Asymmetric Diels Alder Reactions - SUMMER SESSION IV: ?· 2016-08-24 · Catalytic Asymmetric Diels-Alder…

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  • Asymmetric Diels Alder ReactionsChiral Auxiliaries

    (-)-8-Phenylmenthol

    H3C

    O

    H3CCH3

    O

    AlCl3H3C

    O

    H3CCH3

    O

    AlCl3

    s-transLewis-acidcomplex

    favorable !-stacking

    OBnfront-face approachof diene

    O OR*

    BnO

    97%de

    H3C

    OH

    H3CCH3

    O

    Cl

    (-)-8-phenylmenthol=R*

    LiAlH4

    auxiliary recovery

    JACS, 1975, 1610

  • Dimenthyl fumarate:

    R*O2C

    O

    O

    O

    Et2AlCl

    O

    CH3

    CH3

    H3C

    O

    O

    OR*

    R'O

    R'=

    CH3

    CH3

    H3C

    H3C

    CH3

    CO2R*

    Et2Al

    AlEt2

    99%deTL, 1986, 4507Tetrahedron, 1963, 2333

    Diene Lewis acid de%

    OTMS

    iBuAlCl

    Et2AlCl

    AlCl3

    Et2AlCl

    95

    95

    96

    94

  • N-acyl oxazolidinone auxiliaries

    ON

    OO

    R

    Et2AlCl

    COXc

    R

    tolerates !-substitutionon dienophile

    -100C

    ON

    OO

    R

    Et2AlCl

    COXc

    R

    -100CH3C Ph

    ON

    OO

    R

    Al

    EtEt

    +

    chelated s-cis formof dienophile

    front faceattack ofdiene

    ON

    OO

    R

    H3C Ph

    Al

    EtEt

    back faceattack ofdiene

    JACS, 1984, 4261JACS, 1988, 1238

    1

    2

    dienophile endo:exo isolated dr

    1, R=H >100:1 >99:1

    1, R=CH3 >100:1 >99:1

    1, R=Ph >100:1 >99:1

    2, R=H >100:1 100:1

  • ON

    OO

    R

    Ph

    Et2AlCl

    -100C

    H3C R

    COXc

    CH3 R

    COXc

    CH3

    R=H, dr=95:5

    R=CH3, dr=94:6

    R=H, dr=>100:1

    R=CH3, dr=95:1

    ON

    OO

    R

    Al

    EtEt

    !-stacking enhances stereoselectivity

    Asymmetric Intramolecular Diels-Alder

    Xc

    O

    n

    Me2AlCl

    -30C, 5h

    diene and dienophilein the same molecule

    H

    H

    OXc

    n

    H

    H

    OXc

    n

    +

    Endo I Endo II

    enantiomers

    Diene Scope:

    XC n Endo I : EndoII

    O N

    O

    Ph

    O N

    O

    C6H11

    1 95:5

    2 97:3

    1 3:97

    2 6:94

    TL, 1984, 4071

    ACIEE, 1987, 1184.

  • COXc

    Camphor-Derived N-enoyl Sultams: Oppolzer

    CH3H3C

    N

    S O

    O

    O

    CH3H3C

    N

    S O

    O

    O

    MLn

    dieneREtAlCl2

    R

    R endo:exo dr

    H 99.5:0.5 97.5:2.5

    CH3 96:4 99:1

    CH3

    H

    H

    s-cis conformer

    !-faceapproach

    Chelated ComplexHelv. Chim. Acta, 1989, 123.

    (1.5 eq.)

    Acyclic dienes:

    CH3H3C

    N

    S O

    O

    O

    R

    R

    O

    Xc

    R dr yield

    H 98.5:1.5 81

    CH3 97:3 64

    for unsubstituted N-acyloyl sultams

    Helv. Chim. Acta. 1984, 1397

    Intramolecular Diels-Alder Reactions:

    CH3H3C

    N

    S O

    O

    O

    s-cis form of dienophilefavored for amides:JACS, 1973, 6365.

    n

    EtAlCl2H

    H

    OXc

    n

    H

    H

    OXc

    n

    +

    Endo I Endo II

    n EndoI:EndoII yield1 >97.4:2.5 752 94:2.6 53

    TL, 1985, 5437

    EtAlCl21.5 eq.

  • Catalytic Asymmetric Diels-Alder ReactionsAn Early Example

    +

    H3C

    O

    H

    OAlCl2

    (15 mol%)toluene, -78C

    CHO

    CH3

    72% eeexo:endo = 98:2

    C2-symmetric Diazaaluminate Catalysis: Corey

    Al

    NN

    Ph Ph

    CH3

    SS

    F3CCF3

    O O OO

    J. Chem. Soc., Chem. Commun. 1979, 437.

    RO

    NR' O

    O

    +

    10-20 mol%

    CH2Cl2, -78C

    R'

    R

    O N O

    O

    JACS, 1989, 5493

    R R' endo:exo ee%

    H H >50:1 91

    H CH3 96:4 94

    CH2OBn H 95

    N

    N

    Al

    Tf

    Tf

    CH3

    O

    N

    O

    O

    Phenylblocks frontface

    non-chelated binding modes-trans dienophile conformer

    Proposed Transition-StateAssembly:

    JACS, 1992, 7938.

    a modified version of this catalyst expands the scope to maleimide dienophiles: JACS, 1994, 12089.

