[2+2] cycloadditions of ketenes 1 - david a.· • most cycloadditions are highly stereoselective

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  • 1[2+2] Cycloadditions of Ketenes

    Leading References:

    Tidwell, T. T. Ketenes, John Wiley and Sons, 1995.

    Ghosez, L.; Marchand-Brynaert, J. Comprehensive Organic Synthesis , Vol. 5, Pergamon, 1991, p. 85-122.

    Patai, S. Chemistry of Ketenes, Allenes, and Related Compounds , John Wiley and Sons, 1980.

    Staudinger, H. Die Ketenes , Verlag Enke, 1912.

    An Evans Group Afternoon SeminarJake Janey

    October 8, 1999

  • 2A Brief History

    Cl

    OPh

    PhCl

    H

    O

    O O

    Cl

    OPh

    PhH

    Ph2C Cl

    O

    Zn

    Ph2C=C=O

    CH2=C=O

    Ph2C-C=O n-Pr3NHCln-Pr3N

    hot Pt wire

    Wanted to make:

    +

    Ketene proposedbut not isolated

    Staudinger, H. Chem. Ber. 1905, 38, 1735-1739.

    Wilsmore, N. T. M. J. Chem. Soc. 1907, 91, 1938-1941.

    Wedekind, E. Chem. Ber. 1901 , 34, 2070-2077.Wedekind, E. Liebigs Ann. Chem. 1901 , 323, 246-257.

  • 3

    C

    O

    R R'

    OR

    R'

    N

    OR

    R'

    O

    OR

    R'

    OR

    R'

    R'

    RO

    O

    OR

    R'

    R'

    R

    ZY

    XO

    RR'

    X

    Y

    Y

    X O

    R'

    R

    O

    R'

    or

    Alkene

    Imine

    R = -CH=CH2

    1,3-Dipole

    Carbonyl

    Summary of Ketene Cycloadditions

  • 4Ketene Preparation

    From Carboxylic Acid and Their Derivatives:

    Staudinger Reaction (very general)

    (CH3CO)2O

    RX

    O

    C OR

    R'

    R3N

    X = Cl, Ts, AcO, DCC, etc...

    H2C C O AcOH+

    RCH2CO2ArOH

    R

    O

    OArC O

    R-ArO

    __

    _

    O

    OO

    H

    O_

    H

    C OO

    PhBr

    O

    Ph2C C OPh Br

    Zn

    R'

    H2O_

    ZnBr2_

  • 5Ketene Preparation

    Other Methods :

    O

    O

    H2C C O550 C

    OR1

    R2R3

    CO

    R1

    R2

    R3h

    or

    RR'

    O

    N2

    hor

    C OR

    R'

    R O

    H

    -CH2CH2

    C OR

    H

    Wolff Rearrangement (variable yields)

  • 6

    C O

    R'

    R

    C O

    R'

    R

    C O

    R

    R'

    C O

    R

    R'

    -+

    -+

    or

    or

    LUMO(* of C=O)

    HOMO

    Ketenes are ambiphilic

    HOMO is orthogonal to the plane of the LUMO

    Ketene Frontier Orbitals

    ( of C=C)

  • 7Silyl Ketene Stability

    Hyperconjugation:

    C OR3Si

    HO

    _R3Si

    H

    +

    Brady, W. T.; Cheng, T. C. J. Org. Chem. 1977, 42, 732-4.

    -> d Donation to Si:

    C O

    R3Si

    H+

    _

    C OR3Si

    H

    +

    _

    Runge, W. Prog. Phys. Org. Chem. 1981, 13, 315-484.

    Si > Donation:C O

    R3Si

    H

    -OH O

    OH

    R3Si

    H

    _

    OH

    O

    R3SiFast

    H2O

    Slow

    H+

    FastC O

    R3Si

    H

    H+ OH

    O

    R3Si

    Gong, L.; McAllister, M. A.; Tidwell, T. T. J. Am. Chem. Soc. 1991, 113, 6021-8.

    ?

    ?

