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JUN 1 51998 Science Efforts Toward the Syntheses of Natural Products: Part A: Paeoniflorin Part B: (+)-Taxusin A thesis presented by Rebecca J. Carazza B.S. Chemistry University of Massachusetts, Amherst, 1993 Submitted to the Department of Chemistry in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Chemistry at the Massachusetts Institute of Technology June 1998 © 1998 Massachusetts Institute of Technology. All rights reserved. SinatureofAuthor: SignatureT- -~- -- .. -uof -Author: -- I- ----- D4pdrtment o('ihemistry May 26, 1998 Certified by: ,Scott C. Virgil Thesis Advisor Acceuted bv: Dietmar Seyferth Chairman, Departmental Committee on Graduate Students O-V .Z\ . JUN 1 51998 Science UR PAES This doctoral thesis has been examined by a committee of the Department of Chemistry as follows: Professor Rick L. Danheiser - Chairman Professor Scott C. Virgil / Th/sis Supervisor Professor Peter H. Seeberger Efforts Toward the Syntheses of Natural Products: Part A: Paeoniflorin Part B: (+)-Taxusin by Rebecca J. Carazza Submitted to the Department of Chemistry on May 26, 1998 in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy in Chemistry Massachusetts Institute of Technology ABSTRACT Part A Efforts toward the synthesis of the monoterpene glycoside paeoniflorin (1) are discussed. Optimization of the previous synthetic route was successful. Synthesis of the key cc-diazo intermediate 30 was achieved and the construction of the carbocyclic frame was completed. Key reactions of the strategy involve a ring contraction via a Wolff rearrangement, and formation of the lactone 78 which undergoes diisobutylaluminum hydride reduction followed by acid catalyzed cyclization to the paeoniflorin ring system 80. A new synthetic strategy was initiated to prepare the key [3.2.1]bicyclooctanone 81 using a palladium mediated olefin cyclization of the acyloin substrate 82. CH 3 OH Paeoniflorin 1, O BnO O TMSO TBSO TCH O 3 CH 3 TMSO 0O OH 78 Part B Efforts toward the synthesis of the diterpenoid natural product (+)-taxusin (110) are discussed. An alternative route to the key intermediate photoprecursor 130 was achieved employing a cerium trichloride mediated addition of an aryl lithium 132 to an aldehyde 141. A mechanism for the exclusive formation of a cis 150 or trans 149 B-C ring system was proposed. Attempts were made to cyclize the A-ring of both cis and trans ring fused intermediates. Ac AcO OAc 0l OCH3 OAc 130 Taxusin, 110 OCH 3 OCH3 0O 150 149 132 Thesis Supervisor: Scott C. Virgil Title: Assistant Professor of Chemistry Acknowledgments I would like to take this opportunity to thank all of the people that have been a major part of my life during my stay at MIT. First and foremost, I am grateful to my mentor, my friend Professor Scott Virgil. The enthusiasm he has for chemistry is matched by none. Scott has been an inspirational advisor who constantly offers positive encouragement. I would like to thank all of the members of the Virgil lab both past and present for their guidance and friendship. Many thanks to Dr. Paige Mahaney, Dr. Richard Allen (mind bomb. mind bomb, mind bomb!), Dr. Edcon Chang, and Dr. Jeffrey Eckert all of whom taught me the important aspects of total synthesis. Justin Miller has taught me all the tricks to ChemDraw, which helped tremendously in writing this thesis. Teaching with Justin has been fruitful and fun. MIT undergraduates that have worked on my projects, or who just can't be left out are Federico Bernal, Junko Tamiya, Sarah Folscraft, Juliet Midgley and Joseph Lee. Not only did the group offer support and guidance, they provided a friendly atmosphere to work in. Thanks to Chris Garrett for making my first two years here enjoyable. I would like to thank Matt Martin for his friendship and for editing my thesis. Evan Powers, may your team always win! I would like to acknowledge the financial support that I received from the Chemistry Department. I am grateful for having such a supportive and encouraging family. They believed in me and helped me maintain my sanity when things got rough. Thanks Mom, Dad, Mike and Chandler. I would like to dedicate this thesis to all of you. Table of Contents Part A: Paeoniflorin Chapter I. Introduction 1.1 B ioactiv ity ...................................................................................................... 7 1.2 Degradation Products of Paeoniflorin ................................................. 9 1.3 Synthetic Strategy........................................... ....................................... 11 Chapter II. Formation of the Carbocyclic Framework 2.1 Retrosynthetic Analysis......................................................................... 