Innovations en Route to Muironolide 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 Krista Cunningham Graduate Program in Chemistry. The Ohio State University 2015 Dissertation Committee: Prof. Craig J. Forsyth, Advisor Prof. Anita M. Mattson Prof. Psaras McGrier Prof. Kalpana Ghoshal Copyright by Krista Cunningham 2015 Abstract Muironolide A is a complex natural product that was isolated from a marine sponge Phorbas sp. This sponge has yielded several potent anticancer drug leads, including the phorboxazoles. However, a very minute quantity of muironolide A was isolated – only 90 micrograms of purified material. Remarkably, this was sufficient for Professor T. Molinski to propose the complete structure, which includes an unprecedented hexahydro- 1H-isoindolone skeleton, a chlorocyclopropane, and a trichlorocarbinol ester. However, the limited amount of material available has prevented evaluation of the biological activities of muironolide A. It is anticipated that the novel chemotype may have associated useful activities, given those of its natural product congeners. We are developing a convergent, biomimetic total synthesis of muironolide A and its close structural analogs to allow full evaluation of their biomedical potential. This involves the preparation of several component fragments and their successive couplings. ii This work is dedicated to all of my teachers, both in and out of the classroom—my family, friends, and many educators who have supported and believed in me. iii Acknowledgments I would like to start by thanking my advisor, Professor Craig Forsyth, for all that he has done for me. Not only has he given me the opportunity to learn and grow as a scientist in his research group, but has been an incredible resource for knowledge, advice, encouragement, and support. For that, I will always be grateful. An additional thanks goes to the muironolide A subgroup, whom have provided me with great amounts of scientific and emotional support. To Dr. Isabelle Modolo, who laid the foundation for the work described herein: your work and friendship are appreciated more than you know. I would also like to thank Charles Clay and Kedwin Rosa for their huge contributions and dedication to this project. I am also happy to have had the opportunity to work with a skilled undergraduate, Mike Hoover, and thank him for his efforts. I have to additionally thank my research group members. I am especially grateful to Antony Okumu and Daniel Adu-Ampratwum, who have been on this journey with me from the beginning. I have enjoyed learning from and laughing with you countless times. To the members of my group who have already moved on, but impacted me greatly— Drs. Matt Jackel, Sean Butler, and Ting Wang: I am grateful to have had your mentorship. I would also like to acknowledge the Forsyth group members who have always been so supportive, including Li Xiao, Jerry Casbohm, Daniel Akwaboah, iv Olumuyiwa (MJ) Adesoye, and Nate Kenton. Additionally, a special thanks goes out to Jen Moore, Emily Prebihalo, and Basil Jafri for making this last summer so much fun. I cannot begin to express the gratitude I have for my many mentors in the classroom. Dr. Peter Norris, you are the reason I decided to pursue graduate school, and you continue to be an inspiration to me as an instructor. I am additionally very thankful to have worked with Drs. Christopher Callam and Noel Paul. Your support, advice, and countless hours of chatter have molded me into the teacher I am today. A special thanks goes out to my cheerleaders in the Stambuli and Hadad groups, namely Chip, Ryan, Bill, Amneh, and Tom, who always made sure I had what I needed, even if it was just a laugh. To Sarah, Kendra, Krishnaja, and Oui: your support, lunch dates, and endless conversations have made these past couple of years so much more enjoyable. To my soon-to-be-husband, Michael: “thank you” does not even begin to express my immense gratitude to have you in my life these past several years. If graduate school has taught me anything, it is that I can always count on you to love and support me, and to make me smile when I need it most. There is no way that I could have done this without you, and I could not have chosen a better person to spend my life with. Lastly, I have to thank my incredible family—both the one I was born into and the one I will join in a few short months. You are my foundation and my rock, and all that I am is built from each and every one of you. You all mean more to me than words could ever express. Above all, I have to thank my parents, Christina and Mike Cunningham, who have molded me to be the woman I am today. Thank you for always believing in me, and teaching me not to give up. v Vita June 2006 .......................................................Boardman High School Diploma May 2010 .......................................................B.S. Chemistry Youngstown State University September 2010 to 2015 ...............................Graduate Teaching and Research Associate The Ohio State University Fields of Study Major Field: Chemistry vi Table of Contents Abstract ........................................................................................................................... ii! Acknowledgments .......................................................................................................... iv! Vita ................................................................................................................................. vi! List of Schemes ............................................................................................................... x! List of Figures ............................................................................................................... xii! List of Abbreviations ................................................................................................... xiii! Chapter 1 : Background .................................................................................................. 1! 1.1 Introduction ........................................................................................................... 1! 1.2 Structure Elucidation of Muironolide A ............................................................... 3! 1.3 Synthetic Studies Toward Muironolide A ............................................................ 6! 1.3.1 Synthetic Studies on Muironolide A by the Molinski Group ........................ 6! 1.3.2 The Mitchell Group’s Approach Towards Muironolide A .......................... 10! 1.3.3 The Zakarian Group Approach to Muironolide A ....................................... 12! 1.4 Zakarian Total Synthesis and Structural Revision of (+)-Muironolide A .......... 16! 1.4.1 Retrosynthetic Analysis ............................................................................... 16! 1.4.2 Synthesis of Diels-Alder Reaction Substrates ............................................. 17 vii 1.4.3 IMDA Reactions and Synthesis of 1.5 ......................................................... 19! Chapter 2 : First Generation Synthetic Approach to Muironolide A ............................ 24! 2.1 Retrosynthetic Analysis ...................................................................................... 24! 2.2 Synthesis of Triene 2.2 ....................................................................................... 26! 2.3 Progress Toward Cyclopropane 2.6 .................................................................... 29! 2.4 Completion of Diene 2.5 ..................................................................................... 31! 2.5 Problems with First Generation Route ................................................................ 32! Chapter 3 : Revised Approach to Muironolide A ......................................................... 34! 3.1 Retrosynthetic Analysis ...................................................................................... 34! 3.2 Revised Route to Triene 3.4 and Synthesis of (17S)-3.4 .................................... 35! 3.3 Synthesis of Cyclopropane 3.5 ........................................................................... 37! 3.4 Completion of Diene 3.6 ..................................................................................... 38! 3.5 Attempts at Assembly of Muironolide A ............................................................ 39! Chapter 4 : Current Approach and Future Directions ................................................... 43! 4.1 Current Retrosynthesis ........................................................................................ 43! 4.2 Cyclopropane 4.5 ................................................................................................ 45! 4.3 Efforts Toward Diene 4.4 ................................................................................... 46! 4.4 Future Directions ................................................................................................ 48! Chapter 5 : Experimental Section ................................................................................. 49! viii List of References ......................................................................................................... 94! Appendix A: 1H NMR Data .......................................................................................... 98! ix List of Schemes Scheme 1.1: Synthesis of Cyclopropanes 1.9a-d ...............................................................