SYNTHETIC EFFORTS TOWARD HYPOESTOXIDE, PLATENSIMYCIN, AND GUTTIFERONE G by Nicholas Adam Mcgrath This thesis/dissertation document has been electronically approved by the following individuals: Njardarson,Jon (Chairperson) Coates,Geoffrey (Minor Member) Ganem,Bruce (Minor Member) SYNTHETIC EFFORTS TOWARD HYPOESTOXIDE, PLATENSIMYCIN, AND GUTTIFERONE G A Dissertation Presented to the Faculty of the Graduate School of Cornell University In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy by Nicholas Adam McGrath August 2010 © 2010 Nicholas Adam McGrath SYNTHETIC EFFORTS TOWARD HYPOESTOXIDE, PLATENSIMYCIN, AND GUTTIFERONE G Nicholas Adam McGrath, Ph. D. Cornell University 2010 Hypoestoxide is a novel diterpenoid isolated from a tropical shrub, hypoestes rosea. It has been shown to exhibit promising anti - cancer, malarial, and inflammatory activity. In particular, the in vivo anti-angiogenic activity that inhibits vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) make it especially interesting. Along with this biological profile, the challenging macrocyclic structure of hypoestoxide makes it a target of great interest to the synthetic community. The synthesis of this molecule’s complex macrocyclic core was accomplished by using relay ring closing metathesis, and post-cyclization modifications were controlled by the shape of the molecule. Platensimycin is a recently isolated natural product produced by Streptomyces platensis. It was discovered in a novel antibiotic assay by screening a large number of South African soil samples. Platensimycin has been shown to have a unique mechanism of action by inhibiting Fab F, an enzyme responsible for bacterial fatty acid synthesis. In addition to the exciting biological activity, platensimycin has an intriguing molecular structure consisting of a hydrophobic and structurally compact core, and a hydrophilic aromatic head group. The synthesis of this molecule relied on a novel vinyl oxirane ring expansion to access the oxa-bicyclic moiety and an alkylative dearomatization to complete the carbocyclic core. Guttiferone G belongs to the family of [3.3.1] bicyclic polyprenylated phloroglucinol derived natural products, which have been isolated from various plant species found primarily in the tropical or subtropical regions. Their biological profiles have been shown to rival any known natural product class in terms of diversity and activity. It is this vast biological activity and structural similarity that make the development of a general approach to this family of particular interest. The common bicyclic core of these compounds was accessed by using an intramolecular bis-radical cyclization into a dienone that was itself made by oxidative dearomatization. BIOGRAPHICAL SKETCH Nicholas Adam McGrath was born in Fairmont, Minnesota, on September 11, 1980, the son of James and Ruth McGrath. From an early age he excelled in school and particularly enjoyed courses in mathematics and science. He attended 1st through 7th grades at three schools while growing up: Budd Elementary (1st - 2nd), Lincoln Elementary (3rd - 4th), and Fairmont Junior High (5th - 7th). Even though classes were easy for him, at that time he was more interested in gym class and chasing girls around the playground than thinking about the underlying scientific principles that surrounded him. After finishing his elementary education he attended 8th through 12th grades at Fairmont High School. Here he continued with his scholastic success even with much of his time being devoted to football or track practice, and the rest working part-time at the local grocery store. It was during this time that his interest in science was really triggered. The excitement and enthusiasm that both his biology teacher Mr. Kerburg and his chemistry teacher Mr. Segar displayed in class inspired him to learn more about the world around him. After graduation, Nick attended the University of Minnesota-Duluth on a full scholarship to study chemistry. During his undergraduate studies at UMD, he was fortunate for the opportunity to conduct research in the lab of Professor Ron Caple studying the stabilizing effect of sulfur on proximal carbocation intermediates. After graduation, Nick elected to stay at UMD and joined the research group of Professor Robert Carlson, this time working with sulfur-stabilized carbanions and their utility in organic synthesis. This two year hiatus was well planned because his fiancée (now wife), Jillian, had two years remaining in her psychology studies at UMD. With Nick’s studies in Duluth drawing to a close, he and Jillian were married iii on June 11, 2005. They moved across the country so that Nick could begin his doctoral studies at Cornell University. There Nick joined the relatively