ABSTRACT TESKE, JESSE ALEXANDER. Natural Product Synthesis via [2+2+2] Cyclotrimerization Reactions. (Under the direction of Dr. Alex Deiters). The transition metal mediated [2+2+2] cyclotrimerization reaction of alkynes is a highly convergent approach to the synthesis of polysubstituted carbo- and heterocyclic aromatic ring systems. However, few examples of the application of cyclotrimerization reactions in natural product synthesis have been reported. In order to supplement the understanding of various aspects of the cyclotrimerization chemistry such as reactivity, regioselectivity, and chemoselectivity of advanced diyne intermediates, we explored the development of the [2+2+2] cyclotrimerization reaction towards benzene and pyridine derivatives as well as its application to the total synthesis of natural products. As an approach to solve the chemoselectivity issues associated with the cyclotrimerization reaction, a solid supported cyclotrimerization reaction was utilized as the key step in the regioselective synthesis of an indanone natural product in only 11 steps. The development of microwave assisted nickel catalyzed cyclotrimerization reactions allowed for the rapid synthesis of fused benzene ring systems and led to the total synthesis of the isoquinoline natural product illudinine in only eight steps. Several strategies towards the synthesis of anthraquinone and anthracycline natural products were investigated. The efficiency of these reactions was sensitive to both the electronic and steric properties of the investigated diynes. A novel approach to the tricyclic cannabinoid ring structure via the cyclotrimerization reaction was developed and led to the total synthesis of three cannabinoid natural products all in >20% overall yield. Furthermore, easy access to cannabinoid analogues is possible with this strategy. Initial investigations into the synthesis of four neolignan natural products from a common precursor were accomplished. The cyclotrimerization reaction successfully provided the core structures; however, subsequent steps to yield the natural products are needed. With respect to pyridine derivatives, the syntheses of the Streptomyces anticancer natural products streptonigrin and lavendamycin were explored. Several model routes, including the use of ynamides, were initiated to access the core structures, and further examination into the substitution of the diynes is necessary to realize the total synthesis of these two natural products. Attempts to synthesize two lycopodium alkaloids, lycopladine A and lycodine, via the cyclotrimerization reaction of alkyne-nitriles have been studied. However, access to the requisite alkyne-nitriles for the cyclotrimerization reaction has been problematic. Natural Product Synthesis via [2+2+2] Cyclotrimerization Reactions by Jesse Alexander Teske A dissertation submitted to the Graduate Faculty of North Carolina State University in partial fulfillment of the requirements for the Degree of Doctor of Philosophy Chemistry Raleigh, North Carolina 2009 APPROVED BY: _______________________________ ______________________________ Dr. Alex Deiters Dr. Daniel L. Comins Committee Chair ________________________________ ______________________________ Dr. Jonathan S. Lindsey Dr. David Shultz DEDICATION To my father, for nourishing my interest in science… To my mother, for support and encouragement… And to my wife, for unfailing love and understanding… ii BIOGRAPHY The author, Jesse Alexander Teske, was born in Monterey, CA on November 18, 1982 to Dewey and Dori Teske. After living briefly in Connecticut and Virginia, he moved to Charleston, SC at the age of three and stayed through high school. After high school, Jesse attended the University of Georgia and graduated magna cum laude with honors with a BSCHEM degree in Chemistry and a BS degree in Biochemistry and Molecular Biology. During his undergraduate research under the direction of Professor George Majetich, his passion for Organic Chemistry developed and inspired him to pursue graduate studies in that discipline. In 2004, Jesse began his graduate career at North Carolina State University under the supervision of Professor Alex Deiters. In July of 2005, Jesse married his high school sweetheart, Amber Mincey. Upon completion of his Ph.D. in 2009, he began a postdoctoral research position at Vanderbilt University under the direction of Professor Gary Sulikowski. iii ACKNOWLEDGEMENTS There are quite a few people worth mentioning from whom I have received help throughout the course of my education. First, I would like to thank my advisor, Dr. Alex Deiters, for relaying some of the finer intricacies of being an organic chemist, for the independence in the lab, and for the high expectations that will ultimately make me a better and more successful scientist. My time in graduate school was enriched by the distinctive personalities of Dabney Hall. The members of the Deiters group, especially Doug, Ramesh, Wesleigh, Andrew, and Yan have contributed to my growth as a scientist as well as provided much needed comic relief. I thank the members of the Melander group, especially The Rob, EB, and VB; the Comins group; and the Lindsey group. Finally, I would not be who or where I am today without my family. To my Mom and Dad, thank you for allowing me to choose my own path as you provided support and advice that continues to this day. To my brother, thanks for introducing me to things outside of school. And to my wife, you have stood by me these last five years and have provided me with your love, understanding, friendship, and support. This achievement is as much yours as it is mine. iv TABLE OF CONTENTS LIST OF TABLES ........................................................................................................... xi LIST OF FIGURES ....................................................................................................... xiii LIST OF SCHEMES ...................................................................................................... xv CHAPTER 1: The Transition Metal Catalyzed [2+2+2] Cyclotrimerization Reaction .................................................................................1 1.1 [2+2+2] Cyclotrimerization Reactions Towards Benzene Derivatives .............1 1.1.1 Background and Mechanism...............................................................1 1.1.2 Regioselectivity of the Cyclotrimerization Reaction..........................3 1.1.3 Chemoselectivity in Cyclotrimerization Reactions ............................7 1.2 [2+2+2] Cyclotrimerization Reactions Towards Pyridine Derivatives .............9 1.2.1 Background and Mechanism...............................................................9 1.2.2 Regioselectivity of the Cyclotrimerization Reaction........................11 1.2.3 Chemoselectivity of the Cyclotrimerization Reaction......................14 1.3 Natural Product Synthesis via [2+2+2] Cyclotrimerization Reactions............15 1.3.1 Synthesis of Benzene Containing Natural Products .........................15 1.3.2 Synthesis of Pyridine Containing Natural Products..........................21 1.4 General Cyclotrimerization Considerations.....................................................23 1.5 Microwave-assisted Cyclotrimerization Reactions..........................................25 CHAPTER 2: Total Synthesis of an Indanone Natural Product .................................31 2.1 Background......................................................................................................31 v 2.2 Diyne Synthesis ...............................................................................................33 2.3 Cyclotrimerization Studies and Completion of the Synthesis .........................35 2.4 Summary..........................................................................................................38 2.5 Experimental....................................................................................................39 CHAPTER 3: Development of Microwave Assisted [2+2+2] Cyclotrimerization Reactions: Total Synthesis of Illudinine ............................................................47 3.1 Microwave Assisted Organic Synthesis...........................................................47 3.2 Nickel-catalyzed [2+2+2] Cyclotrimerization Reactions ................................50 3.2.1 Nickel-catalyzed [2+2+2] Cyclotrimerization Reactions in Literature...............................................................................50 3.2.2 Optimization of the Microwave-mediated Nickel-catalyzed Cyclotrimerization Reaction ......................................................................52 3.2.3 Scope of the Microwave-mediated Nickel-catalyzed Cyclotrimerization Reaction......................................................................54 3.2.4 Development of Open-Vessel Microwave-Mediated [2+2+2] Cyclotrimerization Reactions.....................................................................56 3.3 Total Synthesis of Illudinine............................................................................59 3.3.1 Background and Retrosynthetic Analysis.........................................59 3.3.2 Model Studies towards Illudinine.....................................................61 3.4 Total Synthesis of Illudinine............................................................................66 3.5 Summary..........................................................................................................68 3.6 Experimental....................................................................................................69