................... 21 1.6.1 Allylic disulfide rearrangement ........................................................... 21 1.7 Allylic selenosulfide rearrangement .......................................................... 24 1.8 Thioether linked glycoproteins from disulfide bonds ................................. 25 1.9 Transition metal based chemoselective ligations...................................... 26 1.9.1 Metal mediated glycoconjugation....................................................... 28 2.0 Goal of this thesis ..................................................................................... 30 CHAPTER II. Dechalcogenative Allylic Selenosulfide Rearrangement; Modification to Cysteine Thiols ...................................................................... 31 2.1 Selenosulfides via selenocyanates........................................................... 31 2.2 Selenosulfide ligation via allylic selenocyanates....................................... 34 2.2.1 Application to simple thiols cysteine thiols ......................................... 34 2.2.2 Application to cysteine thiols .............................................................. 36 2.2.3 Application to cysteine containing peptides........................................ 37 2.3 Application of selenocyanate methodology to the allylation of a protein... 39 2.4 Application to a fluorous system ............................................................... 39 2.5 Application to carbohydrate chemistry...................................................... 41 2.6 Effect of various substituents on allylic selenosulfide rearrangement....... 42 2.6.1 Rearrangements requiring triphenylphosphine ...................................... 42 2.7 Attempts toward the synthesis of S-linked glycoconjugates through selenocyanate methodology........................................................................... 46 2.8 Secondary selenocyanates....................................................................... 49 2.9 Conclusion................................................................................................ 53 vi CHAPTER III. Desulfurative Allylic Disulfide Rearrangement ...................... 54 3.1 Background and significance.................................................................... 54 3.2 Drawbacks of triphenylphosphine............................................................. 54 3.2.1 Use of other thiophilic reagents.......................................................... 55 3.3 Synthesis of secondary allylic disulfides................................................... 57 3.3.1 Modified synthesis of a secondary allylic disulfide ............................. 58 3.3.2 Synthesis of tridecenyl containing allylic disulfide .............................. 59 3.4 Synthesis of a tertiary allyl disulfide.......................................................... 60 3.5 Application of secondary and tertiary allylic disulfides .............................. 61 3.6 Phosphine free thiophilic reagent ............................................................. 62 3.6.1 Silver mediated allylic disulfide rearrangement .................................. 62 3.7 Synthesis of an allyl aryl sulfide................................................................ 63 3.8 Application to carbohydrate chemistry...................................................... 64 3.8.1 Rearrangements involving anomeric thiol .......................................... 64 3.8.2 Application to cysteine functionalization............................................. 66 3.9 Olefinic stereoselection............................................................................. 67 3.9.1 Application to the synthesis of glycoconjugate................................... 68 4.0 Conclusion...............................................................................................
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