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  • DESIGN, SYNTHESIS AND EVALUATION OF CHIRAL AUXILIARIES, LIGANDS AND

    CATALYSTS FOR ASYMMETRIC SYNTHESIS

    Arun A. Narine Bachelor of Science, Okanagan University College, 1 999

    THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF

    DOCTOR OF PHILOSOPHY

    In the Department

    of Chemistry

    O Arun A. Narine 2004

    SIMON FRASER UNIVERSITY

    August 2004

    All rights reserved. This work may not be reproduced in whole or in part, by photocopy

    or other means, without permission of the author.

  • Partial Copyright Licence

    The author, whose copyright is declared on the title page of this work, has

    granted to Simon Fraser University the right to lend this thesis, project or

    extended essay to users of the Simon Fraser University Library, and to

    make partial or single copies only for such users or in response to a

    request from the library of any other university, or other educational

    institution, on its own behalf or for one of its users.

    The author has further agreed that permission for multiple copying of this

    work for scholarly purposes may be granted by either the author or the

    Dean of Graduate Studies.

    It is understood that copying or publication of this work for financial gain

    shall not be allowed without the author's written permission.

    The original Partial Copyright Licence attesting to these terms, and signed

    by this author, may be found in the original bound copy of this work,

    retained in the Simon Fraser University Archive.

    Bennett Library Simon Fraser University

    Burnaby, BC, Canada

  • ABSTRACT

    A series of chiral acetals were prepared from 7-hydroxyindan- 1 -one and a variety

    of substituted chiral nonracemic C2-symmetric 1,2-ethanediols [R = Me, Ph, CH20Me,

    CH20Bn, CH20(l -Np), i-Pr] in an experimentally simple acid-catalyzed condensation

    reaction. These acetals were evaluated as chiral auxiliaries for use in asymmetric

    synthesis. Saturated and a,gunsaturated substrates were attached to the chiral acetals

    and alkylation, cyclopropanation, 1,3-dipolar cycloaddition as well as Diels-Alder

    reactions were performed. A high degree of stereochemical induction was observed in

    the diethylaluminum chloride-promoted Diels-Alder reaction of an acrylate derivative

    (R = i-Pr) with cyclopentadiene (9 1:9 diastereomeric ratio). This result demonstrated that

    these acetals could serve as effective chiral directors in asymmetric synthesis.

    A chiral bidentate 1,2-amino alcohol and several chiral tridentate Schiff bases

    were synthesized in one or two steps from the chiral auxiliary (R = Ph). These novel

    acetals were evaluated as chiral ligands in metal-catalyzed sulfoxidation, Diels-Alder and

    hetero Diels-Alder reactions as well as in alkylzinc addition reactions. The

    chromium(111)-complex of a tridentate Schiff base was found to catalyze the hetero Diels-

    Alder reaction of 1 -methoxy-3-trimethylsilyloxy- l,3-butadiene and benzaldehyde in good

    yield (88%) and enantioselectivity (74:26 enantiomeric ratio).

    Heterocyclic analogs of the chiral acetals were also prepared for evaluation as

    chiral catalysts in a variety of asymmetric transformations. Chiral pyridine and NJV-

    pyrrolidinopyridine-derived acetals were synthesized in three and twelve steps,

    respectively. These chiral pyridine and substituted pyridine derivatives were evaluated as

    chiral catalysts in the kinetic resolution of a racemic secondary alcohol under a variety of

    reaction conditions. These structures were found to be ineffective catalysts in these

    asymmetric processes. The two chiral substituted pyridine derivatives (R = Me, Ph) were

  • examined in several other catalytic asymmetric reactions. A modest level of asymmetric

    induction was observed in the dihydroxylation reaction of (E)-stilbene involving catalytic

    quantities of both osmium tetroxide and the chiral substituted pyridine

    (R = Ph , 54:46 enantiomeric ratio).

