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Xerox University Microfilms 300 North Z««B Road Am* Artor, Michigan 48106 75-26,549 BQKFLMAN, Gordon Herman, 1948- the CHEMISTRY of a MOLD METABOLITE

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Xerox University Microfilms 300 North Z««B Road Am* Artor, Michigan 48106 75-26,549 BQKFLMAN, Gordon Herman, 1948- the CHEMISTRY of a MOLD METABOLITE INFORMATION TO USERS This material was produced from a microfilm copy of the original document. While the moat advanced technological means to photograph and reproduce this document have bean used, the quality is heavily dependent upon the quality of the original submitted. The following explanation of techniques is provided to help you understand markings or patterns which may appear on this reproduction. 1. The sign or "target" for pages apparently lacking from the document photographed is "Missing Paga(s)". If it was possible to obtain the missing page(s) or section, they are spliced into the film along with adjacent pages. This may have necessitated cutting thru an image and duplicating adjacent pages to insure you complete continuity. 2. When an image on the film is obliterated with a large round black mark, it is an indication that the photographer suspected that the copy may have moved during exposure and thus cause a blurred image. You will find a good image of the page in the adjacent frame. 3. Whan a map, drawing or chart, etc., was part of the material being photographed the photographer followed a definite method in "sectioning" the material. It is customary to begin photoing at the upper left hand comer of a large sheet and to continue photoing from left to right in equal sections with a small overlap. If necessary, sectioning is continued again - beginning below the first row and continuing on until complete. 4. The majority of users indicate that the textual content is of greetest value, however, a somewhat higher quality reproduction could be made from "photographs" if essential to the understanding of the dissertation. Silver prints of "photographs" may be ordered at additional charge by writing the Order Department, giving the catalog number, title, author and specific pages you wish reproduced. 5. PLEASE NOTE: Some pages may have indistinct print. Filmed as received. Xerox University Microfilms 300 North Z««b Road Am* Artor, Michigan 48106 75-26,549 BQKFLMAN, Gordon Herman, 1948- THE CHEMISTRY OF A MOLD METABOLITE. The Ohio State University. Ph.D., 1975 Chemistry, organic XSTOX University Microfilms , Ann Arbor, Michigan 4«10fl THIS DISSERTATION HAS BEEN MICROFILMED EXACTLY AS RECEIVED. THE CHEMISTRY OF A MOLD METABOLITE DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Gordon Herman Bokelman, A.B. A A A A A The Ohio State University 1975 Reading Committee: Approved by Prof. J. L. Beal Prof. R. W. Doskotch Prof. L. A. Mitscher Adviser College of Pharmacy To Ann and Jennifer i i ACKNOWLEDGMENTS I would like to express my1 gratitude to my adviser, Professor Lester A. Mitscher, for the opportunity to work on the challenging research projects which he envisioned. Professor Mitscher has been a gifted teacher of the princi­ ples and philosophy of chemistry. I am also indebted to Professors Jack L. Beal and Raymond W. Doskotch for their contributions to my under­ standing of the field of natural products chemistry. The friendship, inspiration, and contribution of the graduate students and postdoctoral fellows I have known are greatly appreciated. Financial assistance from the Chemistry Department of The Ohio State University, Abbott Laboratories, N.I.H., and The American Foundation for Pharmaceutical Education is gratefully acknowledged. VITA April 15, 1948 .............. .Born-Bloomington, Indiana 1970 ............................. A.B., Chemistry, Indiana University, Bloomington, Indiana. 1970- 1971........................ Teaching Assistant, Chemistry Department, The Ohio State University, Columbus, Ohio. 1971-1975 ........................ Research Associate, College of Pharmacy, The Ohio State University, Columbus, Ohio. FIELDS OF STUDY Major Field: Natural Products Chemistry iv TABLE OF CONTENTS Page DEDICATION ......................................... ii ACKNOWLEDGMENTS............ iii VITA .......................................................... iv LIST OF FIGURES................................................. vii INTRODUCTION ................................................. 1 The purpose of the research........................... 31 Previous studies on terrein ........................... 34 EXPERIMENTAL ....................................... 35 Methodology.................................... 35 Purity of reagents and solvents ...................... 36 1-Iodo-7-octene (34i) . .................................. 36 7- Iodoheptanoic acid (.39)............................. 3 8 7-Iodo-1-heptanol (4 0) First procedure ..................................... 