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Cyclic Enaminones: Methodology Development, Total Synthesis, and Library Construction a Dissertation Submitted to the Faculty Of CYCLIC ENAMINONES: METHODOLOGY DEVELOPMENT, TOTAL SYNTHESIS, AND LIBRARY CONSTRUCTION A DISSERTATION SUBMITTED TO THE FACULTY OF THE GRADUATE SCHOOL OF THE UNIVERSITY OF MINNESOTA BY HAJIME SEKI IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY GUNDA I. GEORG DECEMBER 2011 ©2011 Hajime Seki ACKNOWLEDGEMENTS Looking back my life as a graduate student, it was undoubtedly one of my best decisions in my life to study chemistry in the University of Minnesota. The path I chose to come to the U.S. from Japan, leaving behind all of my family, friends, and comfortable environments, was certainly not the easiest trail that one could go through. During the course of my graduate study, however, a countless people supported me, and taught me things that I would not be able to learn in Japan, such as an appreciation to the diversity and how to be an independent individual/scientist. It was also the first opportunity to see Japan from outside and realize where it stands in the world. All the things I have learned will definitely be my invaluable treasures in the future. Herein, I would like to acknowledge the people who have stood by me. I owe my first acknowledgement to my parents for their unconditional love. It was their encouragements and dedications that I was able to step out of Japan and study in the U.S. I thank my academic advisor, Prof. Gunda I. Georg, for her guidance and support. On a snowy day of Jan. 15th in 2007, she kindly welcomed me in her group. Since then, I immersed myself in chemistry in a very best environment one could ever imagine. Her deep understanding in both chemistry and biology always guided me to the best outcome in multidisciplinary science. I would like to show my greatest appreciation to my advisor in Japan, Prof. Fumitoshi Kakiuchi. Without him, my life would be entirely different. He showed and taught me what a scientist is in a most sincere manner. He always considers what is best for his student, and I am truly proud to be one of his first students. i Dr. Micah J. Niphakis, a former senior graduate student, provided me countless academic advices. He was the best student I have ever met, and I was extremely fortunate to have him as a senior student. Prof. Thomas R. Hoye kindly served as a chair of my thesis committee. He was the first professor I had in touch with in MN, and also wrote a letter of recommendation for me. It was my pleasure to learn organic chemistry in his class. Prof. Christopher J. Douglas and Prof. Robert A. Fecik kindly served as members of my thesis committee and reviewed my thesis. Prof. Douglas graciously wrote a letter of recommendation for me. Wayne Gu supported me both inside and outside of the lab. It was because of him that I was able to survive in the US. I greatly appreciate all the advices and encouragements that he provided. Letitia Yao taught me NMR in great details. I was really fortunate to take her class. She welcomed me whenever I visited her office. I appreciate all her encouragements and academic/non-academic advices Institute of Therapeutics Discovery and Development is where I spent most of my time in Minnesota. A number of people are involved in this institute to create one of the best multidisciplinary environments. It was my great pleasure to be a member of ITDD. Department of Chemistry, University of Minnesota is the place that accepted me in the first place. I met a number of fantastic faculty, students and staff. I am proud to be a part of this great community. ii Lastly, I would like to add my special gratitude to the following people: Aaron Gerow, Amy Doan, Andrea Knickerbocker, Asayuki Kamatani, Bryant Gay, Caitlin Boley, Chris Schneider, Chuck Tomlinson, Eiichiro Mizushima, Enver Izgu, Feifei Li, Jae Chul Lee, Jane Wissinger, Kriangsak Khownium, Kristi Kun, Kwon Ho Hong, Matthew Leighty, Mary Crosson, Mary Smart, Michael Walters, Mitsuo Sato, My students from Chem 2311, Nancy Thao, Oliver Hutt, Peter Dosa, Sara Alanee, Sean Murray, Secil Koseoglu, Sreedhar Tummalapalli, Subhashree Francis, Terra Carey, Tim Ward, Van Vu, Victor Young Jr., Yong Wook Kim, Yutaka Miura, Yuyun Yu iii THIS WORK IS DEDICATED TO MY PARENTS, YOJIRO & MACHIKO. iv ABSTRACT The cyclic enaminone lies at the core of this entire doctoral work. It possesses exceptionally versatile reactivities, and can thus be utilized in the synthesis of various alkaloids. The first chiral-pool approach to synthesize enaminones was reported in 2006 from the Georg group. However, partial racemization was observed in some cases. Also, homologated amino acids were synthesized or purchased as a starting material. To address these issues a novel strategy, that retained the use of amino acids was sought. We found that enaminones can be