  • 8Dimerization

    H2C C O440 C O

    O Valuable synthetic intermediate Clemens, R. J. Chem. Rev. 1986, 86, 241-318.

    Wilsmore, N. T. M. J. Chem. Soc. 1907, 91, 1938-1941.

    In General:O

    C

    H R

    O

    C

    R' R

    2

    2

    O

    O

    O

    O

    R'

    R OR

    RHO

    R'

    R

    R'

    R

    +

    O

    C

    O

    RR

    R

    R

    _

    +O

    C

    O

    R R

    RR

    _+

    vs.

  • 9Catalyzed Dimerization

    Favors -lactones:

    O

    C

    R H

    ZnCl2O

    C

    R H

    ZnCl2_

    +RCH=C=O O

    C

    Cl2ZnO_

    RR

    +-ZnCl2

    O

    O

    R

    R

    Base catalyzed isomerization:

    O

    O

    R

    REt3N

    O

    O

    R

    R_

    C OR

    O

    R

    _

    [2+2]OR

    HO R

    O

    O

    R R

    OHRCH2

    RCH=C=O

  • 10Dimerization Mechanism

    C

    C

    C

    O

    O

    C

    H

    H

    H

    H

    C

    C

    C

    C

    OH

    H

    OH

    H

    1.726 2.673 1.613 2.532

    +

    +

    G = 32 kcal/mol G = 36 kcal/mol

    Seidl, E. T.; Schaeffer, H. F. J. Am. Chem. Soc. 1991, 113, 5195-5200.

    C O

    O

    CO

    _

    +

    O

    O

    O

    O

    +

    anti:syn5:1

    "A one step concerted process has never been proven for any one example."

    Hoffmann, H. M. R. Angew. Chem., Int. Ed. Eng. 1985, 607-608.

  • 11Ketene-Alkene [2+2]

    O

    C

    O

    C

    O

    O O

    +

    Fast

    A B1 : 2

    +

    +

    OC +

    C

    Me

    Me

    CHMe

    MeH

    O _

    +

    C

    Me

    Me

    CMeH

    MeH

    O _

    +

    B A

    Frey, H. M.; Isaacs, N. J. J. Chem Soc. B, 1970 , 830-832.

  • 12Regiochemistry

    C

    O

    RR

    O

    R

    R+

    _ O

    R

    R

    Major

    C

    O

    CNt-Bu

    O

    CN

    t-Bu

    +

    _O

    t-BuNC

    Exclusive

    Hassner, A.; Cory, R.; Sartoris, N. J. J. Am. Chem. Soc. 1976 , 98, 7698-7704.

    Diastereoselectivity:

    C

    O

    CNt-Bu

    +t-Bu

    NC

    O

    +

    _

    O

    CN

    t-Bu

    Gheorghiu, M. D.; Draghici, C.; Parvulescu, L. Tetrahedron , 1977, 33, 3295-3299.

  • 13Endo -Exo Selectivity

    Cl

    O+

    Et3N H

    R

    OR

    H

    O

    +

    endo exo

    R

    F

    Cl

    Me

    Ph

    Et

    i-Pr

    t-Bu

    endo

    89

    87

    76

    67

    64

    57

    10

    exo

    11

    13

    24

    33

    36

    43

    90

    Product ratios at equilibrium

    H7 H5

    RO

    H1

    1H NMR Conformation

    Hyperconjugative interaction between H 5 ,H7 and * of C=O

    Endo position is more sterically crowded

    Ghosez, L.; et. al. Helv. Chim. Acta, 1982, 65, 703-720.

    R

  • 14[2+2] Versus [4+2]

    Machiguchi, T.; Yamabe, S.; et. al. J. Am. Chem. Soc. 1999, 121, 4771-4786.