    In a related study, a series of chiral tetrahydroquinolines were synthesized by

    experimentally simple acid-catalyzed three-component imino Diels-Alder reactions of

    cyclopentadiene with substituted aldehydes and anilines. The racemic

    tetrahydroquinolines were resolved and the absolute stereochemical configurations were

    determined by X-ray crystallography. The chiral nonracemic tetrahydroquinolines were

    evaluated as secondary amine catalysts in the iminium ion-promoted Diels-Alder reaction

    of cinnamaldehyde and cyclopentadiene and good levels of stereochemical induction

    were observed (79:2 1 enantiomeric ratio).

  • DEDICATION

    To my parents, Lois and Swaresh, and my brothers, Sacha and Anil.

  • ACKNOWLEDGEMENTS

    1 would like to thank my mentor and friend, Pete Wilson.

    He has taught me many things about chemistry.. . and much more.

    1 must give him credit for both getting me excited and intrigued by the world of

    organic chemistry.

    I am deeply indebted to my past and present colleagues; Jay, Hongjuan, Mike,

    Peggy and Jeremy and Darren, for their friendship and insightful discussions.

    1 would also like to thank my supervisory committee members, Andrew Bennet

    and Dipankar Sen for much help along the way.. . and for reading my thesis!

    Without Marcy and Alan Tracey, my work would have ground to a halt. Their

    NMR expertise was essential.

    1 thank Mickey Yang and Greg Owen for elemental and mass spectral services.

    As well, several faculty members of the chemistry department, particularly, Erika

    Plettner, were kind enough to allow me the use their equipment for my research.

    As well, I thank SFU for the research fellowships that they have provided and the

    Department of Chemistry for generously providing conference funds.

    Last but not least, 1 am indebted to, particularly, Neil Draper, as well as Daniel

    Leznoff, Ray Batchelor and Fred Einstein for lending their expertise to both acquiring

    and solving X-ray crystal structures of several of my compounds.

  • TABLE OF CONTENTS

    APPROVAL ..................................................................................................................... -11

    ABSTRACT ............................................................................................................... 111

    DEDICATION ................................................................................................................... V

    ACKNOWLEDGEMENTS ........................................................................................ VI

    TABLE OF CONTENTS .............................................................................................. VII

    LIST OF SCHEMES .................................................................................................... XI11

    LIST OF FIGURES ..................................................................................................... XVII LIST OF TABLES ......................................................................................................... XX

    LIST OF ABBREVIATIONS .................................................................................... XXII

    CHAPTER 1: INTRODUCTION DESIGN, SYNTHESIS AND E VAL UA TION OF CHIRAL A UXILIA RIES, LIGANDS AND CA TAL YSTS FOR .ASYMMETRIC SYNTHESIS ......................... 1 1.1 General Overview ........................................................................... I 1.2 Asymmetric Synthesis ........................................................................ I 1.3 Strategies for Asymmetric Induction: Substrate, Auxiliary

    and Reagent Control ........................................................................ 3 .................... 1.4 C2-Symmetry in Chiral Auxiliary and Reagent Design 1 1

    1.4.1 Chiral C2-Symmetric 1,2-Diols .................................................................... 1 1 1.5 Chiral Cyclic Acetals in Asymmetric Synthesis .............................. 13 1.6 Proposed Studies: Indan-1-one Derived Cyclic Acetals for

    Use as Chiral Auxiliaries, Ligands and Catalysts in Asymmetric Synthesis ...................................................................... 14

    1.7 Proposed Studies: Chiral Tetrahydroquinolines as Secondary Amine Catalysts ............................................................. 16

    1.8 Thesis Overview .............................................................................. 16

    CHAPTER 2: RESULTS AND DISCUSSION THE SYNTHESIS AND E VALUA TlON OF 7-HYDROXYINDAN-I -0NE- DERIVED CYCLIC ACETALS FOR USE AS CHIRAL AUXILIARIES IN

    ....................................................................................... ASYMMETRIC SYNTHESIS 1 8 2.1 Introduction ................................................................................................ 18

    2.2 Synthesis of 7-Hydroxyindan-1-one (46) .............................................. 19

    vii

  • ............................................................... Chiral C2-Symmetric 1. 2.Diols 20 Synthesis of 7-Hydroxyindan-1-one-Derived Chiral

    ................................................................................................... Auxil