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Signature: ___________________________ ___________ Jutatip Boonsombat Date Application of IMDAF and Rh(II)-Catalyzed Cascade Reactions for Total Synthesis of Natural Products By Jutatip Boonsombat Doctor of Philosophy Chemistry _______________________________ Dr. Albert Padwa Advisor _______________________________ Dr. Frank E. McDonald Committee Member _______________________________ Dr. Simon Blakey Committee Member Accepted: _______________________________ Lisa A. Tedesco, Ph.D. Dean of the Graduate School ________________ Date Application of IMDAF and Rh(II)-Catalyzed Cascade Reactions for Total Synthesis of Natural Products By Jutatip Boonsombat B.S. (1999) & M.S. (2002), Chulalongkorn University, Bangkok, Thailand Advisor: Dr. Albert Padwa An Abstract of A dissertation submitted to the Faculty of the Graduate School of Emory University in partial fulfillment of the requirements for the degree of Doctor of Philosophy In Chemistry 2008 Abstract Application of IMDAF and Rh(II)-Catalyzed Cascade Reactions for Total Synthesis of Natural Products By Jutatip Boonsombat There are two major themes to this thesis. In part A, an intramolecular [4 + 2]-cycloaddition/rearrangement cascade of an indolyl- substituted amidofuran (IMDAF) was utilized as a key strategy for the synthesis of various natural products containing the hydroindoline or hydroquinoline ring system. The total synthesis of several Strychnos alkaloids were developed. The central step consists of an IMDAF reaction that delivers an aza-tetracyclic ABCE- rings of the Strychnos alkaloid family. Closure of the remaining D-ring was carried out by an intramolecular palladium-catalyzed enolate-driven cross- coupling reaction. The IMDAF approach was successfully applied to the synthesis of (±)-strychnopivotine, (±)-tubifolidine, and (±)-valparicine. A variation of this tactic was utilized for a synthesis of the heptacyclic alkaloid (±)-strychnine. Another aspect of the thesis was to test the IMDAF strategy for an approach toward the fawcettimine alkaloid family. We were able to assemble the BCD core structure of the carbinolamine portion of fawcettimine. An efficient route for the construction of the methyl furanyl carbamate necessary for the alkaloids was also developed. However, attempts to cyclize the A-ring using an internal displacement reaction were unsuccessful. Further work is therefore necessary to determine the appropriate precursor for A-ring formation. Part B of the thesis involves the application of Rh(II)-catalyzed cyclization/cycloaddition cascade for preparing natural products containing the oxabicyclo[3.2.1]octane ring system. The intramolecular Rh(II)-catalyzed reactions of an ortho-carbomethoxy aryl diazo dione was investigated as a potential route to the oxatricyclo[6.3.1.00,0]dodecane substructure found in komaroviquinone. Preparation of the hexa-substituted arene required for the natural product is also described. Part B also describes attempts to prepare a furan precursor for a synthesis of furanether B by a Rh(II)-catalyzed reaction. An efficient strategy to prepare the requisite 3,4-disubstituted furan is described. Further investigations dealing with the critical diazo furanyl ketone needed are underway. We have also investigated the Rh(II)-catalyzed reaction of the Z- isomer of 2-diazo-3,6-dioxo-6-phenyl-hex-4-enoic acid methyl ester and found that we were unable to trigger a [5+2]-cycloaddition. Instead, an unknown dimer was formed as the major product. The Rh(II)-catalyzed reaction of the E-isomer was carried out in the presence of various carbonyl compounds and was found to give 1,3-dioxoles as products. Acknowledgments I am very thankful to have had the opportunity to come to Emory and work with Dr. Padwa over the last few years. I very much appreciate his guidance and support. He taught me so much from his intellectual knowledge and experience while giving encouragement for me to develop my own independence. He is also an outstanding person who is a great example to me in a number of ways, not only in chemistry but also toward the success in life. It was an invaluable experience to work under his supervision. I am indebted to the faculty of the chemistry Department and the various Professors who shared their wisdom as well as other support, Dr. McDonald, Dr. Balkey, Dr. Liotta, Dr. Liebeskind, and Dr. Mohler. I also would like to thank the staff of the department for their excellent service, especially instrumental support and for their excellent technical and intellectual assistance. I also would like to thank the past and present members of the