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  • The Dissertation Committee for David Frederic Cauble, Jr. certifies that this is

    the approved version of the following dissertation:



    Michael Krische, Supervisor

    Eric Anslyn

    Stephen Martin

    Philip Magnus

    Christian Whitman


    David Frederic Cauble, Jr., B.S


    Dissertation Presented to the Faculty of the Graduate School of

    the University of Texas at Austin in Partial Fulfillment of the Requirements

    for the Degree of Doctor of Philosophy

    The University of Texas at Austin December 2004

  • UMI Number: 3150558

    3150558 2005

    UMI Microform Copyright

    All rights reserved. This microform edition is protected against unauthorized copying under Title 17, United States Code.

    ProQuest Information and Learning Company 300 North Zeeb Road

    P.O. Box 1346 Ann Arbor, MI 48106-1346

    by ProQuest Information and Learning Company.

  • Dedication

    To my parents, David and Alice Cauble, whose support and encouragement have made

    all the difference.

  • Acknowledgements

    I am grateful to my mentor, Professor Michael J. Krische, for his support and

    guidance and for providing a challenging environment within which to grow personally

    and intellectually. I am indebted also to the members of the Krische group, with whom I

    spent much time and from whom I learned a great deal. Finally, special thanks are due to

    those who helped proof-read this dissertation: Alice Cauble, Diane Lam, Wendy Mariner,

    Susan Garner and Pablo Mauleon.



    Publication No.

    David Frederic Cauble, Jr., Ph.D. The University of Texas at Austin, 2004

    Supervisor: Michael J. Krische Transition metal-catalyzed carbon-carbon bond-forming reactions are attractive

    methodological targets, as they enable the rapid build-up of molecular complexity.

    Herein is described research directed toward the development of highly practical,

    efficient and selective transition metal-catalyzed processes that facilitate the succinct,

    sequential formation of multiple chemical bonds: i. Catalysts derived from rhodium and

    copper are featured in tandem conjugate addition-electrophilic trapping reactions (tandem

    vicinal difunctionalization), leading to products of formal aldol, Dieckmann and Blaise

    cyclizations. In this context, the use of diastereotopic 1,3-dione electrophilic acceptors is

    examined. ii. Related rhodium catalysts are employed successfully in the catalytic

    reductive arylation of 1,3-cyclohexadiene. iii. The classical Gilman reagent

    (dimethyllithium cuprate-lithium iodide) is shown to catalyze the [2+2]cycloaddition of


  • bis(enone) substrates in high yield. Effective partitioning between the 1,4-addition and

    cycloaddition manifolds is showcased and discussed.

    Finally, a strategy for the enantioselective catalysis of photo-mediated reactions in

    solution is described, involving the use of chiral molecular receptors possessing

    appendant triplet sensitizing moieties. Energy transfer is selectively directed to bound

    substrate as a consequence of the distance dependence of triplet-triplet energy transfer.

    This effect, which is equivalent to a binding induced rate enhancement, enables

    substoichiometric chirality transfer from the receptor template to the substrate, as

    observed in the intramolecular enone-olefin photo[2+2]cycloaddition of a quinolone



  • Table of Contents

    List of Schemes xiv

    List of Tables xviii

    List of Figures xix

    Glossary xx

    Chapter I. Tandem Vicinal Difunctionalization of α,β-Unsaturated Carbonyl

    Compounds: Catalytic Tandem Conjugate Addition-Electrophilic Trapping


    Part 1. Recent Advances 1

    A. Introduction 1

    B. Reactions Proceeding via Copper Catalysis 4

    i. Addition of Grignard Pronucleophiles: The Kharasch Reaction 4

    a. Mechanistic Features 4

    b. Application to Lycopodine and Prostanoid Syntheses 5

    c. Tandem Conjugate Addition-Claisen Rearrangement 6

    d. Tandem Conjugate Addition-Intramolecular Alkylation 7

    ii. Addition of Organozirconium Pronucleophiles 7

    a. Organozirconium Pronucleophiles via Hydrozirconation of Alkynes 7

    b. Zirconocyclopentene Pronucleophiles via Oxidative Cyclization 9

    c. Organozirconium Pronucleophiles via Hydrozirconation of Alkenes 10

    iii. Addition of Organozinc Pronucleophiles 13

    a. Mechanistic Features 13

    b. Zinc Homoenolate Pronucleophiles 15

    c. Organozincate Pronucleophiles 16

    d. Diorganozinc Pronucleophiles 18


  • C. Reactions Proceeding via Rhodium Catalysis 22

    i. Additions of Organoboronic Acid and Organoboronate Pronucleophiles 22

    a. Background and Mechanistic Features 22

    ii. Tandem Reactions Employing Organoborane Pronucleophiles 24

    iii. Tandem Reactions Employing Organotitanium and Organozinc 26

    D. Reactions Proceeding via Nickel Catalysis 27

    i. Additions of Organozinc Pronucleophiles: Background and Mechanistic Features 27

    ii. Tandem Reactions Employing Organozinc Pronucleophiles 28

    iii. Tandem Reactions Employing Aryl Iodide Pronucleophiles 29

    E. Conclusion 30

    Part 2: Graduate Research: Metal-Catalyzed Conjugate Addition-Electrophilic Trapping Reactions 32

