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Total Synthesis of a Virotoxin and Analogs for Conformational Studies

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Total Synthesis of a Virotoxin and Analogs for Conformational Studies Louisiana State University LSU Digital Commons LSU Doctoral Dissertations Graduate School 2012 Total synthesis of a virotoxin and analogs for conformational studies Benson Jumba Edagwa 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 Edagwa, Benson Jumba, "Total synthesis of a virotoxin and analogs for conformational studies" (2012). LSU Doctoral Dissertations. 804. https://digitalcommons.lsu.edu/gradschool_dissertations/804 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]. TOTAL SYNTHESIS OF A VIROTOXIN AND ANALOGS FOR CONFORMATIONAL STUDIES 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 Benson Jumba Edagwa BSc, Moi University, Kenya, 2005 May 2012 ACKNOWLEDGEMENTS I would like to express my gratitude to my advisor, Dr. Carol Taylor, for her invaluable guidance and support during my research studies. I would also like to thank my committee members Dr. William Crowe, Dr. Graca Vicente, Dr. Evgueni Nesterov and Dr. Frederick Enright for their advice and meaningful suggestions. Sincere thanks to Dr. Dale Treleaven and Dr. Thomas Weldeghiorghis for their help with NMR studies. My appreciation goes to my wife Teresa Mutahi for her moral support. It is because of her understanding that I am able to complete my degree. My gratitude goes to my parents, brothers, sisters and the Kamau family. Without their encouragement and faith in me, I would not have made it this far. I thank members of the Taylor research group, Doug, Ning, Chamini, Saroj, Chyree, Molly and Jarret for the discussions, friendship and encouragement. I also thank Stefan of Dr. Crowe group and Kevin of Dr. Macnaughtan group for their good friendship. My gratitude goes to the department of Chemistry, Louisiana State University for their financial support. ii TABLE OF CONTENTS ACKNOWLEGEMENTS ........................................................................................................................... ii LIST OF TABLES .......................................................................................................................................v LIST OF FIGURES ................................................................................................................................... vi LIST OF SCHEMES................................................................................................................................ viii LIST OF ABBREVIATIONS AND SYMBOLS ...................................................................................... xi ABSTRACT ...............................................................................................................................................xv CHAPTER 1. BACKGROUND AND SIGNIFICANCE ...........................................................................1 1.1 STRUCTURE AND OCCURRENCE OF AMANITA TOXINS ...................................................1 1.2 BIOLOGICAL ACTIVITY AND POTENTIAL APPLICATIONS ...............................................3 1.3 BIOSYNTHESIS .............................................................................................................................6 1.4 PREVIOUS SYNTHETIC STUDIES AND ANALOGS................................................................8 1.4.1 Kahl and Coworkers ..................................................................................................................9 1.4.2 Zanotti and Coworkers .............................................................................................................11 1.4.3 Ongoing Synthetic Studies .......................................................................................................13 1.4.3.1 Guy and Coworkers ....................................................................................................13 1.4.3.2 Schuresko and Lokey ..................................................................................................15 1.5 GOALS OF THE CURRENT WORK .........................................................................................15 CHAPTER 2. SYNTHESIS OF A DIHYDROXYLEUCINE-VALINE DIPEPTIDE ............................19 2.1 PREVIOUS SYNTHESIS OF THE 4,5-DIHYDROXYLEUCINE RESIDUE .........................20 2.2 THE SHARPLESS ASYMMETRIC DIHYDROXYLATION ...................................................20 2.3 PREPARATION OF (2S)-4,5-DIHYDROXYLEUCINE RESIDUE .........................................27 2.4 THE DIHYDROXYLATION REACTION ................................................................................30 2.4.1 Stereochemical Analysis of the Dihydroxylation Reaction ....................................................38 2.4.2 Summary .................................................................................................................................40 2.5 EXPERIMENTAL SECTION .....................................................................................................41 2.5.1 General Methods ....................................................................................................................41 2.5.2 Spectra....................................................................................................................................51 CHAPTER 3. THE PEPTIDE FRAGMENTS .........................................................................................76 3.1 Overview ........................................................................................................................................76 3.2 2-METHYLSULFONYL-TRYPTOPHAN AND THE TETRAPEPTIDE FRAGMENT............77 3.3 THE PROLINE BUILDING BLOCKS AND THE TRIPEPTIDE FRAGMENTS ......................82 3.3.1 L-Proline Benzyl Ester Hydrochloride.....................................................................................83 3.3.2 L-4-cis-Hydroxyproline Building Block ..................................................................................83 3.3.3 L-3-trans-Hydroxyproline Building Block ..............................................................................85 3.3.4 L-2,3-trans-3,4-trans-3,4-Dihydroxyproline ...........................................................................86 iii 3.3.5 Completion of the Tripeptide Fragments .................................................................................89 3.3.6 Summary ..................................................................................................................................92 3.4 EXPERIMENTAL SECTION .......................................................................................................93 3.4.1 General Methods .......................................................................................................................93 3.4.2 Spectra and HPLC Chromatograms ........................................................................................120 CHAPTER 4. FRAGMENT CONDENSATION AND CYCLIZATIONS ...........................................173 4.1 THE LINEAR HEPTAPEPTIDES ..............................................................................................173 4.1.1 Overview ................................................................................................................................173 4.1.2 The Risk of Epimerization in Fragment Condensation ..........................................................174 4.1.3 Execution of the Condensations.............................................................................................177 4.2 THE CYCLIZATIONS ...............................................................................................................178 4.2.1 The Importance of Cyclic Peptides .......................................................................................178 4.2.2 Types of Peptide Cyclization ................................................................................................179 4.2.3 Suppressing Epimerization of the C-Terminal Residue........................................................181 4.2.4 Conformational Control to Facilitate Cyclization.................................................................184 4.2.5 Cyclizations and Deprotections ............................................................................................188 4.2.6 Summary/Conclusions ..........................................................................................................193 4.3 EXPERIMENTAL SECTION ....................................................................................................194 4.3.1 General Methods ...................................................................................................................194 4.3.2 Spectra and HPLC Chromatograms ......................................................................................202 CHAPTER 5. CONFORMATION .........................................................................................................219 5.1 NMR, CD AND X-RAY STUDIES ............................................................................................219
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