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INFORMATION to USERS the Most Advanced Technology Has Been Used to Photo­ Graph and Reproduce This Manuscript from the Microfilm Master 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 World’sUMI Information since 1938 300 North Zeeb Road, Ann Arbor, Ml 48106-1346 USA Order Number 8824558 Part I. Studies toward a synthesis of gelsemine using free radical cyclization reactions. Part II. Asymmetric synthesis of /9-lactams Lee, Chih-Shone, Ph.D. The Ohio State University, 1988 UMI 300 N. Zeeb Rd. Ann Arbor, MI 48106 PART L STUDIES TOWARD A SYNTHESIS OF GELSEMINE USING FREE RADICAL CYCLIZATION REACTIONS PART H. ASYMMETRIC SYNTHESIS OF B-LACTAMS DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Chih-Shone Lee, M.S. ft**** The Ohio State University 1988 Dissertation Committee: Approved by Dr. David J. Hart Dr. Matthew S. Platz Advisor Dr. John S. Swenton Department of Chemistry For My Parents ACKNOWLEDGMENTS The author is deeply indebted to Professor David J. Hart for providing inspiration and guidance throughout the course of this work. His encouragement and excitement about chemistry have been inspirational. Additionally, the author wishes to thank Professor Yu-Shia Cheng in National Taiwan University for her initial enthusiasm in Organic Chemistry. For the numberous discussions and encouragement provided I would also like to thank past andpresent members of Hart's group, especially Dr. H.-C. Huang, Mr. J. Dener. Also I am grateful to Dr. C. Hoffman for 200 MHz NMR spectra, Mr. C. Engelman for 250 MHz NMR, Dr. C. Cottrell and Dr. B. Chenera for 500 MHz NMR, Mr. R. Weisenberger and Mr. David Chang for mass specta. Most of all, I wish to thank my wife, Vicki for her patience and support. VITA October 17,1954 ............................... Bom, Tainan, Taiwan, Republic of China 1978.................................................... B. S. National Tsing Hua University, Taiwan 1978-1980.......................................... M. S. National Taiwan University, Taiwan 1980-1982.......................................... ROTC service, Chinese Army 1982-198 3.......................................... Teaching Associate, NationalTaiwanUniversity 1983-198 4.......................................... Teaching Associate, The Ohio State University Columbus, Ohio 1984-198 8.......................................... Research Associate, The Ohio State University Columbus, Ohio PUBLICATIONS Hart, D.J.; Lee, C.-S; Pirkle, W.H.; Hyun, M.H.; Tsipouras, A.T. "Asymmetric Synthesis of fi-Lactams and the Carbapenem Antibiotic (+)-PS-5", /. Am. Chem. Soc. 1986,108,6054. Pirkle, W.H.; Tsipouras, A.T.; Hyun, M.H.; Hart,D.J.; Lee, C.-S. "Use of Chiral Stationary Phases for the Chromatographic Determination of Enantiomeric Purity and Absolute Configuration of some fi-Lactams", J. Chromatography 1986,358, 377. Choi, J.-K; Ha, D.-C; Hart, D.J.; Lee, C.-S.; Ramesh, S.; Wu, S. "a-Acylamino Radical Cyclizations: Application to the Synthesis of a Tetracyclic Substructure of Gelsemine", submitted for publication. Cheng, Y.-S.; Lee, C.-S. "Composition of Leaf Essential Oils fromTen Citrus Species", Pro. Natl. Sci. Counc. B. (ROC) 1981 5 (3), 278. Cheng, Y.-S,; Lee, C.-S.; Chou, C.-T; Chang, C.-C. "The Chemical Constituents of the Peel of Citrus tankan Hayata" J. Chin. Chem. Soc. (Taipei) 1985,32 (1), 85 (Eng). FIELD OF STUDY Major Field: Organic Chemistry iv TABLE OF CONTENTS DEDICATION..................................................................................................... ii ACKNOWLEDGMENTS................................................................................... iii VITA.................................................................................................................... iv LIST OF TABLES............................................................................................... vii LIST OF FIGURES............................................................................................. viii LIST OF SCHEMES........................................................................................... ix CHAPTER I STUDIES TOWARD A SYNTHESIS OF GELSEMINE USING RADICAL CYCLIZATION REACTIONS................................. 1 Introduction ..................................................................... 