Florida State University Libraries Electronic Theses, Treatises and Dissertations The Graduate School 2010 Addition / C-C Bond Cleavage Reactions of Vinylogous Acyl Triflates and Their Application to Natural Product Synthesis David Mack Jones Follow this and additional works at the FSU Digital Library. For more information, please contact [email protected] THE FLORIDA STATE UNIVERSITY COLLEGE OF ARTS AND SCIENCES ADDITION / C-C BOND CLEAVAGE REACTIONS OF VINYLOGOUS ACYL TRIFLATES AND THEIR APPLICATION TO NATURAL PRODUCT SYNTHESIS By DAVID MACK JONES A Dissertation submitted to the Department of Chemistry and Biochemistry in partial fulfillment of the requirements for the degree of Doctor of Philosophy Degree Awarded: Spring Semester, 2010 Copyright © 2010 David M. Jones All Rights Reserved The members of the committee approve the dissertation of David M. Jones defended on December 3, 2009. __________________________________ Gregory B. Dudley Professor Directing Dissertation __________________________________ Kenneth Taylor University Representative __________________________________ Jack Saltiel Committee Member __________________________________ D. Tyler McQuade Committee Member __________________________________ Kenneth Goldsby Committee Member Approved: _____________________________________ Joseph B. Schlenoff, Chair, Department of Chemistry and Biochemistry The Graduate School has verified and approved the above-named committee members. ii This manuscript is dedicated to my Mother and Father, without whom I would have been lost. Their constant and unwavering support has made all that I am, and all that I will be, possible. iii ACKNOWLEDGEMENTS This body of work has been made possible not only through my hard work, but through the personal and academic support of many people. I would like acknowledge Professor Gregory Dudley. He was charged with the difficult task of not only providing challenging problems for me, his student, to explore, but also he had to provide an environment in which I could hone my own set of tools for future scientific endeavors. As a naïve 1st year graduate student I joined his research group and his constant guidance set me on the right path. As the years progressed he no longer provided answers, but only answered my questions with yet more questions. I remember being completely frustrated at the time with this tact. However now, in the waning moments of my graduate studies, I understand the role that a research advisor must play in the development of a Ph.D. student. I owe much to Dr. Dudley and I am very appreciative of his ability to change me from that naïve graduate student into the independent scientist that I have become today. I would also like to thank the members of the Dudley research group: Dr. Tim Briggs, who introduced me to lab techniques, and guided my early research; Dr. Shin Kamijo, who made my work possible through his early efforts; Dr. Doug Engel, who entered the lab at the same time as I and provided constant competition; Sami Tlais and Jingyue Yang, who often provided company late into the night in the lab; Marilda Lisboa, who provided several intermediates in my palmerolide research; and the rest of the members, past and present. I would like to acknowledge my family for providing constant support, financial and otherwise. Mom and Dad, you have truly been the foundation of my life. Although many times in grad school, you could not offer any advice to help me with my problems, you always made sure that I knew you would do anything in your power to help me. Amy, Laura, Ken, and your families, you have provided support to me in ways that you cannot even understand. I am thankful for your understanding of my inability to attend family gatherings, niece and nephew birthday parties, and other important milestones. Bamp, June, Grammy, and everyone else in the family, thank you. I would like to thank Kerri, a very big part of my life throughout graduate school; you have helped me through many difficult times. I would like to thank the Pritchard family for being like a second family to me. Thanks to Doug, Kerry, Phil, Chris, Antonio, Matt, Mike, Scott and all the other great friends in my life. I wish I had more space to mention all of those people that deserve recognition for supporting me in the generation of this manuscript, please forgive me for any omissions. Lastly, I would like to thank all of those who helped me edit this manuscript, without whom, this document would not have been possible: Kerry Gilmore, Sami Tlais, Marilda Lisboa, and Professor Dudley. iv TABLE OF CONTENTS List of Tables .................................................................................. ….. vi List of Figures ................................................................................. ….. vii List of Abbreviations ....................................................................... ….. xii Abstract .................................................................................... ….. xviii 1. INTRODUCTION: C-C BOND CLEAVAGE AND FRAGMENTATION REACTIONS IN ORGANIC SYNTHESIS........ 