DEANTIAROMATIZATION AS A DRIVING FORCE IN AN ELECTROCYCLIZATION OF CYCLOPENTADIENONE AND THE TOTAL SYNTHESIS OF 1-EPI - SECO - PSEUDOPTEROXAZOLE ________________________________________________________________________ A Dissertation Presented to The Faculty of the Graduate school University of Missouri-Columbia ________________________________________________________________________ In Partial Fulfillment of The Requirements for the Degree Doctor of Philosophy ________________________________________________________________________ by PINGUAN ZHENG Dr. Michael Harmata, Dissertation Supervisor DECEMBER 2007 The undersigned, appointed by the dean of the graduate school, have examined the dissertation entitled, PART 1 DEANTIAROMATIZATION AS A DRIVING FORCE IN AN ELECTROCYCLIZATION OF CYCLOPENTADIENONE AND PART 2 TOTAL SYNTHESIS OF 1-EPI-SECO-PSEUOPTEROXAZOLE presented by Pinguan Zheng a candidate for the degree of Doctor of Philosophy and hereby certify that in their opinion it is worthy of acceptance. _______________________________________________________ Professor Michael Harmata _______________________________________________________ Professor Kent S. Gates ________________________________________________________ Professor Timothy Glass ________________________________________________________ Professor Peter A. Tipton ________________________________________________________ Professor Renee Jiji To Rong Xu and Ryan Miancheng Zheng ACKNOWLEDGEMENTS First and foremost I thank my advisors Dr. Michael Harmata for his guidance, encouragement, and insights in the course of my graduate studies. He is always available in the office and ready to help me when I was stuck in my experiments. Without him, this dissertation would not have been possible. His expertise in the organic chemistry improved my research skills and prepared me for future challenges. I would like to thank my committee members: Dr. Kent S. Gates, Dr. Timothy E. Glass, Dr. Peter A. Tipton, Dr. Renee Jiji and former committee member Dr. Paul R. Sharp for their helpful suggestions on the thesis. I also want to give my gratitude to Dr. Wei Wycoff for NMR training, Dr. Charles Barnes for performing X-ray crystallography. I appreciate Bill Vellema for his continuous technical support for a wide range of instruments. I will also never forget the “coffee break” with Mary Laney, who helped me improve my English in my first two years. I thank the administrative staffs of chemistry department, especailly Jerry Brightwell and Ashley Francher, for their assistance. I want to thank Nathan Calkins, Derrick Seiner and Roberts Braun for proof-reading my thesis. I thank Weijiang Ying, Dr. Yugang Chen, Dr. Xuechuan Hong, and Nathan Calkins for the gifts of benzothiazines 548, 550, 552, and 559 in the chiral sulfinamide project. I would like to thank Dr. Xuechuan Hong, who offered the sincere help and helpful discussion especially in the beginning of my graduate studies. I also want to thank other Harmata group members: Nathan Calkins, Chaofeng Huang, Maria Gomes, Weijiang Ying, ii Dr. Yugang chen and previous members: Dr. Sumrit Wacharasindhu, Dr. Kanok-on Raynil (Amy), Dr. Dong Reoul Lee, Gayatri Balan for their friendship during my graduate studies. I want to give my greatest thanks to my family: my parents, Meihua Zheng and Xianfeng Yin, and my brother, Guanbo Zheng, whose love has been providing precious supports all these years. Last, I want to thank my son, Ryan Miancheng Zheng, whose smile is the sweetest thing I have ever seen. He is the angel in my life. At last but most importantly, I wish to sincerely thank my wife, Rong Xu, for all of her support these years. Insightful scientific discussions and her encouragement help me get through the difficulties in the course of graduate studies. Without her, I would never accomplish this thesis. iii PART 1 DEANTIAROMATIZATION AS A DRIVING FORCE IN AN ELECTROCYCLIZATION OF CYCLOPENTADIENONE PART 2 TOTAL SYNTHESIS OF 1-epi-seco-PSEUDOPTEROXAZOLE Pinguan Zheng Dr. Michael Harmata, Dissertation Supervisor ABSTRACT Deantiaromatization has been successfully demonstrated as a driving force in an electrocyclization of cyclopentadienones. The reaction was found to be general for a number of substrates and provides a unique way to access tricyclic ring systems with high stereoselectivity. Some evidence was uncovered to show that the process is indeed an 8π conrotatory electrocyclic ring closure. During the exploration of substituent effects in the electrocyclization, a novel coupling reaction of an organolithium with primary halides was discovered. The experimental data suggested the engagement of the silicon atom and the important role of terminal alkene in the coupling reaction. However, the application of thiw methodology to