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Tao Wang Phd Thesis Diels–Alder Reactions in I. the Biosynthesis of Paracaseolide A and II. the De Novo Construction of Benzenoid Structures A DISSERTATION SUBMITTED TO THE FACULTY OF THE GRADUATE SCHOOL OF THE UNIVERSITY OF MINNESOTA BY Tao Wang IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY Thomas R. Hoye, Advisor December 2016 © Tao Wang 2016 i Acknowledgements As I reach this important milestone of my career, I want to express my sincere gratitude to all people who have been tremendously helpful in my doctoral studies. First and foremost, I would like to thank Juanjuan Bu for her unconditional love and support. She helped me on countless things, many of which I may not even be aware of. She is my best friend, my soul mate and will soon become my life-long companion. I want to thank her for making me who I am today. I want to thank my parents, who have been working tirelessly in the past 27 years to give me the best education. I want to thank them for answering probably millions of questions I had about Nature when I was still a kid. Their patience in taking care of my curiosity encouraged me to become a researcher myself and to probe more of those interesting phenomena. I am also very grateful for all the great foods made by them. I would like to thank my advisor, Professor Thomas R. Hoye. I met Tom in the winter (mid-December) of 2010 during his lecture at Peking University. At that time, I was not yet able to fully capture every detail in his presentation. However, I knew immediately that he is a great advisor and is someone who will guide students with extreme patience and care. Now, six years later, I feel exceedingly fortunate to have become a member of his lab. Tom is not only a research advisor with great knowledge, but also a friend with good sense of humor, a counselor with extreme patience, a chemist with cutting-edge skills of communication, a role model with high self-discipline, and a senior who we can trust, rely on, and admire. I cannot say enough good things about Tom, but I would like to end my acknowledgement to him by telling a story. I was once asked by an incoming new student “can you describe what it’s like working in the Hoye lab?” I concluded my answer in two words: “freedom & independent”. Tom has always been open-minded and allow us to freely explore chemistry driven by our own curiosity. He also treats students with great respect and trust, which is not easy. He is willing to adapt to our styles of working and give us a hand whenever we are in trouble. ii I also want to thank Dawen Niu, a former member of the Hoye lab and one of the best colleague I have ever had. Without doubt, he is one of the smartest person I know of. He is knowledgeable, easy to work with, and willing to offer help to young members in the lab. I am also impressed by his love of chemistry and familiarity of literature. When chatting with other chemists, he will never waste more than five sentences before rushing to the main topic of chemistry. He taught me a lot in reaction setup, problem solving, and spectroscopic analysis. My doctoral study would be a lot harder without his generous help. He has also been a great role model in career planning. I am very grateful for all the suggestions and guidance on computational chemistry from Professor Christopher J. Cramer during his class and throughout my graduate research. I found myself learned much more than I could imagined during his lecture, in which he has completely changed my view of this unique science. I gained a lot of confidence in his class to use calculation as a powerful tool in research. I also want to thank Kaining Duanmu in Truhlar lab for sharing his expertise in theoretical chemistry and being a great friend of mine. I appreciate all the healthy discussion I had with Sean Ross and Junhua Chen in the lab. I also want to thank Dr. Beeraiah Baire, Dr. Vedamayee Pogula, Dr. Patrick Willoughby, and Dr. Brian Woods for being great coworkers. I want to thank all other members in the Hoye group for creating a happy atmosphere in the lab. I want to thank Wayland Noland Fellowship, Doctoral Dissertation Fellowship, and Chinese Government Award for Outstanding Self-Financed Students Abroad for their financial support. Lastly, I would like to thank my cat Wu, who has been able to maintain cute and stupid at the same time in the past three years. I want to thank him for petting away my stress and worries and being a wonderful companion. iii To Juanjuan Bu, My source of happiness and spiritual support iv Abstract Part I: Paracaseolide A, a natural product characterized by a tetracyclic dilactone core structure containing six adjacent stereocenters, has an unprecedented skeleton and occupies unique structural space among the >200,000 characterized secondary metabolites. Researchers from six different groups have published a chemical synthesis of this compound; five used a thermal, net Diels–Alder cycloaddition and dehydration at high temperature under neat and O2-free condition to access this target by dimerization of a simple butenolide precursor. In my study, I found (i) that this dimerization proceeds under much milder (ambient temperature) conditions and with a different stereochemical outcome (exo instead of endo), rationalizable by a bis-pericyclic transition state, than previously recognized; (ii) that spontaneous epimerization, necessary to correct the configuration at one key stereocenter, is viable; and (iii) that natural paracaseolide A is racemic—a fact that directly points to the absence of enzymatic catalysis (namely, Diels– Alderase activity) in the cycloaddition. Together these results strongly suggest that a non- enzyme-mediated dimerization of butenolide monomer is the actual event by which paracaseolide A is produced in Nature. Part II: The hexadehydro-Diels–Alder (HDDA) reaction has recently grown as a powerful alternative in the generation of benzyne intermediates as well as a de novo approach in accessing highly substituted aromatic systems. Like other members of the venerable Diels–Alder cycloaddition, HDDA reaction starts from linear precursors and is also highly atom economical. I have contributed to several projects in this area of study. These includes (i) mechanism of cycloisomerization step (concertedness of reaction), (ii) origin of distortion in the geometry of benzyne, (iii) mechanism in the trapping reactions of tethered silyl ether, tethered arene and intermolecular trapping of alcohols, and (iv) synthesis of dichloroarene and carbazole derivatives via a HDDA-based strategy. v Table of Contents Acknowledgements ............................................................................................................... i Abstract .............................................................................................................................. iv List of Figures .................................................................................................................. viii List of Schemes ..................................................................................................................... x List of Tables ..................................................................................................................... xii List of Abbreviations ........................................................................................................ xiii Chapter 1. Hypotheses in the biosynthesis of paracaseolide A ................. 2 1.1 Isolation, bioactivity and structure paracaseolide A ................................................. 2 1.2 Our hypothesis ........................................................................................................... 3 1.3 Previous studies of the dimerization reaction in the synthesis of paracaseolide A ... 7 Chapter 2. Total synthesis of paracaseolide A ........................................... 9 2.1 Preparation of paracaseolide A ................................................................................. 9 2.2 Total synthesis of the truncated paracaseolide A .................................................... 10 2.3 Previous synthetic efforts towards paracaseolide A ................................................ 12 2.3.1. Reported total synthesis via dimerization of monomer ................................... 12 2.3.2. Kraus’s total synthesis of paracaseolide A ...................................................... 14 Chapter 3. Mechanistic studies of the dimerization event ...................... 15 3.1 Model study with truncated series ........................................................................... 15 3.1.1 Unexpected Diels–Alder reaction at ambient temperature ............................... 15 3.1.2 DFT Study: Locating the exo and endo Diels–Alder transition states ............. 16 3.1.3 Bis-pericyclic dimerization in the synthesis of paracaseolide A ...................... 17 3.1.4 Close vs. open-chain ketoester ......................................................................... 19 3.2 Studies on the dimerization of natural monomer .................................................... 21 3.3 Mechanistic insights in the epimerization step ....................................................... 23 3.4 Specific rotation of paracaseolide A ....................................................................... 25 3.5 Summary ................................................................................................................. 26 Chapter 4. The Hexadehydro-Diels–Alder Reaction ..............................
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