MULTICOMPONENT CYCLIZATION REACTIONS: A GENERAL APPROACH TO DIBENZOCYCLOOCTADIENE LIGNAN NATURAL PRODUCTS DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Wei Gong Graduate Program in Chemistry The Ohio State University 2012 Dissertation Committee: Professor T. V. RajanBabu Professor Jovica Badjic Professor Anita Mattson Copyright by Wei Gong 2012 Abstract Aiming at finding a general and broadly applicable route to dibenzocyclooctadiene (DBCOD) lignans, an important class of natural products with wide-ranging biological activities, we applied Pd-catalyzed bis-metallative cyclizations mediated by a [B-Sn] reagent, 1-trimethylstannyl-2,5-dimethyl-2,5-diazaborolidine, to access the core DBCOD systems. 2,2’-Dipropargyl biphenyls are suitable precursors of [B-Sn] reagent mediated cyclizations and their acetylene moieties can be installed by addition of lithium acetylides to 2’-substituted biphenyl aldehydes. Most of these acetylide additions are highly stereoselective and chelating models have been proposed to rationalize their stereochemical results. The viability of the [B-Sn]-mediated cyclizations of these dipropargyl biphenyls depends on the chirality of the biphenyl scaffolding and the configuration of the propargylic center. Models based on steric arguments can be used to rationalize the stereochemical outcomes in successful cyclizations, and the reluctance in others to undergo the cyclization. A racemic synthesis of steganone was achieved from a 1,2-bisalkylidenecyclooctadiene prepared via the [B-Sn]-mediated cyclization. A novel AD-mix mediated tandem process quickly led to the formation of the key lactone, which was converted to steganone after three steps. ii Eight fully substituted DBCOD lignans, including compounds such as kadsuralignan B, tiegusanin D, and schizanrin F, with a tertiary center at C7, were first synthesized using an intermediate prepared by the [B-Sn]-mediated cyclization. The unique conformations of DBCOD intermediates are crucial for different reactivities of certain functional groups (e.g., C-C double bonds, hydroxyl and carbonyl groups), which can explain the stereochemical outcome of related transformations, for example, the hydrogenation reactions, Mitsunobu reactions, electrophilic additions to C-C double bonds and nucleophilic additions to carbonyl groups. The conformations of DBCODs containing C6 and/or C9 carbonyl groups are also discussed based on experimental data. We provide a general approach to the syntheses of highly functionalized DBCOD lignan natural products (>100) and unnatural analogs with different configurations and/or oxidation states at C6, C7, C8 and C9. iii Dedication This document is dedicated to my family. iv Acknowledgments First and foremost, I would like to thank Professor T.V. RajanBabu for allowing me to join his group in early 2008 and therefore get the chance to spend the following five years doing research under his guidance. It has been such an incredible experience that I believe I will benefit from it for the rest of my life. Babu is a real mentor to me, because I have learned a lot from him, not only about chemistry, but also the attitude towards many aspects of the life as a person. Before joining the graduate program at the Ohio State University, I knew that I would learn much about chemistry here, however, it turned out that chemistry is only a part of it. I have been so fortunate to stay in Babu group and thus could have intensive discussion with him about our research as well as my personal career plan. The latter could be equally as important as the former, because the time I leave this group could just be when my real career starts. Another important thing I feel lucky about is that I chose the research projects that I like and during the whole four years in Babu group, I have worked on projects that are directly related. Everyday is a joyful experience working in Babu’s lab, as in every morning I would expect something new or exciting in our research and I would never be hesitate to tell Babu in the first instance. One important philosophy of life I have learned from Babu is that although life is tough at most occasions, I have to get used to it and persist on my goal. If I am lucky, I will get the rewards I v deserve, and if not, the lessons you have learned are equally important, as they could direct you towards the correct road leading to success. I would also like to thank all other current and former group members. Dr. Singidi made significant contributions to the [B-Sn] chemistry, which laid the basis of all my work. Dr. Sharma has been one of my best friends in this lab, with whom I had thorough discussion about chemistry and personal life as well. Dr. Galucci in this department is