other silane systems was successful. The total synthesis of 1-epi-seco-pseudopteroxazole was accomplished in 17 steps, featuring the Buchwald-Hartwig coupling, a stereoselective intramolecular Michael reaction, a Heck coupling and asymmetric reduction of trisubstituted alkene. In the course of reductive cleavage of the C-I bond to access key intermediate 358, a novel dephenylation of Harmata benzothiazines was discovered to provide chiral cyclic iv sulfinamides with complete stereocontrol. Preliminary mechanistic studies were carried out and a plausible mechanism was proposed based on our experimental results. v TABLE OF CONTENTS ACKNOWLEDGEMENTS .......................................................................................…........ii ABSTRACT.............................................................................................…......……........... iv LIST OF TABLES ........................…..................................................................…............ viii LIST OF FIGURES ............................................................................................…..............ix LIST OF SCHEMES ............................................................................................…...........xii Chapter I Deantiaromatization as a Driving Force in an electrocyclic Reaction 1 Background on Electrocyclization ……………………........…….............…...................1 1.1 All-carbon Systems …………………………………….….…............…….............2 1.1.1 2π Systems ………......................................…..........……...........…................2 1.1.2 4π Systems ……….......................................…...............…….......…..............2 1.1.3 6π Systems ………........................…………....…................……...…............8 1.1.4 8π Systems ………........................…………......…..............…....…….........11 1.2 Heteroatom-containing Systems ………………………………….….……....…...13 1.2.1 Oxa-6π Systems ………..................................……..……..….............….….13 1.2.1.1 Access 2H-pyran Ring System ………………...……..…...……….. 13 1.2.1.2 Access 2H-chromene Ring System …………………….…...…….…15 1.2.2 Aza-6π Systems ………...............................…………....…....…....……......16 2 Background on the Cyclopentadienones Chemistry ………………………....………..18 2.1 Preparation ……………………………………………...….............….….....….....19 2.2 Reactions of Cyclopentadienones …………………………………....…...…….... 21 3 Results and Discussion ………………………………………………………...….…. 24 vi 3.1 Discovery of Electrocyclization Reaction ……….……….......…....….…............ 24 3.2 Exploration of Electrocyclization of a Number of Substrates …………….…….. 29 4 Summary …………………………………………………………………...…..……. 40 Chapter II An Unusual Observation During a Lithium-bromine Exchange Reaction 1 Introduction ……………………….…………………........……......….........…........... 41 1.1 Characterization of Pentaorganosilicates …….…………..……….……..……….. 41 1.2 Reactions Involving Pentaorganosilicates …………………………….…..….…. 44 1.2.1 Nucleophilic Substitution …………………..……….……….…...…......…. 44 1.2.2 Rearrangement Invovlving Pentaorganosilicate Intermediates ……..………47 2 Results and Discussion …………………………………………………...………….. 52 2.1 Discovery of a Novel Coupling Reaction with Primary Halides ……...…………. 52 2.2 Preliminary Mechanistic Studies …………………………………….…..………. 55 2.3 Phenyldimethylsilane Derivate ……………………………………….…..……… 62 2.4 Attempts of Coupling Reaction on Other Silane Substrates ………….……….…. 65 3 Summary ……………………………………………………………..…….………… 67 Chapter III Total Synthesis of 1-epi-seco-pseudopteroxazole 1 Introduction ……………………………..………………………………….…..…….. 69 1.1 Serrulatane Diterpenoids from Pseudopterogorgia Elisabethae …….….……….. 69 1.2 Serrulatane Diterpenoids from Other Sources ………………………..…....…….. 71 1.3 Biosynthesis of Serrulatane Diterpenoids …………………………..…….……… 73 1.4 Synthetic Efforts ……………………………………………………...……...…... 74 vii 1.4.1 seco-pseudopterosin Aglycone ………………………….….……….…… 75 1.4.2 Erogorgiaene …………………………………………………...……….... 78 1.4.3 Synthetic Efforts from Our Group …………..………………………...…. 82 1.4.3.1 Formal Synthesis of Erogorgiaene ………………………….……. 82 1.4.3.2 Total Synthesis of Pseudopteroxazole ……………………....…… 84 2 The Studies Towards the Total Synthesis of seco-Pseudopteroxazole ………………………………...………………………………………………………..86 2.1 Synthetic Plan ………………...……………………………………………….…. 86 2.2 Results and Discussion …………………………………………….….………… 87 2.2.1 1st Approach to Introduce the Stereochemistry at C-4 and C-11 position ………………………………………………………………………….… 87 2.2.2 2nd Approach to Introduce the Stereochemistry at C-4 and C-11 position …………………………………………………………………………… 103 2.2.3 Finish the Total Synthesis of 1-epi-seco-Pseudopteroxazole ……...…… 107 3 Summary ……………………………………...………………………...………. 108 Chapter IV A Novel Approach to Chiral Cyclic