DEVELOPMENT OF NOVEL METHODS AND APPLICATIONS IN TOTAL SYNTHESIS OF NATURAL PRODUCTS A Dissertation Submitted to the Temple University Graduate Board in Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY by Gopal Sirasani January, 2012 Examining Committee Members: Prof. Rodrigo B. Andrade, Department of Chemistry, Temple University Prof. Franklin A. Davis, Department of Chemistry, Temple University Prof. Magid Abou-Gharbia, Department of Chemistry, Temple University Prof. David R. Dalton, Department of Chemistry, Temple University Prof. Kevin C. Cannon, External Examiner, Pennsylvania State University ! "! © by Gopal Sirasani 2012 All Rights Reserved ! ""! ABSTRACT DEVELOPMENT OF NOVEL METHODS AND APPLICATIONS IN TOTAL SYNTHESIS OF NATURAL PRODUCTS Gopal Sirasani Doctor of Philosophy Temple University, 2012 The olefin cross metathesis reaction has been sequenced with four common organic transformations in a one-pot manner to rapidly access useful building blocks. Those reactions are: (1) phosphorus-based olefination (e.g., Wittig and Horner- Wadsworth-Emmons); (2) hydride reduction; (3) Evans propionate aldol reaction; and (4) Brown allyl- and Roush crotylboration. The products of these reactions include stereodefined 2,4-dienoates, trans allylic alcohols, syn-propionate aldols and chiral non- racemic homoallylic alcohols, respectively, which can be carried further in the context of chemical synthesis. Two approaches toward the total synthesis of cytotoxic polyketide natural product (+)-crocacin C have been accomplished. The first-generation approach used a Crimmins aldol reaction and reagent-controlled double asymmetric crotylboration (Brown and Roush) reaction, which was not selective. The first-generation approach was replaced altogether with a second that afforded (+)-crocacin C in 10 steps from commercially available Evans’ chiral propionimide (5% overall yield). ! """! The key reactions in the second-generation approach included an Evans dipropionamide aldol reaction, 1,3-anti reduction and a vinylogous Horner-Wadsworth- Emmons olefination. No protecting groups were utilized in the total synthesis of (+)- crocacin C. A novel method to access the ABCE tetracyclic framework of the Strychnos alkaloids has been developed. Five different strategies were utilized toward this goal, out of which the first four were unsuccessful. The fifth-generation strategy featured a novel sequential one-pot bis-cyclization method. Specifically, the AgOTf-mediated spirocyclization of an appropriately functionalized indole 3-carbinamide afforded a stable spiroindolenine intermediate; subsequent addition of DBU to the reaction mixture effected an unprecedented intramolecular aza-Baylis-Hillman reaction, delivering tetracyclic product in 70% isolated yield. The bis-cyclization was showcased in concise racemic total syntheses of akuammicine and strychnine in six and thirteen operations, respectively. Key steps include (1) the vinylogous Mannich reaction; (2) our sequential one-pot spirocyclization/intramolecular aza-Baylis-Hillman reaction; and (3) a Heck cyclization. The synthesis of strychnine proceeded via the Wieland-Gumlich aldehyde. We have also utilized our method to prepare other biologically active Strychnos alkaloids (-)- akuammicine, (-)-leuconicines A and B, (-)-norfluorocurarine, (-)-dehydrotubifoline, (-)- dihydroakuammicine, (-)-tubifoline and (-)-valparicine in a concise, asymmetric manner. ! "#! Dedication I dedicate this dissertation to all my wonderful family members whose support and encouragement throughout my graduate school journey made it possible ! #! ACKNOWLEDGMENTS This is by far the most important part of my thesis. Synthetic organic chemists often define their achievements in terms of the number of natural products they made or the number of novel reactions they developed. Yet, I realize that my greatest achievements have been the professional and personal relationships I have developed that have gotten me to this stage in life. It is with tremendous gratitude that I write these acknowledgements to show my appreciation to the people who have helped me throughout the years. First and foremost, I would like to thank my advisor Rodrigo B. Andrade for his unwavering support, enthusiasm and general concern for my development as an organic chemist. The excitement with which Rod approaches synthesis and his dedication to the goal of producing “good science” is inspiring. Rod’s teaching style, both in the classroom and the laboratory with all of the historical background, motivated me to join the group, and his willingness and openness to discussion are what kept me excited. It has been a privilege to work under his tutelage and an even greater pleasure to be one of his first Ph.Ds. Rod has had a tremendous influence on how I think of chemistry and I hope to continue to learn from him in the future. Rod’s persistent enthusiasm is a great source of inspiration. As an advisor, he has always encouraged me to explore my ideas and he has always guided me in the