TOTAL SYNTHESIS OF GOMISIN O; ASYMMETRIC TOTAL SYNTHESES OF EUPOMATILONES 1, 2 & 5; AND STUDIES TOWARD TOTAL SYNTHESIS OF MAYOLIDE A DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By SOUMYA MITRA, M.S. ***** The Ohio State University 2007 Dissertation Committee: Approved by Professor Robert S. Coleman, Advisor Professor Craig J. Forsyth _________________________________ Professor Gideon Fraenkel Advisor Graduate Program in Chemistry ABSTRACT Gomisins are oriental medicinal plant lignans characterized by a highly electron- rich dibenzocyclooctadiene core structure with a stereogenic axis about the biaryl bond, exhibiting atropisomerism. The cyclooctane ring is additionally substituted with several stereogenic methyl and hydroxyl groups, thereby diversifying this class of lignans. Most members of this family possess anti-HIV, anti-hepatitis, analgesic, antitussive and central nervous system depressant activities. A convergent, highly efficient total synthesis of gomisins O and E would be discussed in this thesis with complete control of absolute and relative stereochemistry. The key steps involved in the total synthesis are a novel indium- mediated methylcrotylation, a diastereoselective B-alkyl Suzuki−Miyaura alkylborane coupling and an intramolecular oxidative biaryl cuprate cross-coupling with total atropdiastereocontrol. Eupomatilones are structurally novel fluxional plant lignans with varying degree of oxygenation on the biphenyl system. The α-methylene-γ-lactone moiety attached to the biphenyl, as found in eupomatilones 1, 2 and 5, readily forms covalent bonds to cellular proteins and is a cause of chronic actinic dermatitis (CAD). This moiety also forms photo adducts with DNA base thymine in sunlight and has been also shown to target the Iκβ kinase addition to the transcription factor regulator nuclear factor (NF-κΒ), signifying their ii potential role in cellular signaling processes. In this thesis, we would discuss a successful asymmetric strategy for the synthesis of a few members of this unique family of lignans. The key to the synthesis depends on a nicely optimized Suzuki−Miyaura biaryl cross- coupling reaction with heavily electron-rich coupling partners. In addition to this, the synthesis is novel in demonstrating the first example of an asymmetric carbomethoxycrotylboration approach to the synthesis of the α-methylene-γ-lactone moiety, involving application of Miyaura’s boryl-copper chemistry. This thesis also describes a novel route to the synthesis of the carbomethoxycrotylboronate reagent in enantiomerically pure form. This reagent could be of much use for further application in other natural product synthesis. Mayolides are cembrane diterpenes found in the lipids of marine soft corals exhibiting potent anti-cancer properties. Mayolide A is an α-methylene-γ-lactone derivative and also the first secocembrane diterpenoid to be isolated. In this thesis, we would discuss the synthetic strategy developed and the progress made towards the total synthesis of this structurally novel molecule, utilizing the carbomethoxycrotylation strategy developed during the total synthesis of eupomatilones as one of the key steps. iii DEDICATION To my parents, Dr. Lakshmi Kanta Mitra & Mrs. Tapati Mitra And My Grandmother, Mrs. Gita Ghosh iv ACKNOWLEDGMENTS My sincerest gratitude goes to my adviser and mentor, Dr. Robert S. Coleman, for all his intellectual support, for allowing me the freedom of independent scientific thinking, to achieve my goals and objectives that made this thesis possible. I would also thank him for all his encouragement and enthusiasm, which motivated me to organize scientific meetings at Ohio State and in ACS national conferences, for his persistent backing and mental support in times of need, and lastly for his patience in correcting my stylistic and scientific errors. It is he who has made me the chemist I am today. I wish to sincerely thank Dr. Srinivas R. Gurrala, who has helped me master the finer skills in experimental organic chemistry. I am also thankful to Dr. Xiaoling Lu and Amy Hayes for being exceptionally considerate, very understanding and co-operative office mates. I further extend my gratitude to the past and present members of Coleman group, who have heartily extended their help, friendship, experience and advice in my research. I am greatly indebted to my mom, dad, younger brother, and my grandmother for all their love, prayers and inspiration from Calcutta, India. Lastly, I would also like to thank the Department of Chemistry NMR facility, the computer support and all other dedicated support staff members, who have helped me in the graduate school at The Ohio State University. v VITA November 23, 1976. ……...Born – Calcutta, India 1999. …………………. B.Sc. (Honors) Chemistry, Presidency College, University of Calcutta, India 1999 − 2001……………………………………… M.S. Organic Chemistry, Indian Institute of Technology Bombay, (Mumbai), India 2001 – 2002. ………... Graduate Student Instructor, Department of Chemistry, University of Michigan, Ann Arbor, MI 2002 – 2007. ………. Graduate Teaching and Research Associate, The Ohio State University, Columbus, OH, USA PUBLICATIONS Research Publications 1. Kyung-Hoon Lee, Manolis Matzapetakis, Soumya Mitra, E. Neil G. Marsh, Vincent L. Pecoraro; “Control of Metal Coordination Number in de Novo Designed Peptides through Subtle Sequence Modifications” J. Am. Chem. Soc. 2004, 126, 9178- 9179. 