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Application of Squarate Ester Cascade Reactions to The APPLICATION OF SQUARATE ESTER CASCADE REACTIONS TO THE SYNTHESIS OF (+/-) HYPNOPHILIN. NEW PHOTOREARRANGEMENTS OF 2-CYCLOPENTENONES. STUDIES TOWARDS THE TOTAL SYNTHESIS OF PECTENOTOXIN-II DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy in the Graduate School of The Ohio State University By Jian Liu The Ohio State University 2002 Dissertation Committee: Approved By Leo A. Paquette, Adviser David J. Hart Adviser Dehua Pei Department of Chemistry ABSTRACT The naturally occurring antibiotic polyquinane, hypnophilin, has attracted synthetic chemists for a number of years due to its reputed antibacterial and antitumor properties. As a highly oxygenated linear triquinane containing six stereocenters, hypnophilin was a suitable target for application of our squarate ester cascade reaction. The success of constructing 72 via a squarate ester cascade reaction allowed us to synthesize hypnophilin in a short route. Two 2-cyclopentenones 137 and 138 were prepared by a convergent pathway involving the coupling of cyclopentenyl bromide 139 and racemic ketone 150 followed by desilylation, perruthenate oxidation, and ring-closing metathesis. New photorearrangements were discovered when 137 and 138 were irradiated through quartz. Convergent pathways for synthesizing building blocks A and B for pectenotoxin II were investigated. Advanced precursor 238 was prepared involving the coupling of iodide 184 and Weinreb amide 185 followed by removal of the two PMB ethers, hydrogenolysis, DMP oxidation, Wittig reaction, reduction, Sharpless' asymmetric epoxidation, DMP oxidation, and Wittig reaction. Four more functional group transformations would be needed to construct building block A. Advanced precursor tetrahydrofuran 283 was prepared involving a Julia olefination via the coupling of sulfone ii 277 and aldehyde 243 followed by a series of chemical operations including Sharpless' asymmetric dihydroxylation. After eight more chemical operations, building block B could be synthesized. iii To my wife, Xiaoling my daughter, Kailin my parents, Hanming and Huijuan and my brothers An and Yan iv ACKNOWLEDGMENTS I would like to thank my advisor, Dr. Leo Paquette for his invaluable support, guidance, and enthusiasm. He has given me the opportunity and intellectual freedom to grow in scientific knowledge and creativity. I would also like to thank my other dissertation committee members Dr. David J. Hart, Dr. Dehua Pei for their time and cooperation. I thank Donna Rothe for her unselfish contributions to me and the group. I would also like to thank Rebecca Martin for her help in a variety of ways. I would like to acknowledge Dr. Robin Rogers for solving a number of crystal structures. I would like to thank the many talented and gifted group members who have shared their advice and expertise during my graduate tenure. Some group members have contributed in ways which have made my experience at The Ohio State University enjoyable. Of them, I thank Drs. Qingbei Zeng, Penglie Zhang, Oliver Yun Long, Andrew Cooks, Daffyd Owens, Ingo Konezki and Maosheng Duan for sharing their experiences in the beginning of my graduate studies. A special thanks goes to Drs. Feng Geng, Zhong Zhao, Fabrice Gallou and Mr. Jiong Yang for their cooperation through some of my research projects. In particular, I thank Drs. Ray Bishop and Ho-Jung Kang for sharing their talents in chemistry and making my lab life enjoyable. v VITA April 8, 1971………………………………Born - Shanghai, China 1993………………………………………..B. S. Chemistry, Fudan University 1997………………………………………..M. S. Chemistry, West Virginia University 1997 - present………………………………Graduate Teaching and Research Associate, The Ohio State Univerity PUBLICATIONS 1. Geng, F.; Liu, J.; Paquette, L.A. “Three-Component Coupling via the Squarate Ester Cascade as a Concise Route to the Bioactive Triquinane Sesquiterpene Hypnophilin” Org. Lett. 2002, 71-73. 2. Paquette, L.A.; Zhao, Z.; Gallou, F.D.; Liu, J. “New Photorearrangements of 2- Cyclopentenenones. The Genesis and Fate of Cyclopropylcarbinyl Biradical Intermediates” J. Am. Chem. Soc. 2000, 122, 1540-1541. vi 3. Paquette, L.A.; Gallou, F.; Zhao, Z.; Young, D.G.; Liu, J.; Yang, J.; Friedrich, D. “Propensity of 4-Methoxy-4-Vinyl-2-Cyclopentenenones Housed in Tri- and Tetracyclic Frameworks for Deep-Seated Photochemical Rearrangement” J. Am. Chem. Soc. 2000, 122, 9610-9620. 4. Soederberg, B.C.; O’Neil, S.N.; Chisnell, A.C.; Liu, J. “A [3.3] Sigmatropic rearrangement of α, β-unsaturated Fischer chromium carbenes: Synthesis of alkynol and dienol esters” Tetrahedron 2000, 56, 5037-5044. 5. Soederberg, B.C.; O’Neil, S.N.; Liu, J. “A novel formal [3+3] sigmatropic rearrangement of alkenyl-substituted Fischer carbenes” Book of Abtracts, 215 th ACS National Meeting, Dallas, Texas, March 29- April 2, 1998. 