Organocatalysis Enabled by N-Heterocyclic Carbenes Organocatalysis Enabled by N-Heterocyclic...

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Transcript of Organocatalysis Enabled by N-Heterocyclic Carbenes Organocatalysis Enabled by N-Heterocyclic...

  • Organocatalysis Enabled by N-Heterocyclic Carbenes

    Jiaming Li 2018/04/27

    Acyl Anions Y

    X N

    Homoenolates

    Acylazolium Azolium enolate Base Catalysis

  • Stability of N-heterocyclic Carbenes

    Bertrand, Chem. Rev. 2000, 100, 39

    a1

    b22s

    2px,y,z

    C

    N

    a1

    b2

    σ

    a1

    b2

    2s

    2px,y,z

    C

    N

    a1

    b2

    σ

    σ-electron-withdrawing substitutents σ-electron-donating substitutents

    • σ-electron withdrawing substitutents favor the singlet state over the triplet state • σ-electron withdrawing substitutents inductively stablize the σ non-bonding orbital by increasing its s character and leaving the pπ orbital unchanged • σ-electron donating substitutents induce a smaller σ-pπ gap, favoring a triplet state

    N

    N σ-electron withdrawal

    π-electron donation..

    ..

    ..

  • Stability of N-heterocyclic Carbenes

    Bertrand, Chem. Rev. 2000, 100, 39

    σ

    b1

    a2

    σ

    π-electron donation

    • The energy of pπ orbital is increased by the interaction with the symmetric combination of the substitutent lone pairs. • Combined effect is to increase the σ−pπ gap and stablize the singlet-state carbene over the more reactive triplet-state carbene.

    N

    N σ-electron withdrawal

    π-electron donation..

    .. ..

    2N pz

    C

  • Overview

    Acyl Anions

    R

    OH

    N

    N R

    R

    O

    R

    Y X N

    OH

    N

    N R

    R

    O

    Homoenolates

    R R

    • Benzoin condensation • Stetter reaction • Hydroacylation

    • Annulation • Cyclopentene synthesis

    O

    N

    N R

    R

    Acylazolium Azolium enolate

    • Claisen rearrangement • Cycloaddition

    Base Catalysis• Transesterification • Michael addition

    R2

    O

    N

    N R1

    R N

    N R

    R

    H R

  • Benzoin condensation

    Ph

    O

    H

    Ph

    O

    H

    Ph

    O Ph

    OH

    Ph

    O

    H

    NaCN

    • First reported benzoin condensation (Wohler, Liebig, 1832)

    Ph

    O Ph

    OH

    CN–

    Ph

    HO H

    N

    OH

    Ph N

    OH

    H2O

    Ph

    HO CNHO Ph

    OH

  • • Ugai discovered thiazolium salts could catalyze benzoin condensation (1943)

    Ph H

    O

    S N

    HO Me

    N

    N Me

    NH2Cl

    NaOH, MeOH Ph

    Ph O

    OH

    • Co-enzyme thiamine diphosphate is responsible for the generation of acyl anion

    S N

    O Me

    N

    N Me

    NH2

    P O

    O

    P HO

    O

    O O

    thiamine diphosphate (TDP)R O

    O

    O R

    O + CO2

    • Pyruvate decarboxylase • Pyruvate oxidase • Pyruvate dehydrogenase • Transketolase

    Ugai, T.; Tanaka, R.; Dokawa, T. J. Pharm. Soc. Jpn. 1943, 63, 296.

    Benzoin condensation

  • Proposed Mechanism by Breslow

    Breslow, R. J. Am. Chem. Soc.. 1958, 80, 3719

    N

    S

    R1R2

    R3 H

    – H+ N

    S

    R1R2

    R3

    N

    S

    R1R2

    R3

    N

    S

    R1R2

    R3

    N

    S

    R1R2

    R3 Ph

    O

    H

    Ph

    O

    N

    S

    R1R2

    R3 Ph

    OH

    Breslow intermediate

    Ph

    O

    H

    N

    S

    R1R2

    R3

    OH

    Ph O Ph

    Ph

    O Ph

    OH

  • Enantioselective Benzoin Condensation

    • First asymmetric benzoin condensation catalyzed by chiral thiazolium salts (Sheehan, 1966)

    Ph H

    O

    S N

    Me

    Br

    Et3N (10 mol%) MeOH

    Ph Ph

    O

    OH

    Sheehan, J. C.; Hunneman, D. H. J. Am. Chem. Soc. 1966, 88, 3666

    O

    Ph O

    (10 mol%)