Padwa group: Chad Stearman, Mike Cassidy, Stefan France, Xuechan (Nick) Hong, Andy Flick, Mike Wilson, Dylan England, Jose Manuel Mejia-Oneto and Jerremy Willis. It has been a great experience working with them in both chemistry and other fun projects we shared. I want to give my particular thanks to all the Padwa girls; Mickea Rose, Maria Alevaro, Qiu Wang, Gokce Merey and especially Carolyn Leverett, who made my life more colorful and much more memorable, Edwin Mmutlane and Shinji Nara who were not only great labmates but are very good friends, Paitoon Rashatasakorn who helped me a lot when I struggled during my first year in Atlanta. In addition, I am much appreciated to Hongjun Zhang who was my terrific lab partner in the strychnos project as well as Majid Chughtai and John Hartung who were also involved in this project. Lastly, Drew Bobeck, and Guido Verniest who gave tremendous help in the editing of my thesis and provided a number of good suggestions through out the process. I want to express my appreciation to the DPST scholarship program as well as all DPST friends and mentors since my high school days in bringing me into the scientific community and giving me a number of opportunities to see, learn, enjoy, and appreciate the world of science. I am also thankful for my undergraduate and Master’s degree teachers for all their guidance and support. Additionally, I am greatly indebted to my advisor Dr. Roderick W. Bates for supporting me to pursue a Ph.D. degree and for mentoring me through my time under his supervision. I also want to thank all my friends back in Thailand for all the experiences we had together which I believe help steer my path at this terrific point of my life. I am also thankful to all my other Atlanta friends who make my life here more delightful, especially Prayut and Nipa, who always make me feel like I have family here while I am so far away from home. Finally, I would like to thank my family for their encouragement, love and support. My parents have always stood behind me in whatever I have strived to achieve. My father has passed away while I was in the middle of my PhD study. He had been very sick with cancer but never let me worry about his health until the last period of his life. I had hoped very much that he could stay with me to see my success but I know that his spirit will be with me forever. I don’t know how to express how much I appreciate my mother’s love, and believing in me through out the time of my life. I am so thankful to have a very lovely sister who is always willing to do everything she can for me. I also appreciate support from my relatives especially my aunt Nani. Another person who I am really bless to have as a part of my life, is my fiancé Sanit Thongnest. It is his love, dedication, and support has helped me overcome all many struggles and made this achievement of an advanced chemistry degree a lot more meaningful. Application of IMDAF and Rh(II)-Catalyzed Cascade Reactions for Total Synthesis of Natural Products By Jutatip Boonsombat B.S. (1999) & M.S. (2002), Chulalongkorn University, Bangkok, Thailand Advisor: Dr. Albert Padwa A dissertation submitted to the Faculty of the Graduate School of Emory University in partial fulfillment of the requirements for the degree of Doctor of Philosophy In Chemistry 2008 Table of Contents Part A: The IMDAF reaction for the construction of natural products containing hydroindole or hydroquinoline system Chapter A.1. General introduction……………………………………..… 2 Chapter A.2. Application of the cycloaddition/rearrangement cascade of 2-amidofurans for the synthesis of Strychnos alkaloids……. 26 A.2.1. Total synthesis of (±)-strychnopivotine……………………..... 37 A.2.2. Total synthesis of (±)-tubifolidine (118)………………….…… 48 A.2.3. Total synthesis of (±)-valparicine (119)…………………..….. 49 A.2.4. Total synthesis of (±)-strychnine (120)……………………….. 51 A.2.5. Lewis acid promoted IMDAF reaction……………………...… 62 Chapter A.3. Application of the cycloaddition/rearrangement cascade of 2-amidofuran toward the synthesis of Fawcettimine alkaloids…………………………………………………………. 75 Experimental section……………………………………………………………... 101 X-Ray Data………………………………………………………………………… 219 References……………………………………………………………………….... 241 Part B: Application of Rh(II) catalyzed reactions for natural product synthesis containing oxabicyclo[3.2.1]octane ring………… Chapter B.1. General introduction………………………………….………… 265 Chapter B.2. Application of the Rh(II)-Catalyzed [3+2]-cycloaddition towards the synthesis of komaroviquinone…………..…...…. 287 Chapter B.3. The application of Rh(II)-catalyzed [3+2]-cycloaddition towards the synthesis of furanether B………………..……….