  • Oxazaborolidine Catalysis:

    +

    Br

    O

    H

    3 (5 mol%)

    CH2Cl2, -78C

    O

    H

    Br

    96:4 exo:endo, 92% eeO

    O

    B-n-BuNTs

    HN

    H

    3, tryptophan-derived

    +Br

    O

    H

    3 (5 mol%)

    CH2Cl2, -78C

    CHO

    Br

    92%ee!-substitution on aldehyde requiredfor high ee

    O

    O

    BN

    HN

    H

    SOO

    Ar

    O

    H

    Br

    H

    H

    exo-TS

    s-cis conformer isreactive species

    formyl C-H---Ohydrogen bond is proposedas an additional organizing element leading to excellentenantioselectivities : TL, 1997, 37.

    Attractive pi-stackinginteractions between indoleand dienophile organizethe T.S., resulting in reactionfrom the unblocked (back)face

    ACIEE, 1990, 256

    Lewis acids complex syn to the formyl proton:

    JACS, 1992, 8290

  • A modified oxazaborolidine catalyzes cycloadditions to furan:

    Br

    O

    H

    +O 4 (10 mol%)

    CH2Cl2, -78C

    O

    CHO

    Br

    92% ee

    O

    O

    B-n-BuNTs

    HN

    H

    H3C4

    Tetrahedron Letters, 1993, 3979

    CHO

    Br

    CH3

    CO2Et

    CH2

    O

    CO2H

    Br

    O

    Corey has demonstrated the utilityof the cycloaddition products:JACS, 1991, 8966.

  • Alkyl Dichloroboranes:

    + O

    OMe

    R

    n

    BCl2

    (10 mol%)

    CO2Me

    R

    nJACS, 1991, 7794

    R n ee%

    H 1 97

    CH3 1 93

    CO2Me 1 90

    H 2 86

    B

    O

    OCH3

    CH3

    ClCl

    s-trans crotonate conformationpi-stacking of crotonate carbonylwith aromatic ring

    complexation of Lewis acid antito ester C-O bond.

    the napthalene substituent forces thedienophile approach from the front face.

  • Titanium TADDOL: TiCl2O

    O

    O

    O

    Me

    Ph

    Ph

    PhPh

    Ph

    5

    +R2

    O

    N O

    O

    5, (10 mol%)R2

    O NO

    O

    R1

    R2

    O

    N O

    O

    +5, (10 mol%) R1 R2

    O

    N O

    O

    JACS, 1989, 5340Chem. Lett. 1995, 1129.

    R2 endo:exo ee%

    H 88

    CH3 87:13 94

    Ph 92:8 80

    R1 R2 ee%

    H H 93

    H CO2Me 91

    CH3 H >96

    CH3 CO2Me 94

    A number of transition state models have been proposed; the analysis is complicated by the number of coordinationpossibilities available in octahedral complexes

    Bull. Chem. Soc. Jpn. 1991, 387.

  • O

    N N

    O

    Cu

    H3C CH3

    2+

    9 2TfO-

    or

    10 2SbF6

    +R

    O

    N O

    O

    9, (5-10 mol%)R

    O NO

    O

    O

    N O

    O

    + 10, (1-5 mol%)X

    O

    N O

    O

    X

    O

    +

    O

    N O

    O

    10, (5 mol%)

    O

    O NO

    O

    6

    11

    12

    Diene X R endo:exo ee%

    6 H 98:2 >98

    6 CO2Et 94:6 95

    6 CH3 96:4 97

    6 Ph 91:9 96

    11 OAc 85:15 96

    11 SPh 98:2 98

    12 80:20 97

    Evans Bis(oxazoline) CopperComplexes

    ACIEE, 1995, 798note: catalyst 10 uniformly provides higher reativityand higher levels of asymmetric induction than 9.

    note:exo product

  • O

    N N

    O

    Cu

    H3C CH3 2+

    10 2SbF6

    The stereochemical results are consistent with the following model:

    O O

    NOR

    Si-face

    Square planar geometry about CuImide binds in a bidentate fashions-cis dienophile configurationdiene approaches from the back face; the front face is blocked by the t-Bu group

    note: acyclic dienes unsubstituted at the 1-position afforded lower enantioselectivities; these dienes are proposed to approach via an exo TS, and the exo TS is only selective in the case of 1-substit