new research group of assistant professor Jón Njarðarson to work on natural product total synthesis. Spending five years at Cornell certainly opened his eyes to the world around him and gave him a taste of life outside the Midwest. Nick has really enjoyed his time in Ithaca and especially appreciates all of people he has met and the countless relationships he had the opportunity to build. He now looks forward to his new position in the lab of Professor Ronald Raines at the University of Wisconsin, Madison and all of the opportunities that will come his way in the future. iv ACKNOWLEDGMENTS Thanks to my family for their praise and love throughout the years. Thanks to my wife, Jillian, for putting up with my long hours and for being there when I needed support. Thanks to the entire Njarðarson group past and present for everything they have taught me over the past 5 years. Thanks to my advisor, Jón Njarðarson, and my committee members, Bruce Ganem and Geoff Coates, for their support and praise during my graduate studies at Cornell. Finally, thanks to all of the wonderful people that I have met and have developed long lasting friendships with while in graduate school. v TABLE OF CONTENTS BIOGRAPHICAL SKETCH iii ACKNOWLEDGMENTS v LIST OF FIGURES viii LIST OF SCHEMES ix LIST OF TABLES xi LIST OF ABBREVIATIONS xii PREFACE xiv Chapter 1 Hypoestoxide and Verticillol 1.1 Background and Significance 2 1.2 Other Relevant Synthetic Work 3 1.3 Our Synthetic Efforts 6 References 15 Chapter 2 Platensimycin 2.1 Background and Significance 19 2.2 Other Relevant Synthetic Work 20 2.3 Our Synthetic Efforts 31 References 37 Chapter 3 Guttiferone G 3.1 Background and Significance 43 3.2 Other Relevant Synthetic Work 45 3.3 Our Synthetic Efforts 52 vi References 57 Appendix 1 A1.1 Experimental Procedures for Chapter 1 62 A1.2 NMR Data for Chapter 1 87 A1.3 DFT Calculations for Chapter 1 165 Appendix 2 A2.1 Experimental Procedures for Chapter 2 169 A2.2 NMR Data for Chapter 2 184 Appendix 3 A3.1 Experimental Procedures for Chapter 3 217 A3.2 NMR Data for Chapter 3 227 A3.3 DFT Calculations for Chapter 3 255 Appendix 4 A4.1 A Graphical Journey of Organic Architectures That Have Improved Our Lives 266 A4.2 Top Selling Brand Name Drugs in 2008 268 References 276 vii LIST OF FIGURES 2.1 Structures of Platensimycin and Platensic Acid 19 2.2 Synthetic Approaches to Complete the Platensimycin Core 20 3.1 Guttiferone G and Hyperforin 43 3.2 Guttiferones Containing Locally Symmetrical Bicyclic Cores 45 A1.1 NMR Overlay of Hypoestoxide Isomers 164 A4.1 Graphical Representation of the 2008 Top Selling Drugs 266 viii LIST OF SCHEMES 1.1 Proposed Biosynthetic Origin of Hypoestoxide and Verticillol 3 1.2 Kato’s First Synthetic Efforts Toward Verticillene 4 1.3 Pattenden’s Synthesis of Verticillene 5 1.4 Kato’s Synthesis of Epiverticillol 6 1.5 Possible Atropisomers of Hypoestoxide 7 1.6 Retrosynthesis of Hypoestoxide 8 1.7 Synthesis of Metathesis Precursor 9 1.8 Tether-Assisted Ring Closing Metathesis 10 1.9 Synthesis of Hypoestoxide Isomer 11 1.10 Synthesis of Desoxy atrop-Hypoestoxide 12 1.11 Synthesis of Another Isomer of atrop-Hypoestoxide 13 1.12 Synthesis of a Verticillol Isomer 14 2.1 Nicolaou’s Total Synthesis of Platensimycin 21 2.2 Nicolaou’s Asymmetric Syntheses of Platensimycin 22 2.3 Snider’s Synthesis of Platensimycin 23 2.4 Nicolaou’s Stetter/Radical Based Synthesis of Platensimycin 24 2.5 Yamamoto’s Synthesis of Platensimycin 24 2.6 Mulzer’s Synthesis of Platensimycin 25 2.7 Corey’s Synthesis of Platensimycin 26 2.8 Nicolaou’s Chiral Pool Based Synthesis of Platensimycin 27 2.9 Eun Lee’s Synthesis of Platensimycin 27 2.10 Matsuo’s Synthesis of Platensimycin 28 2.11 Daesung Lee’s Synthesis of Platensimycin 29 2.12 Ghosh‘s Synthesis of Platensimycin 30 ix 2.13 Nicolaou‘s Fifth Synthesis of Platensimycin 30 2.14 Wang‘s Synthesis of Platensimycin 31 2.15 Retrosynthetic Analysis of Platensimycin 32 2.16 Synthesis of the Functionalized Aryl Fused Oxatropane 33 2.17 Oxidative Dearomatization/Cyclization Attempts 34 2.18 Intramolecular Alkylative Dearomatization 35 2.19 Efficient Synthesis of the Platensimycin Core 36 3.1 Nicolaou’s Synthetic Efforts Toward Garsubellin A 46 3.2 Stoltz’s Synthetic Approach to [3.3.1] Bicyclic Core 46 3.3 Shibasaki’s Synthesis of Garsubellin A and ent-Hyperforin 47 3.4 Danishefsky’s Total Synthesis of Three Members of This Family 48 3.5 Porco’s Synthesis of Clusianone 49 3.6 Marazano’s Synthesis of Clusianone 50 3.7 Simpkins’s Synthesis of Clusianone and Garsubellin A 50 3.8 Other Synthetic Contributions 51 3.9 Guttiferone G Retrosynthesis 52 3.10 Attempted Bis-Radical Cyclization 53 3.11 Synthesis of the Bridged Bicyclic Core of the Guttiferones 54 3.12 Rationalization of Stereochemical