acknowledged for assistance for X-ray crystallographic analysis of more than ten compounds. I would like to acknowledge my father Jingfu and my mother Yuyi. They provide me whatever they have and never ask for anything. They are great parents and always support my decisions. I would like to acknowledge my wife Yongxue and two boys Chuxuan (Eric) and Hanyuan (Samuel). All of the nice memories of this time in my life will be cherished because they were shared with them. You are always accompanying me and supportive during the years. I can never thank Yongxue enough for taking care of the boys and doing an excellent work for educating them. Without your support, this work could not have been possible. vi Vita Oct 13, 1979…………………………………Born - Jianli, China June 2002……………………………………B. S. Chemistry Wuhan University, China June 2005……………………………………M. S. Organic Chemistry Wuhan University, China 2005-2006………………………………… Research Scientist Shenzhen Taitai Pharmaceutical Co., China 2006-2007………………………………… Research Scientist Shanghai Chempartner Co., China 2007-2008………………………………… Mathematical and Physical Sciences Fellow The Ohio State University 2008-2010………………………………….Teaching Assistance The Ohio State University 20010-2012………………………………...Research Assistance The Ohio State University Publications 1. Wei Gong, T. V. RajanBabu. “A General Approach to Dibenzocyclooctadiene (DBCOD) Natural Products via Borostannylative Cyclization of 2,2’-Dipropargyl biaryls. Syntheses vii of Prototypical Lignans including Steganone, Ananolignans, Tiegusanin D and Schizanrin F”, Manuscript in preparation. 2. Wei Gong, T. V. RajanBabu. “Multi-component Cyclization Reactions Mediated by [X-Y] Reagents [X-Y= R3Si-SnR’3 or (R2N)2B-SnR’3]”, Manuscript in preparation. 3. Wei Gong, T. V. RajanBabu. “Borostannylative Cyclization of 2,2’-Dipropargylbiaryls and New Chemistry of the Resulting bis-Alkylidenes. Total Synthesis of Steganone”, Manuscript in preparation. 4. Wei Gong, T. V. RajanBabu. “Conformation and Reactivity in Dibenzocyclooctadiene Derivatives. A General Approach to Fully Substituted Dibenzocyclooctadiene Lignans”, Submitted. 5. Wei Gong, Ramakrishna Reddy Singidi, Judith C. Gallucci, T. V. RajanBabu. “On the Stereochemistry of Acetylide additions to Highly Functionalized Biphenylcarboxaldehyde and Multi-component Cyclization of 1, n- Diynes. Syntheses of Dibenzocyclooctadiene Lignans”, Chemical Science, 2012, 3, 1221-1230. 6. Wei Gong, Qianqian Li, Suyue Li, Changgui Lu, Zhen Li, Jing Zhu, Zhichao Zhu, Zhong'an Li, Qingrong Wang, Yiping Cui, Jingui Qin. “New Y type nonlinear optical chromophores with good transparency and enhanced nonlinear optical effects”, Materials Letters, 2007, 61, 1151-1153. 7. Qianqian Li, Zhen Li, Fanxin Zeng, Wei Gong, Zhong'an Li, Zhichao Zhu, Qi Zeng, Shanshan Yu, Cheng Ye, and, and Jingui Qin, “From Controllable Attached Isolation Moieties to Possibly Highly Efficient Nonlinear Optical Main-Chain Polyurethanes Containing Indole-Based Chromophores”, Journal of Physical Chemistry B, 2007, 111, 508-514. viii 8. Wei Gong, Qianqian Li, Zhen Li, Changgui Lu, Jing Zhu, Sueyue Li, Junwei Yang, Yiping Cui, Jingui Qin, “Synthesis and Characterization of Indole-Containing Chromophores for Second-Order Nonlinear Optic”, Journal of Physical Chemistry B, 2006, 110, 10241-10247. 9. Zhen Li, Wei Gong, Jingui Qin, Zhou Yang, Cheng Ye, “Second-Order Nonlinear Optical Property of Polyphosphazenes Containing Charge-transporting Agents and Indole-Based Chromophore”, Polymer, 2005, 46, 4971–4978. Fields of Study Major Field: Chemistry ix TABLE OF CONTENTS Abstract…………………………………………………………..……….……………… ii Dedication……………………………………………………………………...………....iv Acknowledgements…………………………………………………………………..…....v Vita……..……………………………………………………………………..………....vii List of Schemes …………………………...…………………………………...………...xx List of Tables ……………………………………………………………...…….…....xxvii List of Figures ………………………………………………………………...…….....xxxi List of Abbreviations………………………………………………………...……......xxxv Chapter 1. Multi-component Cyclization Reactions and Dibenzocyclooctadiene Lignans………………………….……………………………………………...1 1.1 Multi-component Cyclization Reactions………………………………………...…....1 1.1.1 R3Si-BR2 Mediated Cyclization of 1, n-Diynes…………………………………1 1.1.2 R3Si-SnR’3 Mediated Cyclization of 1, n-Diynes……………………………….2 1.1.3 R3Si-SnR’3 Mediated Cyclization of 1, n-Allenynes and Allene-aldehyde……..4 x 1.1.4 R3Si-SnR’3 Mediated Cyclization of Enynes……………..……………..………7 1.1.5 (R2N)2B-SnR’3 Mediated Cyclization of 1, n-Diynes and Enynes…………...…8 1.2 Dibenzocyclooctadiene Lignans…………………………………………………..…14 1.2.1 Biological Activities of Dibenzocyclooctadiene Lignans…...............................14 1.2.2 Previous Synthetic Studies of DBCOD Lignans……...…………………….…16