2. Robert S. Coleman and Soumya Mitra; “2(methyldithio)-1H-isoindole-1,3(2H)- dione”, Electronic Encyclopedia of Reagents for Organic Synthesis, Ed. Leo A. Paquette, Wiley, NY, August 2004. vi 3. Robert S. Coleman, Srinivas R. Guralla, Soumya Mitra, Amresh M. Raao; “Asymmetric Total Synthesis of Dibenzocyclooctadiene Lignan Natural Products,” J. Org. Chem. 2005, 70, 8932-8941. 4. Francois-Xavier Felpin, Tahar Ayad and Soumya Mitra; “Pd/C: An Old Catalyst for New Applications – Its Use for the Suzuki–Miyaura Reaction”, Eur. J. Org. Chem. 2006, 2679-2690. 5. Soumya Mitra, Srinivas R. Guralla and Robert S. Coleman; “20.7 Product Class 7: Peroxy Acids and Derivatives”, Science of Synthesis: Houben-Weyl Methods of Molecular Transformations, Ed. James S. Panek, Thieme, Stuttgart, 2007, Vol. 20b, 1553-1594. 6. Soumya Mitra, Srinivas R. Gurrala and Robert S. Coleman; “Total Synthesis of Eupomatilones,” J. Org. Chem. 2007, 72, asap article. FIELDS OF STUDY Major Field: Chemistry vii TABLE OF CONTENTS Page Abstract............................................................................................................................ii Dedication........................................................................................................................iv Acknowledgements..........................................................................................................v Vita...................................................................................................................................vi List of Schemes................................................................................................................xii List of Tables ...................................................................................................................xv List of Figures..................................................................................................................xvi List of Abbreviations .......................................................................................................xvii Chapters: Page 1. Dibenzocyclooctadiene lignans: Isolation, biological activity and structural elucidation....................................................................................................1 2.1. Introduction...........................................................................................................1 2.2. Isolation and structure determination of gomisin O and structurally related dibenzocyclooctadiene natural products ...................................................4 1.3. Biological activity of gomisins and dibenzocyclooctadiene lignans ....................7 2. Review of previous synthetic strategies towards the construction of the dibenzocyclooctadiene core.........................................................................................10 2.1. Kende’s approach .................................................................................................11 2.2. Raphael’s approach...............................................................................................12 viii 2.3. Zeigler’s approach ................................................................................................14 2.4. Magnus’ approach ................................................................................................15 2.5. Meyers’ approach .................................................................................................16 2.6. Motherwell’s approach .........................................................................................18 2.7. Molander’s approach ............................................................................................19 3. Brief review of atropisomerism, oxidative biaryl cross coupling, problems in methylcrotylation, and the B-alkyl Suzuki−Miyaura cross-coupling reaction ............21 2.1. Atropisomerism in biaryls ....................................................................................21 2.2. Atropselective intramolecular couplings ..............................................................22