[4+3] cycloadditions and their application in 4+3] cycloadditions and their application in synthesis...

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  • [4+3] Cycloadditions and Their Application in Synthesis

    X

    + Xconcerted or

    stepwise

    An Evans Group Friday Afternoon Seminar

    February 4th, 2004

    Jonathan F. Lawrence

    NNO

    H

    Dactylol Sarain A

    Me

    MeMe

    Me H

    HO

    O

    OMe

    OMeMeO

    MeONHAc

    Colchicine

    HO

    OH

  • Review articles:

    H.M.R. Hoffmann:"Synthesis of Seven- and Five-Membered Rings from Allyl Cations", ACIEE, 12, 819 (1973). "The Cycloaddition of Allyl Cations to 1,3-Dienes", ACIEE, 23, 1 (1984)."8-Oxabicyclo[3.2.1]oct-6-en-3-ones: application to the Asymmetric Synthesis of Polyoxygenated Building Blocks", ACIEE, 43, 1934 (2004).

    "The Synthetic Utility of Oxyallyl Cations", John Mann, Tetrahedron, 42, 4611 (1986).W. Carruthers, Cycloaddition Reactions in Organic Synthesis, Ch.4, Pergamon Press, 1990.A. Hosomi and Y. Tominaga, "[4+3] Cycloaddition Reactions", Comprehensive Organic Synthesis; Trost, B. M.,Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 5, p 593. J. Rigby and F. Pigge, "[4+3] Cycloaddition Reactions", Organic Reactions, Paquette, L.A. et al, Eds.; Wiley & Sons: 1997; Vol. 51, p. 351."Intramolecular Cycloaddition Reactions of Allylic Cations", Michael Harmata, Tetrahedron, 53, 6235 (1997)."Cycloaddition Reactions of Vinyl Oxocarbenium Ions", Miichael Harmata, Tetrahedron, 59, 2371 (2003).

    Contents:

    Reactivity of (oxy)allyl cations Mechanism of [4+3] cycloadditions Intermolecular reactions Intramolecular reactions Asymmetric reactions Miscellaneous uses in complex synthesis

  • First Report

    Fort, 1962:

    Ph

    Cl

    OPh

    2,6-lutidine

    O

    O

    OPh

    Ph

    DMF, rt, 4d18%

    (all three possiblestereoisomers)

    Cookson subsequently improved the yield of cycloadducts by modifying the conditions:

    Cookson, 1963-1967:

    conditions yieldalkaline alumina in furan 40%Zn/Cu couple 29%Hg 35%NaI in furan quant.

    Fort, JACS, 1962, 84, 4979.

    Cookson, Proc.Chem.Soc.London, 1963, 129. J.Chem.Soc., 1965, 2009.

    J.Chem.Soc. B., 1967, 473.

  • Mechanism of [4+3] Cycloadditons

    X

    +

    concerted

    "A"

    stepwise

    "B"

    aa

    Z

    Z X

    Z

    Z X

    transition state

    intermediate

    X

    -H+

    "C"

    Z

    X

    electrophilic aromaticsubstitution adduct

    b

    b

    [3+2] adduct

    Z

    X

    Z

    X

    Claissenrearrangement

    or

    Hoffmann, H.M.R., ACIEE ,1984, 23, 1.for calculations on the [3+2]-Claissen pathway, see: Cramer, C., J.Phys.Org.Chem., 2000, 13, 176.

  • Methods of Generating Allyl Cations IEarly work focused on reductive dehalogenation of polyhalo ketones with low valent metals:

    R

    Br

    O

    Br

    R

    Zn/Cu coupleFe2(CO)9 or Fe(CO)5Zn/Ag couple

    RO

    R

    M2+Br

    Other methods used with polybromoketones:

    R

    Br

    O

    Br

    R NaI, Cu

    MeCNrt - 60C4-24 h

    RONa

    R

    R

    I

    O

    I

    R

    2I- SN2

    I-R

    I

    OR

    Na

    SN1

    Hoffmann, TL 1976, 51, 2379

    oxidative insertionor

    SET

    R

    Br

    O

    M2+Br

    R R

    Br

    OR

    M0

    M2+Br

    SN1

    Zn/Cu: Hoffmann, JACS 1972, 94, 3940.Fe: Noyori, JOC 1975, 40, 2681.

    Zn/Ag: Noyori, Bull.Chem.Soc.Jpn., 1978, 51, 2745.