16 2.2 a-D iazoketone Synthesis...........................................................................17 Chapter III. Attempts to Form the Paeoniflorin Fing System 3.1 Aldehyde Formation Promoted Side Reactions..................................26 3.2 Successful Construction of the Paeoniflorin Ring System ............... 33 Chapter IV. Revised Strategy 4.1 Novel Approach to Carbocyclic System..............................................38 4.2 Oxygenation of the C-3 Position.......................................42 4.3 Future Prospects with the Barton Reaction..............................45 Part B: (+)-Taxusin Chapter V. Introduction 5.1 Biological Activity..................................................47 5.2 Stru ctu re .................................................... ............................................. 53 5.3 Synthetic Strategy...................................................55 Chapter VI. Synthetic Modifications 6.1 Retrosynthetic Analysis............................ ................. 60 6.2 Modifications to the Original Synthetic Route...................... 61 Chapter VII. B-Ring Formation 7.1 Previous Work .......................................................... 68 7.2 New Proposed Mechanism..........................................70 7.3 Oxidative Cleavage Attempts...........................................................72 Chapter VIII. A-Ring Cyclization Attempts 8.1 Swindell's A-Ring Cyclization...................................................... 74 8.2 A-Ring Cyclization Attempts with the trans-Fused Ring System ...................................................... ............ .............. 75 8.3 A-Ring Cyclization Attempts with the cis-Fused R in g System ................................................ ........................................... 79 Experimental Section and Selected Spectra.......................... ........... 83 Chapter I: Introduction 1.1 Bioactivity Paeoniae Radix i (Shaoyao) is an important herbal drug widely used in traditional Chinese medicine. It consists of a crude mixture of substances derived from the roots of several species of Paeoneaceae; major harvests are from Paeonia lactiflora and Paeonia Suffruticosa.2 Shaoyao has been used for centuries as an analgesic, antispasmodic, astringent and sedative. The interesting bioactivity displayed by this drug sparked interest in identifying the components responsible for the therapeutic behavior. Efforts began in the 1960's and several highly oxygenated terpenoids were isolated and characterized. 3 HOCH 2 PhCO 2 /O HO~ OH -- CH 3 OH 1, Paeoniflorin Paeoniflorin (1) was the most abundant of the components and it was determined to be a highly oxygenated, complex, cage-like monoterpene l(a) Kimura, M.; Kimwla. I.,Nojirna, H.; Takashi, K.; Hayashi, T.; Shimizu, M.; Morita, N. Jpn. J. Pharmacol. 1984, 35, 61. (b)Hikino, H.; In Economic and Medicinal Plant Research; Wagner, H., Hikino, H., Farnsworth, N. R, Eds.; Academic Press, Inc.: London, 1985, pp. 5 5 - 8 5 . 2 yu, J.; Elix, J.A.; Iskander, M. N. Phvtochemistrv 1990, 29, 3859. 3(a) Hattori, M.; Shu, Y. Z.; Shimizu, M.; Hayashi, T.; Morita, N.; Kobayashi, K.; Xu, G. J.; Nanba, T. Chem. Pharm. Bull. 1985, 33, 3838. (b) Akao, T.; Shu, Y. Z.; Matsuda, Y.; Hattori, M.; Namba, T.; Kobayashi, K. Clihemn. Pharm. Bull. 1988, 36, 3043. (c) Shibata, S.; Nakahara, M. Chem. Pharm. Bull. 1963, 11, 372. ChapterI: Introduction * 8 gylcoside. 4 Other components included lactiflorin (2)2, albiflorin (3)4c and aglycones paeonisuffrone (4)5 and paeonilactones A (5) and C (6), (Scheme 1).6 Scheme 1: Minor components of the herbal drug Paeoniae Radix. 0 0 0 0 HOCH 2 PhCO 2 0 HOCH 2 0N H O OH HOHO OH CH BzO H 2, Lactiflonn 3, Albiflorin HO HH HO CH3 HO O R 5, Paeonilactone A: R=Me 4, Paeonisuffrone 6, Paeonilactone C: R=CH 20Bz Many research groups conducted experiments to evaluate paeoniflorin's therapeutic potential. Paeoniflorin has provided positive results in a wide range of studies. Recently paeoniflorin has been reported to exhibit anti-inflammatory, anticoagulant and sedative activities.la Paeony root extracts have been found to exhibit protective effects against neuron damage in the hippocampus when induced by metallic cobalt (an epilepsy 4 (a) Shibata, S.; Aimi, N.; Watanabe, M. Tetrahedron Lett. 1964, 20, 1991. (b) Aimi, N.; Inaba, M.; Watanabe, M.; Shibata, S. Tetrahedron Lett. 1969, 25, 1825. (c) Kaneda, M.; litaka, Y.; Shibata, S. Tetrahedron 1972, 28, 4309. 5 (a) Hatakeyama, S.; Kawamura, M.; Mukagi, Y.; Irie, H. Tetrahedron Lett. 1995, 36, 267. (b) Yoshikawa, M.: Harada, E.; Kawaguchi, A.; Yamahara, J.; Murakami, N.; Kitagaqa, I. Chem. Pharm. Bull. 1993, 41, 630. 6 (a) Hayashi, T.; Shinbo, T.; Simizu, M.; Arisawa. M.; Morita. N.; Kimura, M.; Matsuda, S.; Kikuchi, T. Tetrahedron Lett. 1985, 31, 3699. (b) Yoshikawa,
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