University of Kentucky UKnowledge University of Kentucky Doctoral Dissertations Graduate School 2010 STUDIES TOWARD THE TOTAL SYNTHESIS OF (±)-α-YOHIMBINE BY DOUBLE ANNULATION Raghu Ram Chamala University of Kentucky, [email protected] Right click to open a feedback form in a new tab to let us know how this document benefits ou.y Recommended Citation Chamala, Raghu Ram, "STUDIES TOWARD THE TOTAL SYNTHESIS OF (±)-α-YOHIMBINE BY DOUBLE ANNULATION" (2010). University of Kentucky Doctoral Dissertations. 78. https://uknowledge.uky.edu/gradschool_diss/78 This Dissertation is brought to you for free and open access by the Graduate School at UKnowledge. It has been accepted for inclusion in University of Kentucky Doctoral Dissertations by an authorized administrator of UKnowledge. For more information, please contact [email protected]. ABSTRACT OF DISSERTATION Raghu Ram Chamala The Graduate School University of Kentucky 2010 STUDIES TOWARD THE TOTAL SYNTHESIS OF (±)-α-YOHIMBINE BY DOUBLE ANNULATION ABSTRACT OF DISSERTATION A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the College of Arts and Sciences at the University of Kentucky By Raghu Ram Chamala Lexington, KY Director: Dr. R. B. Grossman, Professor of Chemistry Lexington, KY 2010 Copyright © Raghu Ram Chamala 2010 ABSTRACT OF DISSERTATION STUDIES TOWARD THE TOTAL SYNTHESIS OF (±)-α-YOHIMBINE BY DOUBLE ANNULATION The indole alkaloids, a class of natural products, have received much synthetic attention for years due to their diverse structures and interesting biological properties. We are particularly interested in synthesizing some of the yohimbine alkaloids extracted from the bark of a tall evergreen African tree (Corynanthe yohimbe, commonly known as fringe tree). Yohimbine and its stereoisomers have been tempting targets for synthetic organic chemists for more than fifty years. These compounds feature a pentacyclic ring system with two heteroatoms and five stereogenic centers. Broadly, the fifteen different synthetic approaches that led to the successful completion of yohimbine alkaloids relied only on two basic synthetic strategies. In the first strategy, the last step almost always was the formation of the C(2)-C(3) bond by either Pictet-Spengler reaction or by Bischler-Napieralski reaction with the concomitant formation of the C ring. The second strategy involved the annulation of the D and E rings onto the intact ABC ring system. With our double annulation methodology, herein, we report a completely different synthetic approach to access the yohimbine alkaloids, and our disconnections are not even remotely close to the synthetic designs used in the past. Our key steps include double Michael reaction to construct the E ring, an intramolecular cyclization to construct the D ring, and finally, the functionality on the D ring can be elaborated to form the C ring of the yohimbine alkaloids. KEYWORDS: Yohimbehe, Yohimbine, Double Annulation, Double Michael Reaction, Total Synthesis Raghu Ram Chamala Student‟s Signature November 22, 2010. Date STUDIES TOWARD THE TOTAL SYNTHESIS OF (±)-α-YOHIMBINE BY DOUBLE ANNULATION By Raghu Ram Chamala Dr. Robert B. Grossman, Ph.D Director of Dissertation Dr. John E. Anthony, Ph.D Director of Graduate Studies November 22, 2010. Date RULES FOR THE USE OF DISSERTATIONS Unpublished dissertations submitted for the Doctor's degree and deposited in the University of Kentucky Library are as a rule open for inspection, but are to be used only with due regard to the rights of the authors. Bibliographical references may be noted, but quotations or summaries of parts may be published only with the permission of the author, and with the usual scholarly acknowledgments. Extensive copying or publication of the dissertation in whole or in part also requires the consent of the Dean of the Graduate School of the University of Kentucky. A library that borrows this dissertation for use by its patrons is expected to secure the signature of each user. Name Date DISSERTATION Raghu Ram Chamala The Graduate School University of Kentucky 2010 STUDIES TOWARD THE TOTAL SYNTHESIS OF (±)-α-YOHIMBINE BY DOUBLE ANNULATION DISSERTATION A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the College of Arts and Sciences at the University of Kentucky By Raghu Ram Chamala Lexington, KY Director: Dr. R. B. Grossman, Professor of Chemistry Lexington, KY 2010 Copyright © Raghu Ram Chamala 2010 Dedicated With Love And Respect To My Dear Parents Smt. RAJESHWARI CHAMALA And Shri. NARAYANA CHAMALA ACKNOWLEDGEMENTS This is by far the most important part of my dissertation. This dissertation is a culmination of an amazing journey that wouldn‟t have been possible without the help and support of several people. So 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 wholeheartedly thank my advisor Dr. Robert B. Grossman for his unwavering support, enthusiasm, and general concern