Studies towards Developing Diastereoselective SN ?· Studies towards Developing Diastereoselective S…

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  • Studies towards Developing Diastereoselective SN1 Reactions of -Keto Carbocations

    by

    Joshua A. Dubland

    A thesis submitted in conformity with the requirements for the degree of Master of Science Graduate Department of Chemistry

    University of Toronto

    Copyright by Joshua A. Dubland (2010)

  • ii

    Studies towards Developing Diastereoselective SN1 Reactions of

    -Keto Carbocations

    Joshua A. Dubland

    Master of Science

    Graduate Department of Chemistry University of Toronto

    2010

    Abstract

    Although -keto carbocations have been demonstrated to be viable intermediates in solvolysis

    reactions, their applications in synthesis are scarce. These species can be considered to be

    equivalent to reversed polarity enolates and, as such, could be useful for the asymmetric

    formation of carbon-carbon and carbon-heteroatom bonds. In principle, facial selectivity in

    additions to -keto carbocations may be induced using easily removed ester, amide, or imide

    chiral auxiliaries. Efforts to achieve such diastereoselective SN1 reactions of -keto carbocations

    are described herein.

  • iii

    Acknowledgments

    First of all I would very much like to thank Prof. Mark Taylor for the opportunity to work in his

    research group, and for all the encouragement and assistance over the course of my studies. The

    last year and a half has been an enjoyable and excellent learning experience. I would also like to

    thank Prof. Andrei Yudin for taking the time to read my thesis. I would like to express my

    gratitude to the University of Toronto, Department of Chemistry for the chance to conduct

    research using state-of-the-art facilities.

    I would also like to thank all the members of the Taylor research group for being exceptional

    people to work in the lab with and for all the help with research problems. Our time outside of

    the lab during group events was also fun and enjoyable.

    I am grateful to my parents and sister Elysia for always being there for me and for encouraging

    me in my endeavors. Finally, I owe my greatest thanks to my fiance Stephanie for all the

    support over the course of my masters studies, my thesis is dedicated to you.

  • iv

    Table of Contents

    Acknowledgments .......................................................................................................................... iii

    Table of Contents ........................................................................................................................... iv

    List of Abbreviations ..................................................................................................................... vi

    List of Tables ................................................................................................................................. ix

    List of Figures ................................................................................................................................. x

    List of Schemes .............................................................................................................................. xi

    1. Introduction ................................................................................................................................ 1

    1.1 Asymmetric synthesis ......................................................................................................... 1

    1.2 Chiral auxiliaries ................................................................................................................. 2

    1.3 SN1 reactions ....................................................................................................................... 9

    1.4 -Keto carbocations .......................................................................................................... 12

    1.5 Research objectives ........................................................................................................... 19

    2. Results and discussion .............................................................................................................. 21

    2.1 Ester substrates .................................................................................................................. 22

    2.2 Amide substrates ............................................................................................................... 46

    2.3 Imide substrates ................................................................................................................ 55

    3. Summary and conclusion ......................................................................................................... 65

    4. Experimental section ................................................................................................................ 68

    4.1 -Keto ester, amide, and imide substrates ........................................................................ 70

  • v

    4.2 -Hydroxy amides and esters ............................................................................................ 74

    4.3 -Tosyloxy & -trifluoroacetoxy esters and amides ........................................................ 77

    4.4 Brnsted acid and Lewis acid-mediated nucleophilic substitutions ................................. 82

    4.5 Lewis acid-mediated oxazole formation ........................................................................... 89

    4.6 -Chloro imides ................................................................................................................ 90

    4.7 -Tosyloxy imides ............................................................................................................ 93

    4.8 -Bromo esters, amides, and imides ................................................................................. 95

    4.9 Silver-mediated nucleophilic substitutions ..................................................................... 102

    References ................................................................................................................................... 107

  • vi

    List of Abbreviations

    AgBF4 silver tetrafluoroborate

    Ag2CO3 silver carbonate

    AgMs silver methanesulfonate

    AgOAc silver acetate

    AgOTf silver trifluoromethanesulfonate

    AgOTs silver p-toluenesulfonate

    AgPF6 silver hexafluorophosphate

    AlCl3 aluminum trichloride

    Ar aryl

    CDCl3 deuterated chloroform

    DCE 1,2-dichloroethane

    DCM dichloromethane

    DIC N,N-diisopropylcarbodiimide

    DMAP 4-N,N-(dimethylamino)pyridine

    DMF N,N-dimethylformamide

    DMSO dimethyl sulfoxide

    d.r. diastereomeric ratio

    ee enantiomeric excess

    EI electron impact

  • vii

    equiv. equivalents

    ESI electrospray ionization

    Et3N triethylamine

    EtOAc ethyl acetate

    FID flame ionization detector

    FT Fourier transform

    g gram

    GC gas chromatography

    HPLC high-performance liquid chromatography

    HRMS high-resolution mass spectrometry

    Hz hertz

    IR infrared

    J coupling constant

    LDA lithium diisopropylamine

    M molarity

    MgSO4 magnesium sulfate

    MHz megahertz

    chemical shift in parts per million

    m/z mass-to-charge ratio

    NaHCO3 sodium bicarbonate

  • viii

    Na2SO4 sodium sulfate

    NaHSO4 sodium bisulfate

    NaS2O3 sodium thiosulfate

    NBS N-bromosuccinimide

    NH4Cl ammonium chloride

    NMR nuclear magnetic resonance

    mmol millimole

    mL milliliter

    L microliter

    MS mass spectrometry

    ppm parts per million

    r.t. room temperature

    THF tetrahydrofuran

    TLC thin layer chromatography

    TMS tetramethylsilane

    TMSOTf trimethylsilyl trifluoromethanesulfonate

    TOF time of flight

    Tr trifluoroethanesulfonyl

    Ts or tosyl para-toluenesulfonyl

    UV ultraviolet

  • ix

    List of Tables

    Table 2.1: Investigation of Lewis acid-mediated nucleophilic substition reactions of -tosyloxy

    esters 39 and rac-40a .................................................................................................................... 28

