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Information to Users INFORMATION TO USERS This manuscript has been reproduced from the microfilm master UMI films the text directly from the original or copy submitted. Thus, some thesis and dissertation copies are in typewriter 6 ce, while others may be from any type of computer printer. The quality of this reproduction is dependent upon the quality of the copy submitted. Broken or indistinct print, colored or poor quality illustrations and photographs, print bleedthrough, substandard margins, and improper alignment can adversely afreet reproduction. 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 copyright material had to be removed, a note will indicate the deletion. Oversize materials (e.g., maps, drawings, charts) are reproduced by sectioning the original, beginning at the upper left-hand comer and continuing from left to right in equal sections with small overlaps. Each original is also photographed in one exposure and is included in reduced form at the back of the book. Photographs included in the original manuscript have been reproduced xerographically in this copy. Ifigher quality 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. UMI A Bell & Howell Infoimation Compaiqr 300 North Zedb Road, Ann Aibor Ml 48106-1346 USA 313/761-4700 800/521-0600 NOTE TO USERS The original manuscript received by UMI contains slanted print. All efforts were made to acquire the highest quality manuscript from the author or school. Microfilmed as received. This reproduction is the best copy available UMI INTRAMOLECULAR CYCLIZATION REACTIONS OF AZIRIDINES WITH ALLYLSDLANES. APPLICATION TO TOTAL SYNTHESIS OF (-)- YOHIMBANE AND ENT-ALLOYOHIMBANE. DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Punit P. Seth, B.S (Pharmacy). ***** The Ohio State University 1999 Dissertation Committee: Approved by Professor Stephen C. Bergmeier, Advisor Professor Robert W. Curley Professor Nigel D. Priestley Advisor Professor Larry W. Robertson College of Pharmacy UMX Nimber: 9919911 UMI Microform 9919911 Copyright 1999, by UMI Company. All rights reserved. This microform edition is protected against unauthorized copying under Title 17, United States Code. UMI 300 North Zeeb Road Ann Arbor, MI 48103 ABSTRACT Two novel reactions for asymmetric synthesis of nitrogen containing heterocycles were studied. More specifically, two modes of intramolecular cyclization between aziridine and allylsilanes were developed. In one mode, treatment of aziridine-allylsilanes with greater than a stoichiometric amount of BF 3*OEt 2 provided aminomethyl substituted carbocycles as the exclusive products (Sakurai reaction). The stereoselectivity of the reaction was found to be dependent on the length of the tether between the aziridine and the allylsilane. The synthetic utility of the intramolecular cyclization reaction was demonstrated by utilizing this reaction as a key step in the synthesis of (-)-yohimbane. In the second mode, treatment of aziridine-allylsilanes with a catalytic amount of BF3*OEt 2 provided bicyclic pyrrolidines as the major products (3+2 annulation reaction). Once again the stereoselectivity was dependent on the length of the tether between the aziridine and the allylsilane. The nature of the silyl group was found to have a profound effect in improving the rate of 3+2 aimulation over that of the Sakurai reaction. The synthetic utility of the 3+2 aimulation was explored by using this reaction for the synthesis of potential ligands for nACh receptors. During the course of this work novel methods for the synthesis and deprotection of enantiopure iV-tosylaziridines were also developed. u Dedicated to my family ui ACKNOWLEDGMENTS I wish to first thank my advisor. Dr. Stephen Bergmeier for his help and guidance. His constant support and encouragement are truly appreciated. I would like to thank Dr. Priestley for all his help over the past five years. I would also like to thank my colleagues and firiends Abhi, Dionne, Susan, Kristjan, Dave, Manesh and Jignesh for their fiiendship. A big thanks to Jim Mobley for his help with the HPLC, to Dr. Brueggemeier for letting me use their machine, to Dr. Doskoteh for his help with nOe experiments and to Kathy Brooks for all her help. I also wish to thank my mom, dad, my sisters Charu and ShaUee and other members of my family for their support and encouragement Finally, a big thanks to Aarti for being such a great and special fiiend. IV VITA May 30, 1972 ...................................................... Bom - Bombay, India 1993....................................................................B.S. Pharmacy, Bombay University 1993 - present .....................................................Graduate Teaching Assistant, The Ohio State University PUBLICATIONS Research Publications 1. Bergmeier, S.C.; Seth, P.P. Tetrahedron Lett., 1995, 36, 3793. 