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INFORMATION to USERS the Most Advanced Technology Has Been INFORMATION TO USERS The most advanced technology has been used to photo­ graph and reproduce this manuscript from the microfilm master. UMI films the original text directly from the copy submitted. Thus, some dissertation copies are in typewriter face, while others may be from a computer printer. In the unlikely event that the author did not send UMI a complete manuscript and there are missing pages, these will be noted. Also, if unauthorized copyrighted material had to be removed, a note will indicate the deletion. Oversize materials (e.g., maps, drawings, charts) are re­ produced by sectioning the original, beginning at the upper left-hand comer and continuing from left to right in equal sections with small overlaps. Each oversize page is available as one exposure on a standard 35 mm slide or as a 17" x 23" black and white photographic print for an additional charge. Photographs included in the original manuscript have been reproduced xerographically in this copy. 35 mm slides or 6" x 9" black and white photographic prints are available for any photographs or illustrations appearing in this copy for an additional charge. Contact UMI directly to order. Accessing the UMIWorld’s Information since 1938 300 North Zeeb Road, Ann Arbor, Ml 48106-1346 USA Order Number 8820267 Studies toward the total synthesis of trixikingolide Cheney, Daniel Ley, Ph.D. The Ohio State University, 1988 UMI 300 N. Zeeb Rd. Ann Arbor, MI 48106 PLEASE NOTE: In all cases this material has been filmed in the best possible way from the available copy. Problems encountered with this document have been identified here with a check mark V . 1. Glossy photographs or pages_____ 2. Colored illustrations, paper or print______ 3. Photographs with dark background____ 4. Illustrations are poor copy______ 5. Pages with black marks, not original copy i S 6. Print shows through as there is text on both sides of page_______ 7. Indistinct, broken or small print on several pages f S 8. Print exceeds margin requirements_____ 9. Tightly bound copy with print lost in spine_______ 10. Computer printout pages with indistinct print______ 11. Page(s)___________lacking when material received, and not available from school or author. 12. Page(s)___________seem to be missing in numbering only as text follows. 13. Two pages numbered . Text follows. 14. Curling and wrinkled pages 15. Dissertation contains pages with print at a slant, filmed as received _________ 16. Other____________________________________________________________________ UMI STUDIES TOWARD THE TOTAL SYNTHESIS OF TRIXIKINGOLIDE 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 Daniel L. Cheney, B.S, ***** The Ohio State University 1988 Dissertation Committee Approved by Dr. Gideon Fraenkel Dr. Leo A. Paquette Dr. John S. Swenton Adviser ” Department of Chemistry To Paivi and ray parents. ACKNOWLEDGEMENTS I would like to thank Dr. Paquette without whose encouragement, guidance, and inspiration, this doctoral work would not have been possible. I would also like to express my indebtedness to those who played important roles in my development as a scien­ tist. Among them, Doc, for imparting to me the thrill of facing a synthetic challenge and the endurance to see it through; Ho Shen, for teaching me the importance of knowing the literature, and for serving as a role model for experi­ mental observation and technique; and of course, Jurgen for teaching me the importance of critical thought. I would also like to acknowledge Denis St. Laurent, Wang, Kevin Moriarty, Jurgen Dressel, Jeff Romine, Dwight MacDonald, Ho Shen Lin and Callie and Tana Pistorius, whose friendship has made these years very precious. I extend my appreciation to Kay Kampsen for her perseverance in completing the task of typing this thesis. I thank my wife, Paivi, for her encouragement, help in the final compilation of this work, and for serving as a source of balance during my graduate years. Finally, I thank my parents for their continual sup­ port, and for instilling in me (for better or worse) the spirit of adventure. iii VITA June 30, 1957 ...... Born - Detroit, Michigan January-February, 1979 Scholarship for Language Study, Goethe Institut, Grafing, West Germany May-August, 1982,1983 Summer Student Reserach, Warner Lamberg/Parke- David, Ann Arbor, Michigan 1983 ............... B.S., Summa Cum Laude, Eastern Michigan Univer­ sity, Ypsilanti, Michigan PUBLICATIONS "A New Dihydrobenz[a]anthraquinone Antitumor Antibiotic (PD) 116740)" Wilton, J.H.; Cheney, D.L.; Hokanson, G.C.; French, J.C. J. Orq. Chem. 1985, 50, 3936. FIELDS OF STUDY Major Interest: Organic Chemistry TABLE OF CONTENTS Page ACKNOWLEDGEMENTS .................................. iii VITA .............................................. iv LIST OF SCHEMES ................................ viii LIST OF TABLES ................................. X LIST OF FIGURES ..... xi CHAPTER I. THE TRIXIKINGOLIDES .................... 1 1.1 Isolation and Structure ........... 1 1.2 Biosynthesis ..................... 1 1.3 Retrosynthetic Analysis ........... 4 II. SYNTHESIS OF TRICYCLIC KETONE 17 ........ 6 2.1 Synthesis and Alkylation of Bicyclic Dione 18 ....................... 6 2.2 Synthesis of Tricyclic Ketone 17 .... 11 2.3 Summary .......................... 21 III. SYNTHESIS AND REACTIONS OF TRICYCLIC UNSATURATED ESTER 16 AND ITS METHYL ENONE ANALOGUE 68 ..................... 22 3.1 Synthesis of Tricyclic Unsaturated Ester 16 ......................... 22 3.2 Reactivity of Unsaturated Ester 16 and Model System 59 toward 1,4 Addition . 24 3.3 Tricyclic a,|3-Unsaturated Methyl Ketone 68. Synthesis and Reactions ...... 28 3.4 Summary ............................ 30 v Table of Contents (continued) Page IV SECOND ROUTE TO ALDEHYDO-ESTER 15 ......... 31 4.1 Strategy .......................... 31 4.2 Nazarov Cyclization Route to 72a .... 32 4.3 Silicon-Mediated Nazarov Cyclization .. 35 4.4 Direct Route to Methyl Ketone 72a ... 42 4.5 Cleavage of the D-Ring ............. 46 4.6 Summary ........................... 48 V APPROACHES TO C(4)-C(5) BOND FORMATION .... 50 5.1 The Prins Cyclization .............. 50 5.2 Aldol Condensation ................. 52 5.3 Intramolecular Alkylation ........... 56 5.4 Cleavage of the A Ring ............. 59 5.5 Summary ........................... 77 VI ALTERNATIVE APPROACHES AND CONCLUSIONS .... 79 6.1 Ramberg-Backlund Route .............. 79 6.2 Effecting Conformational Change at C ( 2 ).............................. 81 6.3 Conclusion ........................ 84 LIST OF SCHEMES Scheme Page I Retrosynthetic analysis ................... 5 II Duthaler's synthesis of 18............... 7 III Improved synthesis of 18 .................. 8 IV Attempted phosphorylation of 32 ........... 11 V Double elimination of 37 .................. 14 VI Hydrolysis of 34 and 43 ................... 15 VII Prins cyclization of 42 ................... 18 VIII Synthesis of enone 51 ..................... 20 IX Synthesis of tricyclic ketone 17.. ......... 21 X Synthesis of unsaturated ester 16.......... 23 XI Mechanisms of carbonylation of 54 and 55 .... 23 XII Functionalization of ester 16 ............. 24 XIII Application of Yamamoto's conditions to 59 .. 27 XIV Application of Oppolzer's conditions to 57 .. 27 XV Synthesis of 15 via ketone 68 ............. 28 XVI Synthesis of methyl ketone 68 ............. 29 XVII Alternate plan to synthesize 15 ........... 31 XVIII Synthesis of divinyl ketones 75a,b ......... 33 XIX Mechanism of the silicon-mediated Nazarov cyclization.......................... 36 XX Synthetic plan for ketone 72a ........... 36 vii List of Schemes (continued) Scheme Page XXI Nazarov cyclization of 7 8 a ................ 38 XXII Dimerization of 79 ........................ 39 XXIII Acid-catalyzed isomerization of 79afb ....... 40 XXIV Initial synthesis of 72a .................. 41 XXV Trost cyclopentaannulation of 17 ........... 43 XXVI Ozonolysis of enol ether 91... ............. 46 XXVII Alpha-hydroxylation of 7 2 a ................ 47 XXVIII Summary of synthesis of 15 ................ 49 XXIX Prins cyclization of 15 ................... 50 XXX Methylation-lactonization of 15 ........... 51 XXXI Hydroboration of 99 and 15 ................ 53 XXXII Synthesis of keto-aldehyde 97 ............. 54 XXXIII First attempted synthesis of 105 ........... 57 XXXIV Intramolecular alkylation of 105 ........... 58 XXXV Expansion of the A ring.................... 60 XXXVI Synthesis of enol ether 116 ............... 61 XXXVII Hydroboration of 117 ...................... 63 XXXVIII Radical cyclization strategy from 119 ....... 64 XXXIX Synthesis of dialdehyde 121 ............. 65 XL Efforts to synthesize 126.................. 67 XLI Synthesis of 133 and 134 ................. 68 XLII Mechanism of silylation with TMS-EtOAc ..... 69 viii List of Schemes (continued) Scheme Page XLIII Synthesis of halo esters 140 and 142.. ...... 71 XLIV Intramolecular alkylation of 140 and 142.... 72 XLV Ramberg-Backlund route .................... 79 XLVI Initial synthesis of 155 ................. 82 XLVII Synthesis of tert-butyldimethy1silvl ether 151 ............................. 83 XLVIII Preliminary attempts to alkylate 151 ..... 84 IL Proposed strategy for C(4)-C(5) closure .... 86 ix LIST OF TABLES Table page 1 The trixikingolides ........................ 2 2 Alkylation of dione 18 ...................... 9 3 Reduction of 32 ............................ 12 4 Prins cyclization of 42 ....................
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