    O

    CO

    O

    +[4+2] (3,3)

  • 15Solvent Effects

    C OMe

    X+ Me

    X

    OX

    Me

    O

    +

    endo exo

    X

    Cl

    Cl

    Cl

    Cl

    Solvent

    hexane

    Et3N

    CHCl3CH3CN

    endo / exo

    4.3 / 1

    2.2 / 1

    1.6 / 1

    0.59 / 1

    X

    Br

    Br

    Br

    Solvent

    hexane

    Et3N

    CH3CN

    endo / exo

    0.71 / 1

    0.28 / 1

    0.14 / 1

    Solvent effects implicate a zwitterionic intermediate

    Brady, W. T.; Roe, R. Jr.; Hoff, E. F.; Parry, F. H., III, J. Am. Chem. Soc. 1970, 92, 146-148.

    C OPh

    Me+ Alkene exo / endo (Me)

    Alkene

    Cp

    EtOCH=CH 2Dihydropyran

    Cyclohexene

    Cyclooctene

    exo / endo (Me)

    >20

    2.3

    1.7

    2

    1

    Not a highly ordered transition state

    Brady, W. T.; Parry, F. H., III; Stockton, J. D. J. Org. Chem. 1971, 36, 1486-1489.

  • 16Woodward-Hoffmann Analysis

    C O

    C O

    (2s + 2a)

    2s + (2s + 2s)

    HOMO

    LUMO

    HOMO

    LUMO (* of C=O)

    Calculations seem to support this orbital analysis

    Or

    HOMO

  • 17Stepwise Versus Concerted

    Concerted Ketenes add stereoselectively to Z alkenes

    Z olefins are much more reactive than E

    H R

    H R

    C O

    R'

    HRH

    H R

    CR'

    HO

    OR'

    R R

    least hinderedbond rotation

    _

    +

    Stepwise Very large polar effects

    E olefins yield a mixture of cis and trans products

    Solvent effects observed, but it could merely be a

    ground state effect

    KIE seen for many reactions support stepwise

    mechanism

    Calculations (Wang and Houk) show a highly

    asynchronus transition state in the gas phase reaction

    All stereochemical outcomes can be rationalized

    assuming a stepwise mechanism

  • 18Transformations of Cyclobutanones

    Recent Progress in the Chemical Synthesis of Antibiotics ;Lukacs, G.; Ohno, M. Eds.; Springer-Verlag: Berlin, 1990. Lorreia, C. R. D. et. al. Tetrahedron Lett. 1993, 27-30.

    Brady, W. T. In The Chemistry of Ketenes, Allenes, and Related Compounds ; Patai, S. Ed.; Wiley: New York, 1980, part 1, ch. 8.

    O

    Cl

    Cl

    O

    O

    R

    CO2H

    R

    Cl

    Cl Cl

    O

    OH

    N N

    OO

    Cl

    Cl

    CO2Bn CO2Bn

    H

    H

    O

    O HO

    Ph3SnH

    or Zn

    AcONHEt3acetone/H2O

    Base

    1. Zn, AcOH

    2. mCPBA, NaHCO 3

    L-Selectride

    O

  • 19Application to Ginkgolide B

    O

    CO2H

    tBu

    MeOO

    tBu

    MeO

    C

    O

    O

    tBu

    MeO

    O

    HH

    O

    O

    O

    O

    O

    H

    Me OHO

    H

    tBu

    HHO

    HO

    1. (COCl)2, PhH

    2. n-Bu3N, PhCH3,

    (80%)

    Ginkgolide B Three stereocenters set via an intramolecular [2+2]

    Corey, E. J.; Kang, M. -C.; Desai, M. C.; Ghosh, A. K.; Houpis, I. N. J. Am. Chem. Soc. 1988, 110, 649.

  • 20

    O

    H H

    O

    C

    H H

    O+O

    H HH H

    +OO

    H HH

    H

    _

    _

    OO

    +

    38 kcal/mol

    32 kcal/mol

    Un-catalyzed [2+2] Mechanism

    path A

    path B

    Pons, J. -M.; et. al. J. Am. Chem. Soc. 1997, 119, 3333.

  • 21

    O

    H H

    O

    C

    H H

    O+O

    H HH H

    +OO

    H HH

    H

    OO

    +

    14 kca

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