    *

    9% yield, 22% ee

  • Enantioselective Benzoin Condensation

    • Improvement in the enantioselectivity of benzoin condensation

    Ph H

    O Ph

    Ph O

    OH

    S N

    Me

    Br

    cat. NHC

    Me 6% yield, 52% ee Sheehan, 1974

    N N N Ph

    ClO4 66% yield, 75% ee Enders, 1996

    O

    O

    Ph

    Me Me

    S N

    TfO 50% yield, 21% ee Leeper, 1997

    OTBS

    N N N

    Cl

    45% yield, 80% ee Leeper, 1998

    O

    Ph Ph

  • Enantioselective Benzoin Condensation

    • Improvement in the enantioselectivity of benzoin condensation

    Ph H

    O Ph

    Ph O

    OH

    S N

    Me

    Br

    cat. NHC

    Me 6% yield, 52% ee Sheehan, 1974

    N N N Ph

    ClO4 66% yield, 75% ee Enders, 1996

    O

    O

    Ph

    Me Me

    S N

    TfO 50% yield, 21% ee Leeper, 1997

    OTBS

    N N N

    Cl

    45% yield, 80% ee Leeper, 1998

    O

    Ph Ph

    N N N

    X

    R1 R2

    n

    Tunable sterics

    Tunable electronics • N-aryl-bicyclic triazolium structure

    N N N

    BF4 Ph

    O

    Me MeMe

    83% yield, 90% ee Enders, 2002

  • Model

    Enders, Chem. Rev. 2007, 107, 5606-5655

  • Enantioselective Benzoin Condensation

    • Highly efficient system for the enantioselective benzoin reaction (Connon, 2009)

    Ar H

    O Ar

    Ar O

    OH

    N N N

    BF4 C6F5Ph

    OHPh

    4-8 mol% NHC 4-8 mol% Rb2CO3 THF, 20 h

    17 - 100%

    Ph Ph

    O

    OH

    O

    OH MeO

    OMe O

    OH Cl

    Cl

    O

    OH

    O

    OH OO

    Cl

    Cl

    90% yield, >99% ee

    91% yield, 92% ee

    92% yield, 90% ee

    17% yield, 43% ee

    26% yield, 97% ee

    Connon, S. J. J. Org. Chem. 2009, 74, 9214

  • Aldehyde-Ketone Cross-Benzoin Reaction

    • Synthesis of Bicyclic Tertiary Alcohols N

    N N

    Cl Mes

    30 mol% cat. 4-8 mol% Cs2CO3 CH2Cl2, 40 ºC, 24 h

    25 - 90%

    67% yield, >99% ee

    37% yield, 94% ee

    43% yield, 95% ee

    50% yield, 78% ee

    47% yield, 86% ee

    Sakai, Org. Lett. 2009, 11, 4866-4869

    O O

    O

    R H

    O O R

    OOH

    O

    O

    Me O

    O O

    Me

    OHOH OH

    O

    O

    Me

    OH

    O

    32% yield, 26% ee

    O Me

    OH O

    O Me

    OOH

  • Aldehyde-Imine Cross-Benzoin Reaction

    • Cross Aza-Benzoin Reaction with N-Boc Imines N

    N N

    BF4

    20 mol% cat. CsOAc (1 equiv) CH2Cl2, 4 Å MS, -20 ºC

    33 - 93%

    83% yield, 96% ee

    89% yield, 96% ee

    86% yield, 84% ee

    71% yield, 92% ee

    84% yield, 96% ee

    Rovis, Angew. Chem., Int. Ed. 2012, 51, 5904-5906

    O

    R H

    O

    33% yield, 98% ee

    + N

    Ar H

    Boc

    R NHBoc

    O

    Ar Cl

    Cl

    Et NHBoc

    Cl

    O

    Et NHBoc O

    Et NHBoc O

    OMe

    Me NHBoc

    Ph

    O

    NHBoc

    Ph

    O

    Ph NHBoc

    Ph

    O

    Me

    Me

  • Acyl Anion Equivalent

    Breslow intermediate

    Ph H

    O

    Ph H

    NS

    R2R3

    R1

    Ph H

    O

    Ph

    O Ph

    OH

    benzoin condensation

    Ph

    O

  • Acyl Anion Equivalent

    EWG R

    Breslow intermediate

    Ph H

    O

    Ph H

    NS

    R2R3

    R1

    Ph H

    O

    Ph

    O Ph

    OH

    Ph

    O

    EWG

    EWG = COR, CO2R, CN SO2R, PO(OR)2

    benzoin condensation

    Stetter reaction

    R

    Ph

    O

  • Seminal Works of Stetter Reaction

    • First general intramolecular Stetter reaction catalyzed by NHC (Ciganek, 1995)

    • First asymmetric intramolecular Stetter reaction (Enders, 1995)

    Ciganek, Synthesis 1995, 1311-1314 Enders, Angew. Chem., Int. Ed. 1995, 34, 1021-1023

    H

    O

    O CO2Me

    20 mol% cat. Et3N (1 equiv)

    DMF, rt

    88%

    O

    O

    CO2Me

    H

    O

    O CO2Me

    20 mol% cat. K2CO3 (1 equiv)

    THF, rt

    73%, 60% ee

    O

    O

    CO2Me

    S N

    HO Me

    Bn

    Cl

    N N N Bn

    ClO4 O

    O Ph

    Me Me

  • Improved Asymmetric Intramolecular Stetter Reaction

    • Highly enantioselective Stetter reaction (Rovis, 2002)

    Rovis, J. Am. Chem. Soc. 2002, 124, 10298

    H

    O

    O CO2Et

    20 mol% cat. KHMDS (20 mol%)

    xylene

    94%, 94% ee

    O

    O

    CO2Et N N N

    BF4 O

    OMe

    N N N

    BF4

    Bn

    H

    O

    CO2Et

    20 mol% cat. KHMDS (20 mol%)

    xylene

    81%, 95% ee

    O CO2Et

  • Asymmetric Intermolecular S