1 Approaches to the Synthesis of Gelsemine ...................... 2 Results and Discussion ....................... 9 Summary ......................................................................... 15 Experimental ................................................................... 17 References.: ..................................................................... 34 v CHAPTER H ASYMMETRIC SYNTHESIS OF B-LACTAMS 36 Introduciton ............................................... 36 Asymmetric Synthesis of Organic Compounds ................... 36 Asymmetric Synthesis of fi-lactams ..................................... 40 Mechanistic Aspects of the Ester-Imine Condensation Route to B-Lactams ............................................................. ^5 Results and Discussion .......................................................... 49 Preparation of Homochiral Esters and Condensations with Imines ................................................................ 49 Determination of Enantiomeric Excess Using Chromatographic Analysis......................................... 56 Determination of Absolute Configuration: Total Synthesis of (+)-PS-5 ................................................ 60 Enantioselective Synthesis of Other B-Lactams 62 Summary ................................................................................ 70 Experimental ....................................................... 72 References ............................................................................. 115 SUMMARY OF REFERENCES............................................................................... 119 vi LIST OF TABLES TABLES 1 Ireland Model of Lithium Enolate Formation ............................ 48 2 Preparation of Homochiral Esters .............................................. 51 3 6-Lactam Formation using Homochiral Ester 75a ..................... 52 4 Stereoselective Synthesis of 6-Lactams using Esters 75b-75d 53 5 Enantioselective Synthesis of 6-Lactams using Ester 86 .......... 55 6 6-Lactams derived from Silylimine 77 and Esters (75a and 86) 59 7 6-Lactams derived from Arylimines and Esters (75a, 86) Condensation...: ........................................................................ 59 8 6-Lactams deirved from Esters 75b, 75c, 75d and Imine 76.. 59 9 Selected [H NMR Chemical Shift Data of Diastereomers (llla-llld) .............................................................................. 66 vii LIST OF FIGURES FIGURES 1 Evaluation of Asymmetric Synthesis of 6-Lactams (87b and 88b) by Chromatography on Chiral Stationary Phase 91 ........ 58 2 Liquid Chromatographic Analysis of Diastereomer 115a and 115b.......................................................................................... 68 viii LIST OF SCHEMES SCHEMES I Fleming's Approach to Gelsemine ........................................ 2 II Stereocontrol in Oxindole Construction ................................ 2 HI Fleming Synthesis of the Tetracyclic Nucleus ...................... 3 IV Stork Approach to the Carbocyclic Portion of Gelsemine... 4 V Overman Synthesis of Gelsemine ......................................... 5 VI Conroy Biosynthesis Proposal .............................................. 5 VII Retrosynthetic Analysis for Gelsemine ................................. 6 VIE Attempted Cyclization of Unactivated Olefin ...................... 7 IX Cyclization of Unsaturated Ester 33 ....................................... 8 X Retrosynthetic Analysis for Compound 39 ............................ 9 XI Preparation of Imide 46 .......................................................... 10 XII Preparation of Carbinol Lactam 49 ....................................... 11 X m Alkylation of Lactam 50 ........................................................ 12 XTV Preparation and Reduction of 56 ............................................ 12 XV Preparation of C(7) Sidechain ............................................... 13 ix XVI Radical Cyclization of Sulfide 59 .......................................... 14 XVH Construction of C(20)-Vinyl Group ...................................... 15 XVm Conversion of Ethyl sorbate 43 to Tricyclic Lactam 39 ....... 16 XIX Enantioselective
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