38 Second procedure....................................... 39 THP-ether of 7-iodo-1-heptanol ( £ 1 ) ............ .. 40 Tetrakis [iodo (tri-n-butylphosphine) copper (I)] (£2) . 41 Attempted conjugate addition of THP-ether £1 to trans- 2-methyl- 2-pentenal........................ 42 Attempted addition of 1-iodo-7-octene (_38) to benzophenone.............. 43 7-Bromoheptanoic acid ( £ £ ) ............................. 46 7-Bromo-1-heptanol (45) First procedure....................................... 47 Second procedure....................................... 47 THP-ether of 7-bromo-1 - heptanol (£6)................. 48 Attempted addition of THP-ether £6 to carbon dio x i d e ................................................. 49 Attempted addition of 2-chloro-1,1- diethoxyethane (48) to benzophenone ............... 51 v Page Attempted addition of 2-bromo-l,l- diethoxyethane (4j)) to benzophenone............... 53 THP-ether of 2-bromoethanol (5_1)...................... 55 Attempted reaction of THP-ether _51_ with lithium................................................. 56 Attempted conjugate addition of THP-ether 51 to trans-2-methyl-2-pentenal ................... 57 Trans-5-methyl-1,5-octadien-4-ol (53) ............... 59 Methyl 5-hexenoate (54) ................................ 62 3-Carbomethoxy- 4 (S) ,1>TR) -dibenzoxy-2- cyclopenten-1 - one etFylenethioketal (56).......... 62 5 (R)-Benzoxv-3-carbomethoxy-2-(2-propenyT)- 7-cyclopcnten-1-one ethy lenethioket al (5^7). 64 Terrein diacetate (58) First procedure....................................... 66 Second procedure....................................... 67 4 (S) ,5(R) -Diacetoxy-3-(trans-1-propenal)- 2- cyclopenten-1-o n e ..................................... 67 4 (S),5(R)-Diacetoxy-3-(3-hydroxy-trans-1- octenyl) - 2-cyclopenten-1-one (6TT) T ............... 69 Attempted thioketalization of ketone (60) .......... 71 4(S),5(R)-Diacetoxy-3-(3-[2-tetrahydro- pyranyloxy]-trans-1-octenyl)-2-cyclopenten- 1-one (6_1). ..................................... 72 4 (S) ,5(S) - Diacetoxy-1-(3-[2-tetrahydropyranyloxy]- trans-1-octenyl) -cyclopenten- 3rQl (62)............ 74 3- (4 (S)", 5 (S) - Diacetoxy -1 - [ 5-hydroxy - trans -1- octenyl]-cyclopentenyl) ethyl malonate............ 76 Attempted manganese dioxide oxidation of alcohol (63). ..................................... 77 Attempted biphasic chromic acid oxidation of alcohol (^3...................................... 78 4 (S),5(S)-Dibenzoxy-1-formyl-3(R)- Kydroxycyclopentene (65).......................... 79 4 (S) ,5 (S) - Dibenzoxy - 3 (R^hydroxy-1- j3-oxo-trans-1-octenyl)-cyclopentene (_66) .... 80 3(R)-(4(S),5(S)-Dibenzoxy-1-(3-oxo-trans- 1 - octenyl ]-cyclopentenyl) ethyl maTonate (67^) . • 81 Attempted cyclization of compound 6jf with disodium salicylate .................................. 83 Attempted cyclization of compound §]_ with sodium methoxide.................................... 83 1 (R) , 5(R),8(R)-Benzoxy-4(R)-carbethoxy-6- X3-OXO-trans-1-octenyl)-3-oxo-2-oxabicyclo [3.3.0] oct-6-ene (6fJ).........' ..................... 84 DISCUSSION................................................ 87 BIBLIOGRAPHY .................................................. 107 vi LIST OF FIGURES Figure Page 1 Some representative prostaglandins .... 6 2 Examples of stereochemical variations of the natural prostaglandins .......... 8 3 Prostaglandin biosyntheses ................. 11 4 Synthetic routes to prostaglandins from a cyclopentane nucleus ................... 13 5 Potential cyclization routes to prostaglandins ............................. 15 6 The Just synthesis of dl-PGF^a (fO and dl-PGE^ methyl ester~T9) - Part I. 16 7 The Just synthesis of dl-PGFia (8) and dl-PGEj methy ester * Part II. 17 8 Upjohn modification of the Just synthesis ..... ...................... , 20 9' The Corey bicycloheptene route to natural prostaglandins - Part I.......... 22 10 The Corey bicycloheptene route to natural prostaglandins - Part II . 24 11 The Corey bicycloheptene route to natural prostaglandins - Part III. 26 12 The Miyano synthesis of dl-PGE. and dl-PGF. - Part I............1 ............. 28 — la 13 The Miyano synthesis of dl-PGE. and dl-PGF. - Part I I ........................ 29 — la 14 Conversion of terrein to one or more series of prostaglandins ................. 32 vii Figure Page 15 Laboratory glassware prepared for organolithium reactions ....................... 45 16 Synthetic routes to the THP-ether of 7-iodo-1-heptanol ( 4 1 ) ................... 87 17 Attempted formation of organolithium compounds from primary alkyl iodides .... 89 18 Synthetic routes to the THP-ether of 7-bromo- 1-heptanol ( 4 j > ) ......................90 19 Reactions between a 99:1 1ithium-sodium alloy and three primary alkylhalides. 92 20 Proposed reaction between a 99:1 lithium- sodium alloy and 2-bromo or chloro-1,1- diethoxyethane ................................. 94 21 Attempted formation
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