synthesized using a ketene cyclization. In this approach, a pendant enamine moiety underwent a nucleophilic addition to a ketene generated by the Wolff rearrangement of a diazoketone. The diazoketone can be synthesized from α-amino acid in a one-pot procedure. Although this approach utilizes α-amino acids and provides enantiopure enaminones, the solubility of amino acids as well as the use of diazomethane to prepare diazoketone became major obstacles to the scalable synthesis of various enaminones. In this regard, alternative methods to synthesize the diazoketones were explored. We found that diazoketones could be obtained from three readily available components: a primary amine, an alkyne, and bromo diazoacetone. Although the incorporation of chirality was not achieved, a wide variety of enaminones were synthesized in two steps from commercially available compounds, providing a facile access to an enaminone library. Enantiospecific syntheses of (–)-(5S,8R,9S)-5-(3-furyl)-8-methyl- octahydroindolizin and its C8-epimer were accomplished using our enaminone chemistry. The devised synthetic routes are conventional but reliable and scalable, providing access to Nuphar alkaloids in 9 steps from N-Boc-(L)-proline. This work led to the correction of multiple prior publications. We were able to disclose the bindings of the major isomer to the central nervous system receptors. v Although phenanthropiperidines are promising anti-cancer agents due to their potency, their neurological toxicities thwart therapeutic use. Assuming that the side-effects are caused by the blood brain barrier permeation of phenanthropiperidines due to their extremely lipophilic nature, endeavors to prepare a polar phenanthropiperidine library were made. Specifically, the synthesis of hydroxylated phenanthroquinolizidines was attempted. However, most of those compounds were found to be unstable. vi Table of Contents List of Tables.......................................................................................................xi List of Figures....................................................................................................xii List of Schemes ................................................................................................xiii Compounds Index ..........................................................................................xviii List of Abbreviations.......................................................................................xxii Chapter 1 THE ENAMINONE CHEMISTRY.........................................................1 1.1 Introduction ........................................................................................................... 1 1.2 Various synthetic approaches to enaminones................................................... 3 1.2.1 Nucleophilic addition to pyridinium salts .......................................................... 3 1.2.2 Nucleophilic addition to 4-pyridones ................................................................ 6 1.2.3 Hetero Diels-Alder reaction .............................................................................. 8 1.2.4 Rh-catalyzed [2 + 2 + 2] cycloaddition ........................................................... 12 1.2.5 Gold-catalyzed ynone cyclization................................................................... 13 1.2.6 Miscellaneous work........................................................................................ 15 1.2.6.1 Direct oxidation of 4-piperidone ........................................................................... 15 1.2.6.2 Oxidation of 4-piperidone via N-oxide formation.................................................. 16 1.2.6.3 Condensation of primary amine and diketone ..................................................... 16 1.3 Georg’s enaminone chemistry........................................................................... 17 1.3.1 Synthesis of enaminones ............................................................................... 18 1.3.1.1 Ynone cyclization[40] ............................................................................................. 18 1.3.1.2 Reaction optimization[41]....................................................................................... 20 1.3.1.3 Scope of the reaction ........................................................................................... 21 1.3.1.4 Mechanistic studies.............................................................................................. 25 1.3.1.5 Application to the synthesis of quinolones[42] ....................................................... 27 1.3.1.6 N-Boc β-lactam approach and its application[43] .................................................. 28 1.3.2 C-5 functionalization......................................................................................
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