6. Soederberg, B.C.; Liu, J.; Ball, T.W.; Turbeville, M.J. “Thermal Decomposition of Pentacarbonyl(1-acyloxyalkylidene)Chromium(0) Complexes: Formation of Z- Enol Esters” J. Org. Chem. 1997, 62, 5945-5952. FIELDS OF STUDY Major Field: Chemistry vii TABLE OF CONTENTS ABSTRACT……………………………………………………………………………....ii ACKNOWLEDGEMENTS………………………………………………………………v VITA……………………………………………………………………………………..vi LIST OF FIGURES………………………………………………………………………x LIST OF SCHEMES……………………………………………………………………..xi CHAPTER 1. ......................................................................................................................1 INTRODUCTION .............................................................................................................. 1 CHAPTER 2. ....................................................................................................................4 APPLICATION OF SQUARATE ESTER CASCADE REACTIONS TO THE SYNTHESIS OF (+/-) HYPNOPHILIN............................................................................. 4 2.1 SQUARATE ESTER CASCADES AND RELATIONSHIP TO POLYQUINANE NATURAL PRODUCTS……………………………………………………………………………… 4 2.2 BACKGROUND AND APPROACHES TO THE SYNTHESIS OF HYPNOPHILIN………. 13 2.3 RETROSYNTHETIC ANALYSIS………………………………………………….. 17 2.4 SYNTHESIS OF VINYL BROMIDE 75 AND ITS UTILIZATION TOWARD THE SYNTHESIS OF (+/-) HYPNOPHILIN…………………………………………………….. 18 2.5 CONCLUSION…………………………………………………………………...28 CHAPTER 3. .................................................................................................................. 29 NEW PHOTOREARRANGEMENTS OF 2-CYCLOPETENONES. ............................. 29 3.1 INTRODUCTION………………………………………………………………... 29 3.2 SYNTHESES OF 2-CYCLOPENTENONES 137 AND 138…………………………… 37 3.3 PHOTOREARRANGEMENTS OF 2-CYCLOPENTENONES 137 AND 138 AND MECHANISTIC ELUCIDATION………………………………………………………….. 43 3.4 CONCLUSION………………………………………………………………….. 47 CHAPTER 4. .................................................................................................................. 49 STUDIES TOWARDS THE TOTAL SYNTHESIS OF PECTENOTOXIN-II………..49 4.1 INTRODUCTION………………………………………………………………... 49 viii 4.2 RETROSYNTHETIC ANALYSIS…………………………………………………...53 4.3 STUDIES TOWARD THE SYNTHESIS OF BUILDING BLOCK A…………………… 56 4.3.1 Synthesis of iodide 184…………………………………………………...57 4.3.2 Synthesis of Weinreb amide 185…………………………………………60 4.3.3 Synthesis of spiroketal 183……………………………………………….61 4.3.4 Synthesis of the framework of building block A…………………………. 74 4.3.5 Future work………………………………………………………………79 4.4 STUDIES TOWARD THE SYNTHESIS OF BUILDING BLOCK B…………………….81 4.4.1 Synthesis of sulfone 242…………………………………………………. 82 4.4.2 Synthesis of aldehyde 243……………………………………………….. 85 4.4.3 Efforts on the Julia-Lythgoe olefination and synthesis of the tetrahydrofuran ring……………………………………………………………….. 86 4.4.4 Future work……………………………………………………………… 95 CHAPTER 5. .................................................................................................................. 97 EXPERIMENTAL SECTION.......................................................................................... 97 APPENDIX……………………………………………………………………………..168 REFERENCES…………………………………………………………………………233 ix LIST OF FIGURES Figure Page 1 Squaric acid………………………………………………………………………4 2 Selected natural polyquinanes…………………………………………………..13 3 Hypnophilin……………………………………………………………………..13 4 2-ethyl-2-methyl-[1,3]dioxolane……………………………………………….20 5 Ingenol………………………………………………………………………….35 6 Compound 131………………………………………………………………….35 7 2-Cyclopentenones 137 and 138………………………………………………..37 8 First generation Grubbs' catalyst………………………………………………..41 9 Computer-generated perspective drawing of 157 as determined by X-ray crystallography…………………………………………………………………..45 10 Computer-generated perspective drawing of 159 as determined by X-ray crystallography…………………………………………………………………..46 11 Pectenotoxins…………………………………………………………………….50 12 MM3 calculations for two possible conformational models 224 and 225 of spiroketal 183……………………………………………………………………73 13 Modified building block A………………………………………………………75 14 Modified building block B………………………………………………………75 x LIST OF SCHEMES Scheme Page 1 Some examples of squarate esters in synthetic applications………..…….6 2 Two-fold addition of 3 to 2……………………………………………….7 3 trans Addition and the electrocyclic reaction channel……………………8 4 cis Addition and the sigmatropic pathway………………………………..8 5 1,4-Addition of the second nucleophile…………………………………..10 6 Helical equilibration………………………………………………………11 7 Regioselective transannular aldol from β-elimination……………………12 8 Little's strategy for the synthesis of Hypnophilin………………………..14 9 Curran's synthesis of Hypnophilin………………………………………15 10 Weinges' enantioselective synthesis of Hypnophilin…………………….16
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