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Synthesis of the Western Hemisphere of Theonellamide C Saroj Yadav Louisiana State University and Agricultural and Mechanical College, [email protected]

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Synthesis of the Western Hemisphere of Theonellamide C Saroj Yadav Louisiana State University and Agricultural and Mechanical College, Syadav3@Tigers.Lsu.Edu Louisiana State University LSU Digital Commons LSU Doctoral Dissertations Graduate School 2013 Synthesis of the western hemisphere of theonellamide C Saroj Yadav Louisiana State University and Agricultural and Mechanical College, [email protected] Follow this and additional works at: https://digitalcommons.lsu.edu/gradschool_dissertations Part of the Chemistry Commons Recommended Citation Yadav, Saroj, "Synthesis of the western hemisphere of theonellamide C" (2013). LSU Doctoral Dissertations. 2836. https://digitalcommons.lsu.edu/gradschool_dissertations/2836 This Dissertation is brought to you for free and open access by the Graduate School at LSU Digital Commons. It has been accepted for inclusion in LSU Doctoral Dissertations by an authorized graduate school editor of LSU Digital Commons. For more information, please [email protected]. SYNTHESIS OF THE WESTERN HEMISPHERE OF THEONELLAMIDE C A Dissertation Submitted to the Graduate Faculty of the Louisiana State University and Agricultural and Mechanical College in partial fulfillment of the requirements for the degree of Doctor of Philosophy in The Department of Chemistry by Saroj Yadav M.Sc., Panjab University, 2008 December 2013 To My Family… To my parents, Jagdish and Sushila Yadav, for believing in and supporting all my life pursuits. To my husband Prathivind Bejgum, whose unconditional love inspires me to fulfill my academic milestones. ii ACKNOWLEDGMENTS I want to offer my sincerest thanks to my adviser, Dr. Carol M. Taylor, for her unwavering support and constant encouragement throughout my graduate school career at LSU. I am also grateful for her abundant generosity and unlimited patience of which I have tested repeatedly. I can truly say that Dr. Taylor is the hardest working woman that I’ve ever had the pleasure of knowing. Thank you so very much for dedicating voluntary hours in proof reading innumerable versions of this dissertation and help polish a rudimentary piece into something worthy. Heartiest thank you to my committee members from the Chemistry Department: Dr. Graca Vicente, Dr. William Crowe, and Dr. Bin Chen for their advice and meaningful suggestions. I would also like to thank Dr. Michael Benton for taking time out to serve as my external invigilator. I am also thankful to the late Dr. Dale Treleaven, Dr. Thomas Weldeghiorghis and Connie David for their help with NMR and Mass Spectrometry studies. My appreciation goes to my siblings Sharmila, Anup and Venky for their moral support. My gratitude goes to my parents-in-law Krishna and Radha Bejgum. Without their encouragement and faith in me, I would not have made it this far. I am indebted to my fellow labmates Benson, Doug, Ning, Chamini, Chyree, and Molly for the discussions, friendship and encouragement. It has been a pleasure to work alongside you for the past five years and I am truly fortunate to have experienced graduate school with you all. And finally, I would like to thank the Department of Chemistry at LSU and the National Science Foundation for all their support. iii TABLE OF CONTENTS ACKNOWLEDGMENTS ............................................................................................................... iii LIST OF TABLES ......................................................................................................................... vi LIST OF FIGURES ...................................................................................................................... vii LIST OF SCHEMES .................................................................................................................... viii LIST OF ABBREVIATION AND SYMBOLS ................................................................................. xii ABSTRACT ................................................................................................................................. xv CHAPTER 1: THEONELLAMIDES A-F: INTRODUCTION .......................................................... 1 1.1 Occurrence of Theonellamides ............................................................................. 1 1.2 Structural Characteristics of Theonellamides ........................................................ 3 1.3 Initial Biological Studies ........................................................................................ 4 1.4 More Recent Biological Studies: Chemical Genetics ............................................ 6 1.5 Previous Studies Directed Toward the Synthesis of Theonellamides ................. 15 1.6 Research Goals of This Dissertation ................................................................... 