2. Bergmeier, S.C.; Seth, P.P. J. Org. Chem., 1997, 52, 2671. FIELDS OF STUDY Major Field: Pharmacy TABLE OF CONTENTS Page Abstract ...........................................................................................................................ii Dedication ......................................................................................................................iii Acknowledgments ......................................................................................................... iv Vita...................................................................................................................................V Table of contents ........................................................................................................... vi List of Tables ..................................................................................................................x List of Figures .............................................................................................................. xii List of Schemes ........................................................................................................... xiii Chapters: I. REACTIONS OF AZIRIDINES WITH ALLYLSILANES...................................1 LI Introduction ....................................................................................................I 1.2 Reactions of Allylsilanes .............................................................................3 1.2.1 Sakurai Reaction of AUylsUanes ......................................................... 3 1.2.1.1 Stereochemical control in allylsilane reactions .....................5 1.2.1.2 Reactions of allylsilanes with imines .................................... 8 1.2.1.3 Reaction of allylsilanes with a,P-unsaturated systems ........ 9 1.2 .1.4 Reactions of allylsilanes with epoxides and aziridines 10 1.2.2 3+2 and 2+2 Aimulation Reactions of Allylsilanes..........................13 1.2.2.1 Mechanistic Rationale .......................................................... 15 1.2.2.2 3+2 Annulation of allylsilanes with aldehydes ................... 16 1.2.2.3 Intramolecular 3+2 annulation of allylsilanes ..................... 17 1.2.2.4 Effect of Silicon in Annulation Reaction .............................18 vi 1.3 Reactions of Aziridines ............................................................................... 20 1.3.1 Nucleophiiic Ring Opening Reactions of Activated Aziridines ..... 2 1 1.3.1.1 Ring opening reactions of Af-sulfonyl aziridines with carbon nucleophiles ............................................................... 21 1.3.1.2 Reactions of iV-acyl aziridines with carbon nucleophiles... 22 1.3.1.3 Reactions of ^-phosphinyl substituted aziridines ................23 1.3.1.4 Reactions of activated aziridines with heteroatom nucleophiles ...........................................................................24 1.3.2 Ring Opening Reactions of Activated and Unactivated Aziridines in the presence of Lewis acids ........................................ 25 1.3.2.1 Reactions with carbon nucleophiles ...................................... 25 1.3.2.2 Reactions with heteroatom nucleophiles ...............................26 1.3.2.3 Reactions of N-acyl aziridines in the presence of azaphilic and oxophilic Lewis acids .....................................................27 1.4 Intramolecular Aziridine-Allylsilane Cyclization Reactions .................... 28 1.4.1 Application of the Sakurai reaction of aziridine-allylsilanes for Rauwolfia alkaloid synthesis ............................................................ 28 1.4.2 Synthetic applications of 3+2 annulation reactions of aziridine- allylsilanes .......................................................................................... 30 1.5 Summary......................................................................................................32 2. SYNTHESIS AND REACTIVITY OF AZIRIDINE-ALLYLSILANES...........33 2.1 Introduction ................................................................................................. 33 2.2 Initial synthesis of aziridine-allylsilanes ....................................................34 2.3 First generation synthesis of aziridine-allylsilanes via metal nitrenoids . 35 2.4 Regiochemistry in aziridine-allylsilane cyclizations ................................38 2.5 Aziridine-allylsilane cyclizations ..............................................................
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