    Table 2.2: Brnsted acid-catalyzed nucleophilic substitution reactions of compound 41a using

    phthalimide as a leaving group ..................................................................................................... 31

    Table 2.3: Initial solvent screening for silver trifluoromethanesulfonate-mediated nucleophilic

    substitution reactions of -bromo ester 47a using N-methylindole .............................................. 37

    Table 2.4: Silver salt screening for nucleophilic substitution reactions of -bromo ester 47a

    using N-methylindole .................................................................................................................... 39

    Table 2.5: Analysis of Lewis acid, Brnsted base, and dynamic kinetic resolution conditions on

    nucleophilic substitution reactions of -bromo ester 47a using N-methylindole ......................... 41

    Table 2.6: Analysis of silver-mediated nucleophilic substitution reactions of -bromo ester 47b

    containing a bulkier 2-(1-naphthalenyl) cyclohexanol auxiliary using N-methylindole .............. 42

    Table 2.7: Analysis of silver-mediated nucleophilic substitution reactions of -bromo esters 47a

    and 47b utilizing an axially chiral phosphate counterion 49 ........................................................ 44

    Table 2.8: Attempted nucleophilic substitution reactions of -trifluoroacetoxy amide 55 ......... 51

    Table 2.9: Investigation of silver-mediated nucleophilic substitution reactions of -bromo amide

    59 using N-methylindole and 1,3,5-trimethoxybenzene ............................................................... 54

    Table 2.10: Observed bromide displacement by chloride in the synthesis of -halo imides 62a

    and 62b using oxalyl chloride ....................................................................................................... 58

    Table 2.11: Silver trifluoromethanesulfonate-mediated nucleophilic substitution reactions of -

    bromo imide 65b ........................................................................................................................... 64

  • x

    List of Figures

    Figure 1.1: Classes of asymmetric synthesis ................................................................................. 1

    Figure 1.2: Represenative chiral auxiliaries employed in asymmetric synthesis .......................... 3

    Figure 1.3: Stabilization of -keto carbocation through -conjugation and n-participation ....... 12

    Figure 1.4: Investigation of -keto carbocation stability using solvolysis rates and the -

    deuterium isotope effect ................................................................................................................ 15

    Figure 1.5: Solvolysis rate studies of tertiary and secondary benzylic -keto carbocations ....... 16

    Figure 1.6: Evidence for the unimportance of -conjugative stabilization in tertiary -keto

    carbocations .................................................................................................................................. 18

    Figure 2.1: Silver-assisted n-participation ................................................................................... 34

  • xi

    List of Schemes

    Scheme 1.1: Asymmetric alkylations and DielsAlder reactions using a camphor-derived chiral

    auxiliary .......................................................................................................................................... 4

    Scheme 1.2: Representative asymmetric alkylations, aldol, and Diels-Alder reactions using the

    Evans auxiliary ................................................................................................................................ 5

    Scheme 1.3: Formation of all possible stereoisomeric aldol products using the Evans auxiliary . 6

    Scheme 1.4: Asymmetric alkylation using an oxazolidinone auxiliary in the synthesis of vinigrol

    ......................................................................................................................................................... 7

    Scheme 1.5: Diastereoselective nucleophilic additions of allyltrimethylsilane to chiral -keto

    imides .............................................................................................................................................. 8

    Scheme 1.6: Diastereoselective radical allylations using Lewis acid-chelated chiral

    oxazolidinone auxiliaries ................................................................................................................ 8

    Scheme 1.7: Acid-catalyzed nucleophilic additions of arenes to chiral -branched benzylic

    carbocations .................................................................................................................................. 10

    Scheme 1.8: Acid-catalyzed nucleophilic additions of arenes to chiral -functionalized benzylic

    carbocations .................................................................................................................................. 12

    Scheme 1.9: Indication of tertiary and benzylic -keto carbocation generation in the norbornyl

    system ........................................................................................................................................... 14

    Scheme 1.10: Evidence for no formation of -delocalized ions in the solvolysis of exo

    trifluoroacetate 19 ......................................................................................................................... 17

    Scheme 1.11: Analysis of secondary -keto carbocation formation using deuterium labeling

    studies ........................................................................................................................................... 18

    Scheme 1.12: n-Participation ....................................................................................................... 19

  • xii

    Scheme 2.1: Lewis acid, chiral Brnsted acid, and silver-mediated SN1 reactions of -keto

    carbocations .................................................................................................................................. 21

    Scheme 2.2: Synthesis of -hydroxy ester 34 and attempted tosylation ..................................... 22

    Scheme 2.3: Brnsted acid and Lewis acid-mediated nucleophilic substitution reactions of -

    hydroxy ester 34 ............................................................................................................................ 24

    Scheme 2.4: Synthesis of -hydroxy ester 38 .............................................................................. 25

    Scheme 2.5: Synthesis of -tosyloxy esters 39, rac-40a, and (S)-40b ........................................ 26

    Scheme 2.6: Phthalimide as a possible leaving group ................................................................. 29

    Scheme 2.7: Mechanistic study of nucleophilic substitution reactions of -tosyloxy esters rac-

    40a and (S)-40b using 4-methoxybenzene thiol ........................................................................... 33

    Scheme 2.8: Synthesis of -trifluoracetoxy ester 45 and attempted nucleophilic substitution

    reaction using 4-methoxybenzene thiol .....................

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