Sulfur Based Cyclizations by Intramolecular Carbometallation and Applications to Natural Product Syntheses by Kai Deng BS, Peking University, 1996 MS, Peking University, 1999 Submitted to the Graduate Faculty of University of Pittsburgh in partial fulfillment of the requirements for the degree of Doctor of Philosophy University of Pittsburgh 2004 UNIVERSITY OF PITTSBURGH FACULTY OF ARTS AND SCIENCES This dissertation was presented by Kai Deng It was defended on Oct. 15, 2004 and approved by Dennis P. Curran Paul E. Floreancig Richard D. McCullough Theodore Cohen Dissertation Director ii Advisor: Professor Theodore Cohen Sulfur Based Cyclizations by Intramolecular Carbometallation and Applications to Natural Product Syntheses Kai Deng, PhD University of Pittsburgh, 2004 The versatility of intramolecular carbolithiation of simple unactivated alkenes to yield cyclopentylmethyllithiums by unconjugated organolithiums is greatly increased (1) by generating the organolithiums by reductive lithiation of phenyl thioethers with aromatic radical anions and (2) by using allylic alcohol groups on the receiving alkenes. This type of reductive lithiation allows virtually any kind of organolithium to be generated, usually in a connective manner. Furthermore, the allylic lithium oxyanionic groups on the alkenes greatly accelerate the reactions and lead, in most cases, to completely stereoselective cyclization at -78 °C. Most significantly, the trans stereoselectivity is the opposite from that observed when the organometallic is allylic. A four-membered ring has also been generated by this method. Using allyl phenyl sulfones instead of using allyl acetates as precursors of Pd-catalyzed allylzinc formation greatly facilitates the efficiency of substrate preparation. The resulting allylzinc smoothly undergoes the Zn-ene cyclization onto a simple alkene or an alkyne. This methodology has been used for the most efficient of the published syntheses of the natural sesquiterpene (-)-erythrodiene in highly stereoselective fashion with an overall yield of 60% in 6 12,14 linear steps from commercially available (-)-perillyl alcohol. 15-Deoxy-∆ -PGJ2 (15d-PGJ2) is a potent anti-inflammatory agent that represses the expression of a number of inflammatory iii response genes in activated macrophages. The high-affinity binding of 15d-PGJ2 to PPARγ (peroxisome proliferator activated receptor-gamma) is believed to be responsible for the repressive effect on gene expression. The total synthesis of this natural product by using the zinc-ene cyclization as the key step has been accomplished in 13 linear steps with good overall yield. Moreover, due to our strategy of installing the double bond on the cyclopentenone ring in 12,14 the late stage of the synthesis, 9,10–dihydro-15-deoxy-∆ -PGJ2, an analogue of PPARγ– binding prostaglandins, has been synthesized as the precursor of the natural product. The addition of a primary amine to 2-phenylsulfonyl-3-methyl-1,3-diene is a very efficient way to construct allyl phenyl sulfones capable of undergoing the Pd-catalyzed Zn-ene cyclization. A nitrogen-containing heterocycle has been synthesized in high stereoselectivity. The total synthesis of (-)–kainic acid by utilizing this methodology is being proposed and initial studies are reported in this thesis. iv PREFACE The five years that I have spent here have amounted to a fantastic experience; I have many people to thank for that. First and foremost, I want to thank my advisor Ted Cohen with my deepest gratitude. He guided me into the wonderful area of intramolecular carbometallation. He is always there to help when I have difficulties in experiments. Especially, he encouraged me to pursue my own ideas in the research. Besides his comprehensive knowledge in chemistry, his zeal for science and his healthy life style impress me too. I would also like to thank Professors Dennis P. Curran, Paul E. Floreancig and Richard D. McCullough for serving on my thesis committee and Professors Kazunori Koide and Kay M. Brummond for being on the committee for proposal defense. Their willingness to share their expertise and provide valuable advice is greatly appreciated. I am very grateful for the help provided by Dr. Fu-tyan Lin, Steven Gelb and Kasi Samayajula in NMR spectroscopy, X-ray crystallography and Mass spectrometry. A large part of my graduate experience has been interacting with the great people in the Cohen’s group, past or present. I want to thank them for their help and friendship. Especially, I want to thank Dr. Darren Harvey for his valuable help when I just started my lab work here. I had the privilege to talk with Dr. Ahlem Bensari on many chemistry problems. Ao Yang and Justin Chalker, Heather Butela, Joseph Whetstone worked with me on several experiments. I enjoyed working with them and want to thank them all. Especially I want to thank Justin Chalker, who read the first draft of this thesis and give me some valuable advice. Last but not the least, I want to thank my wife Hanbin Liu, whose constant love and understanding supports me during the past five years. A special thank goes to my son David, who was born during this period, for being a good boy. v TABLE OF CONTENTS PREFACE...................................................................................................................................... v 1. Chapter 1.......................................................................................................................... 1 1.1. Introduction ................................................................................................................. 2 1.1.1. Background for the Available Methods to Produce Organolithiums in Intramolecular Carbolithiation................................................................................................ 2 1.1.2. Background for Lithium Oxyanionic Effect in Accelerating Cyclization Rate and Exerting Stereocontrol over Intramolecular Carbolithiation Reactions................................ 12 1.2. Results and Discussion ........................................................................................... 19 1.2.1. Intramolecular Carbolithiation Using Tertiary and Secondary Alkyllithiums Produced by Reductive Lithiation of Phenylthioethers ........................................................ 19 1.2.2. Stereoselective Intramolecular Carbolithiation of Alkenyllithiums Bearing an Allylic Lithium Oxyanionic Group....................................................................................... 26 1.2.3. Attempted Cyclization, Mediated by an Allylic Lithium Oxyanion, to Form a Six- Membered Ring .................................................................................................................... 51 1.3. Conclusions ............................................................................................................... 52 1.4. Experimental ............................................................................................................. 54 APPENDIX A.............................................................................................................................. 93 The COSY spetrum of compound 1.80 .................................................................................... 93 APPENDIX B .............................................................................................................................. 94 The ROSEY spetrum of compound 1.80.................................................................................. 94 vi APPENDIX C.............................................................................................................................. 95 The COSY spetrum of compound 1.101 .................................................................................. 95 APPENDIX D.............................................................................................................................. 96 The ROSEY spetrum of compound 1.101................................................................................ 96 2. Chapter 2........................................................................................................................ 97 2.1. Introduction ............................................................................................................... 98 2.1.1. Background for the Metallo-ene Reaction............................................................ 98 2.1.2. Intermolecular Metallo-ene Reactions.................................................................. 99 2.1.3. Intramolecular Metallo-ene Reactions................................................................ 104 2.1.4. Background for the Total Synthesis of (-)-Erythrodiene .................................... 116 12,14 2.1.5. Background for the Total Synthesis of 15-Deoxy-∆ -PGJ2 ........................... 119 2.2. Results and Discussion ......................................................................................... 125 2.2.1. Pd-catalyzed Zn-ene Cyclization to Construct Spirobicyclic Molecules Using Allyl Phenyl Sulfones as Precursors of Allylzincs ............................................................. 125 12,14 12,14 2.2.2. Total Synthesis of (±)-15-Deoxy-∆ -PGJ2, (±)-9,10-2H-15-deoxy-∆ -PGJ2 130 2.2.3. The Use of the Zn-ene Cyclization to Synthesize N-Containing Heterocycles.. 149 2.3. Conclusions ............................................................................................................. 153 2.4. Experimental ..........................................................................................................