for my development as an organic chemist. I have immeasurably benefited from his wisdom, and his dedication and passion to produce “good science” are inspiring. It has been a great privilege to work under his tutelage. I also would like to thank my dissertation committee: Dr. Arthur Cammers, Dr. Folami Ladipo, and Dr. Jürgen Rohr. I especially like to thank Dr. Arthur Cammers, for teaching me a great deal about organic synthesis in his advanced synthetic chemistry class, for his thoughtful insights, and entertaining group meetings in the initial years of my graduate school. I only wished we continued our group meetings together and did more of those “Synthetic Challenge” assignments. I would also like to thank Dr. Robert Houtz for serving as my outside examiner. I thank Mr. John Layton for his assistance in obtaining several NMR spectra, and Dr. Sean Parkin for obtaining all of my crystal structures. I would like to thank Dr. Fitzgerald Bramwell and Dr. Manjiri Patwardhan for their help and support. I thank all the office and the technical staff, especially, the ever-energetic, Mr. Art Sebesta for providing the technical support to our lab. I am grateful to the Department of Chemistry, University of Kentucky for giving me an opportunity to pursue my graduate career. I gratefully acknowledge the financial assistance I received in support of my research from the Department of Chemistry, the Research Challenge Trust Fund, the National Institutes of Health, the National Science Foundation, and the Pearson Education. I would like to thank my former lab mates, Dr. Freddie Hughes Jr., Dr. Roxana Ciochina, Mr. Uma Prasad Mallik, Dr. Syed Raziullah Hussaini, Dr. Suresh Jayasekara, Mr. Ronghua Lu, and Mr. Sujit Pawar for all their help and support in the lab. I would like to thank all my childhood teachers, and special thanks to my organic chemistry teacher, Dr. Ashok (Professor, Department of Chemistry, Osmania University), for his unique and exhilarating teaching method that inspired and enabled me to choose my career path. Also, my special thanks to my guru-cum-friend, the ever-youthful, Mr. Srinivasa Rao Deshpande (fondly called “Master” garu). I will forever be grateful for all his help, support, and encouragement. Throughout my life, I am fortunate enough to have developed some great friendships that helped me define myself. One of my good friends, Mr. Gangadhara Srinivas Annambhotla, is the root cause for my liking and understanding of the basic organic chemistry. He kindled my interest by initiating and leading several months of daily peer study at his home. Gorging out oodles of scratch paper, we together learned drawing out organic reaction mechanisms, and all this effort consequently led me to pursue my PhD in organic chemistry. I will forever be grateful for his help. The caring and the mirthfully mischievous, Dr. Pramod Nednoor, was my classmate at University of Pune; since then, with the passing time, we travelled our individual career paths together, iii nurturing our springing relationship into an everlasting friendship. I thank him very much for that amazing time we spent at the University of Pune and at the University of Kentucky, and also for his substantial role in my career growth. I would like to thank my noble-hearted friend, Dr. Maruthi Krishna Prakash Chittapragada, for all his help, for his ever-witty chat, and of course for our Ghantasala singing sessions over the hostel roof (just a prudent practice to keep our “golden” voices away from the innocent people). Mr. Mayuresh Moghe, the ever-blissful, eased out the enormous stress in the initial years of my graduate school. I can never forget his friendship or those 2 AM-dinners, coffee at Huddle House (South Limestone/Maxwell) while solving assignments and studying for the exams. I thank him for those gleeful couple of years. I like to thank the powerhouse of largely undiscovered talent, Dr. Gururaj Joshi, and the inimitable, Mr. Navneeth Singh Daundikhed, for their friendship and also for satiating my music palate by introducing me to the legendary maestros of Ghazals. My friend, Smt. Laxmi Sirisha Sadhu, though submerged with loads of work, being a software professional, wife, and mother of cute little Prabhav, always finds time to call me up and know my well-being. I thank for her concern and words of encouragement. I thank Mr. Suman Kumar Pulusu, an expression of free spirit, for overwhelming this itinerant with his extremely gracious gesture of hospitality. I would like to thank Mr. Vinay Srinivas Adepu for his concern and ever- entertaining phone conversations. I also would like to thank all my other friends, especially, Mr. Venkata Rajni Srikanth Vemuri, Dr. Gnaneswar Yadav Duggeni, and Mr. Narayana Reddy Bongunuri, for their help and support. I and my family will forever be grateful and indebted to these extremely generous and magnanimous people, Smt.