1 2. SYNTHESIS OF (Z)-6-HENEICOSEN-11-ONE: THE SEX PHEROMONE OF THE DOUGLAS-FIR TUSSOCK MOTH ..... ….. 13 The Doulas-Fir Tussock Moth ........................................... ….. 13 Synthesis of (Z)-6-Heneicosen-11-one ............................. ….. 16 Experimental ..................................................................... ….. 21 3. A FRAGMENTATION / BENZANNULATION STRATEGY TO PROVIDE ACCESS TO BENZO-FUSED INDANES ................. 37 Introduction ....................................................................... ….. 37 The Alcyopterosins ........................................................... ….. 37 Retrosynthetic Analysis of Alcyopterosin A ....................... ….. 53 Exploring Gold and Copper Catalyzed Benzannulations .. .. 59 Experimental ..................................................................... ….. 70 4. SYNTHESIS OF THE EASTERN HEMISPHERE (C1-C15) OF PALMEROLIDE A ............................................................... ….. 115 Introduction ....................................................................... ….. 115 The Melanoma Problem .................................................... ….. 116 Palmerolide A ................................................................... ….. 121 Synthesis of the Eastern Hemisphere of Palmerolide A ... ….. 138 Experimental ..................................................................... ….. 145 5. RE-EXPLORING THE CLAISEN-TYPE CONDENSATIONS OF VINYLOGOUS ACYL TRIFLATES ...................................... ….. 170 New Insights into the Mechanism ..................................... ….. 170 Synthesis of -Ketophosphonates .................................... ….. 177 Experimental ..................................................................... ….. 184 REFERENCES .............................................................................. ….. 202 BIOGRAPHICAL SKETCH ............................................................. ….. 222 v LIST OF TABLES Table 1: Scope of Original Fragmentation Reaction with Respect to Nucleophiles ............................................................................... 11 Table 2: Grignard Triggered Fragmentation of 2 ....................................... 20 Table 3: DNA Binding Assay Performed by Iglesias et al. ......................... 51 Table 4: Average Values (MG-MID) for In Vitro Antitumor Activity on the NCI 60-Cell Line Panel ................................................................ 52 Table 5: Preliminary Screening of Benzannulation Reactions of Substrates 84a-f.......................................................................... 65 Table 6: Selected Data from Nicolaou’s SAR Study (GI50 Values in M) .. 133 Table 7: Claisen-Type Condensation of Vinylogous Acyl Triflate 2 ........... 141 Table 8: Comparison of the Acidities of Several Acetophenone Phosphonate and Phosphine Oxide Derivatives in DMSO .......... 174 Table 9: Reactions of Vinylogous Acyl Triflates with 1.1 Equivalents of Dimethyl lithiomethylphosphonate (152b) ................................... 180 Table 10: Fragmentation of VAT 2 Using 1.1 Equivalents of Various Phosphonate Derived Nucleophiles .......................................... 182 vi LIST OF FIGURES Figure 1: Representative examples of the (1) Diels-Alder, (2) Michael Addition, (3) Evans Aldol, (4) and Sonogashira Cross Coupling Reactions in Synthesis ............................................................... 2 Figure 2: Examples of Tandem Bond Forming / Bond Breaking Strategies in Organic Synthesis .................................................................. 3 Figure 3: Examples of Transition Metal Catalyzed C-C Bond Cleavage Reactions in Synthesis ............................................................... 4 Figure 4: Possible Mechanistic Pathways of Grob Fragmentations .......... 6 Figure 5: General Representation of the Wharton Fragmentation ............ 6 Figure 6: Wood and Njardarson’s Wharton fragmentation approach to CP-263,114 ................................................................................ 7 Figure 7: Base Promoted Eschenmoser-Tanabe Fragmentation Process. ..................................................................................... 8 Figure 8: Mander’s Reduction-Epoxidation-Oxidation Solution for the Eschenmoser-Tanabe Fragmentation in the Synthesis of GB 13 ......................................................................................... 9 Figure 9: Comparison