    A. Background: Conjugate Reduction-Electrophilic Trapping Reactions Developed by the Krische Group 32

    i. Cobalt-Catalyzed Reductive Aldol and Reductive Michael Cyclizations 32

    ii. Cobalt-Catalyzed Intramolecular [2+2] Cycloaddition 33

    iii. Borane-Mediated Reductive Aldol Cyclizations 34

    iv. Hydrogenative Rhodium-Catalyzed Aldol Cyclizations 35

    B. Metal-Catalyzed Conjugate Addition-Aldol, Blaise, Dieckmann and Darzens Condensation Sequences 39

    i. Respective Contributions 39

    ii. Rhodium-Catalyzed Conjugate Addition-Aldol Cyclizations 39

    a. Mono-Enone Mono-Methyl Ketone Substrates 39

    b. Conjugate Addition-Aldol Cyclizations Using Symmetrical Dione Acceptors 41

    c. Application Towards the Synthesis of Steroidal Ring Systems 42

    d. Parallel Kinetic Resolution 43

    iii. Cu-Catalyzed Conjugate Addition-Aldol, Dieckmann 43

    and Blaise Cyclizations 43


  • iv. Higher-Order Tandem Reactions 47

    a. Latent Functionality and Chemoselectivity 47

    b. Cu-Catalyzed Conjugate Addition-Darzens Condensation 48

    c. Cu-Catalyzed Conjugate Addition-Aziridination 49

    Part 3. References 50

    Part 4. Experimental Section 57

    A. Synthetic Procedures 57

    i. General 57

    ii. Representative procedure for the preparation of I-2.7 – I-2.10 58

    iii. Representative procedure for the preparation of I-2.11 – I-2.14 58

    iv. Representative procedure for the preparation of I-2.1 – I-2.4 59

    v. Procedures for the preparation of I-2.19 – I-2.21 59

    vi. Procedures for the synthesis of substrates I-2.22 – I-2.24 59

    vii. Procedure for Yandem CA-Dieckmann cyclization of I-2.7 and I-2.9 61

    viii.Procedure for Tandem CA-Dieckmann cyclization of I-2.8 and I-2.10 61

    ix. Procedure for Tandem CA-Blaise cyclization of substrates I-2.11 – I-2.14 62

    x. Procedure for Cu-Catalyzed Aldol Cyclizations 62

    xi. Procedure for the Preparation of Product I-2.1e 63

    xii. Procedure for the Preparation of Products I-2.21, I-2.22 and I-2.25 63

    xiii.Procedure for the Preparation of Product I-2.24 64

    xiv.Procedure for the Preparation of Substrate I-2.6 64

    xv.General procedure for Rh-Catalyzed Aldol Cylizations 64

    B. Spectroscopic and Crystallographic Characterization Data 66


  • Chapter II. Rhodium-Catalyzed Additions to Conjugated Dienes: Reductive Arylation of 1,3-Cyclohexadiene Part 1. Introduction: Metal-Catalyzed Additions to Conjugated Dienes 119

    A. Reactions Involving Electrophilic π-Allyl Complexes 119

    i. Electrophilic π-Allyl Complexes Derived from Palladium(II) 119

    ii. Electrophilic π-Allyl Complexes Derived from Palladium(0) 120

    B. Reactions Involving Neutral π-Allyl Complexes 120

    i. Mechanistic Features 120

    C. Reactions Involving Nucleophilic π-Allyl Complexes 121

    i. Tandem Hydrometallation-Aldehyde Additions 121

    ii. Carbocyclizations Involving Oxametallocycle Intermediates 122

    iii. Carboxylative Processes 123

    iv. Coupling of Dienes and Glyoxals Under Catalytic Hydrogenation Conditions 124

    Part 2. Rhodium-Catalyzed Reductive Arylation of 1,3-Cyclohexadiene 125

    A. Background and Objective 125

    B. Results and Discussion 127

    i. Initial Results and Mecha


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