right direction. Whenever I was losing motivation for a project, I knew that a five-minute conversation with him would be enough to inspire me. The other members of my thesis committee have been a true pleasure to interact with. Prof. Davis, the chair of my committee is the most well organized person I have ever met. I would like to thank him for providing me with many scientific insights. ! #"! I am grateful for all the scientific and career advice Prof. Dalton has provided me over the years. He was like a living library for me throughout these years and I will never forget the conversations I had with him. Prof. Magid Abou-Garbia may be the most down-to-earth genius I know. I am grateful for all the opportunities he provided to interact with him. In addition to serving as an external examiner on my thesis committee Prof. Cannon was one of the great teachers I had. Although Prof. Wuest is the newest member in the department, I have already gotten to know him quite well. Sitting in his organic class this past semester was a great learning experience for me. Most of all, I value his highly interactive teaching style and I would like to thank him for providing me with some good career plans. I would like to thank our collaborators Drs. Abou-Gharbia, Wayne, Krynestsky, Kiss, Frederick, Shrome and Roger for their valuable suggestions and support in biological activity testing. I am grateful for the support and friendship of the wonderful staff at Temple Chemistry Department: Bobbi, Regina, Sharon, Leena, Lia, Jenette and Dave Plasket. They do the behind the scenes work that makes it possible for us to conduct our research. For facilities, I would like to thank Dr. Debrosse in the NMR lab and for helping with some 2D analysis. I would also like to thank Dr. Shivaiah and Sandeep from Dr. Zdilla’s lab for solving several crystal structures for the Melotenine and Sungucine projects (not included in this thesis). During my graduate career I have had the privilege of working with a number of interesting and exceptional people and I would like to take the opportunity to thank them individually. ! #""! I would like to thank the first group members of the Andrade group; we all had a part in turning this young lab into a chemical powerhouse. I convey my special thanks to Dr. Tapas Paul, the first post doc in the Andrade lab for teaching me some techniques and helping me with the end games in crocacin and strychnine projects. I want to especially thank Justin Kaplan who kindly and patiently took the time to proofread my thesis. He deserves credit for any coherence in the following pages. I would like to thank the other alkaloid gang (Chary, Praveen, Senzhi) for taking up these projects and progressing with shining glitters. I thank rest of the current Andrade gang (Bharat, Ian, Justin, Miseon, Vijay and Gary) for their friendship and support throughout the years. I also want to thank the Andrade group alumni Venkat, Sharon, Natalie for providing me a good experience working with them. Being a part of the Andrade group has been a great honor. The science comes and goes as I hope my contributions here are quickly overshadowed by even greater advances. However, the experiences from the people here is the most valuable part of my education. Although I am sad to be leaving, I am looking forward to the future and will enjoy watching the lab develop during the upcoming years. I convey my special thanks to my best friend Manasa for all her support throughout the years. At Temple I have learned some of my most valuable lessons from my peers. I would like to express my gratitude to the entire chemistry class that arrived at Temple chemistry department in the fall of 2006. I would like to specially thank Naresh, Svitlana and Bo for having good discussions while we were taking courses. I want to thank Goutham Kodali for proving a great deal of guidance during the early years. The lunch club has made last couple of years at Temple my happiest years. ! #"""! I also want to thank my friends Rao, Kavita, Nagesh, Andrew, Gopee, Riley, Varma, Peng, Hoan, Paul, Conrad, and Matt for their friendship at Temple. I would like to thank the Sieburth and Schafmeister groups for their generosity with reagents, equipment and discussions. This thesis certainly would not have been possible without the love and encouragement of my family and friends. I must thank the most important people in my life, my family. I am nothing without them. My desire to seek answers for unanswered questions, which eventually drove me to pursue graduate studies in chemistry, was developed when I was very young. I would like to take this opportunity to thank all my childhood teachers. I had the pleasure of attending JNTU for masters and Loyola Academy for bachelors. Prof. Dubey has encouraged and inspired me in getting a doctoral degree through his lectures on alkaloids chemistry and exciting discussions. Before I came to Temple, I was fortunate enough to develop some amazing friendships that have withstood the test of time.