18 1.7 Retrosynthetic Analysis ....................................................................................... 18 CHAPTER 2: INITIAL APPROACH TO (2S,4R)-α-AMINO-γ-HYDROXY ADIPIC ACID (AHAD): COREY-LYGO METHOD .................................................................... 20 2.1 Structural Determination of (2S,4R)-α-Amino-γ-Hydroxy Adipic Acid (Ahad) ..... 20 2.2 Biogenesis of Ahad and α-AAA ........................................................................... 22 2.3 Previous Synthesis of (2S,4R)-ɣ-Hydroxy-α-Amino Adipic Acid (Ahad) ............. 23 2.4 Retrosynthesis of Ahad via Alkylation of a Glycine Ester Enolate ...................... 25 2.5 Phase-Transfer Catalysis (PTC) and the Corey-Lygo Approach ........................ 25 2.5.1 The Concept ............................................................................................ 25 2.5.2 Previous Examples ................................................................................. 27 2.6 Synthesis of an Electrophile for Ahad Synthesis ................................................ 28 2.7 Alkylation of Glycine Ester Enolates ................................................................... 30 2.8 Experimental Section .......................................................................................... 33 2.8.1 General Methods .................................................................................... 33 2.8.2 Procedures .............................................................................................. 34 2.8.3 Spectra .................................................................................................... 43 CHAPTER 3: AN AMINE CONJUGATE ADDITION APPROACH TO AHAD ........................... 69 3.1 Conjugate Addition Reaction to Afford β-Amino Acids ........................................ 69 3.2 MacMillan Conjugate Addition ............................................................................. 72 3.3 Application of the MacMillan Strategy to Ahad .................................................... 74 3.4 Experimental Section .......................................................................................... 81 3.4.1 General Methods .................................................................................... 81 3.4.2 Procedures .............................................................................................. 81 3.4.3 Spectra .................................................................................................... 88 iv CHAPTER 4: PROTECTING GROUP STRATEGY FOR (2S,4R)-α-AMINO-γ-HYDROXY ADIPIC ACID (AHAD) AND α-AMINO ADIPIC ACID (α-AAA) .......................... 108 4.1 The Protecting Group Challenge ........................................................................ 108 4.2 Acetol Esters ...................................................................................................... 110 4.3 SEM Esters ........................................................................................................ 111 4.4 Synthesis of α-AAA-α-Esters .............................................................................. 112 4.4.1 Precedents for N-Protection ................................................................... 112 4.5 Liberation of δ-COOH from Protected α-AAA Derivatives .................................. 115 4.6 Synthesis of Ahad Building Block. ...................................................................... 118 4.7 Experimental Section ......................................................................................... 122 4.7.1 General Methods .................................................................................... 122 4.7.2 Procedures ............................................................................................. 123 4.7.3 Spectra ................................................................................................... 134 CHAPTER 5: PEPTIDE FRAGMENT ASSEMBLY AND CYCLIZATION OF THE WESTERN HEMISPHERE OF THEONELLAMIDE C .......................................................... 158 5.1 Retrosynthesis for the Western Hemisphere of Theonellamide C…….…….…..158 5.2 Formation of a Dipeptide Containing erythro-HydroxyAsparagine (eHyAsn) ..... 158 5.3 Side Reactions of the Unprotected Side Chain Amide of Asparagine ................ 161 5.4 Formation of Tetrapeptide .................................................................................. 163 5.4.1 Deprotection of α-Amine ........................................................................ 163 5.4.2 Elongation to Tetrapeptide ..................................................................... 165 5.5 Model Studies for Cyclization. ............................................................................ 165 5.6 Precedent for Pairs of Palladium-Labile Protecting Groups. .............................. 168 5.7 Future Work. .....................................................................................................
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