    R

    Br

    O

    Br

    R (EtO)3B

    Zn, THFrt, 24 h

    ROB(OEt)2

    R

    Hoffmann, TL 1975, 50, 4487.

    Br

    R

    Br

    O

    Br

    R R

    Br

    OR

    SN1(EtO)2B

    H

    EtO-

    B(OEt)2

    Br

  • Transition State Analysis

    Stereoselectivity of a [4+3] reaction is more complex than its lower [4+2] homolog:

    OMHOMO4(4C)

    LUMO2(3C)

    There are two topologically distinct transition states:

    compact(boat-like)

    OM

    HOMO4(4C)

    LUMO2(3C)

    extended(chair-like)

    The cation can adopt three different configurations, which further complicates stereochemical analysis

    OMRR"W-shaped"

    OMR"sickle"

    R

    OM

    R R"U-shaped"

    E

    OM

    endo & compact

    R

    R O

    R

    R

    HH

    OM

    RR

    O

    R

    R

    HH

    exo & extended

    O

    H

    H

    RR

  • Stereoselectivity of Oxallyl CationsThe electrophilicity of the oxyallyl cation determines transition state topology

    Me

    Br

    OMe

    BrO

    Me

    Me O

    MeMe

    ConditionsNaI, Cu 6.4 1 (91% yield)Zn/Cu 1.7 1 (N.R.)Fe2(CO)9 0.89 1 (86% yield)

    More covalent oxygen-metal bonds give more stable and electrophilic oxallyl cations factors determining extended/compact modes: dipole minimization favors compact mode for more highly charged oxygen larger steric environment around the metal center favors extended mode destabilizing secondary orbital interactions favor extended mode for unstable oxyallyl cations

    OMLUMO4(4C)

    HOMO2(3C)

    compact mode

    In general, greater electrophilicity of the allyl cation favors an extended transition state

    Hoffmann, ACIEE 1984, 23, 1.

    note: =0.71 for furan =0.41 for CPD

  • Product distribution implicates a concerted or stepwise mechanism

    Me

    Br

    OMe

    Br

    furan O

    O

    Me

    Me

    O

    O

    O

    OMe

    MeMe Me

    ConditionsNaI, Cu 48% 5% ---Zn/Cu 69% 8% 7%Fe2(CO)9 40% --- 50%

    Stereoselectivity of Oxyallyl Cations II

    oxyallyl cations are assumed to have a "W" conformation, therefore: di-axial and di-equatorial products are assumed to arise via a concerted mechanism axial-equatorial product is assumed to arise via a stepwise mechanism More electrophilic cations (i.e. iron conditions) give access to a stepwise cycloaddition due to a greater mismatch in reactivity with dienes (think hard-soft interactions!)

    Me

    Br

    OMe

    Br

    MeN

    O

    Me

    Me

    MeN

    O

    MeMe

    ConditionsNaI, Cu 76% 13% ---Zn/Cu --- --- 60%Fe2(CO)9 --- --- 81%

    NMe

    NMe

    Me

    OMe

    This is emphasized in the following reactions with the nucleophilic pyrrole:

    [4+3] products arise from Zn/Cu and Fe2(CO)9 conditions by using N-acyl and N-carboalkoxypyrroles to temper the reactivity of the diene component.

    Rigby, J., Org. React., 1997, 51, 351.

  • Oxyally cations do not eliminate (E1) readily:

    Reactivity of Allyl Cations

    Me

    TMS

    OCOCF3

    MeMe

    ZnCl2

    MeCN, 0C

    MeMe

    MeMe

    Me

    TMS

    + iPr2NEt: 14% 55%no iPr2NEt 60% 10%prepared from alcohol

    and TFAA at

  • Reactivity of Allyl Cations II

    Solvent can have an effect on the mechanism of reaction:

    Cl

    OTMSCl

    AgClO4, furan

    solvent, 0C

    O

    O

    Me

    Cl

    O

    O

    Cl

    SolventMeNO2 89% --- ---THF/Et2O (1:1-3) 2.6% 0.4% 61%

    Me Me

    Me O

    OTMSCl

    MeMe

    MeMe

    Cl

    OTMSMe

    AgClO4, furan

    solvent, 0C

    O

    O

    t-Bu

    Me

    O

    O

    Me

    SolventMeNO2 63% 37% ---THF/Et2O (1:1-3) 16% 22% 10%

    t-Bu

    t-BuO

    OMe

    t-Bu

    The authors suggest that a concerted cycloaddition takes place in MeNO2 while a stepwise mechanism operates in THF/Et2O

    Hoffmann: "A reaction of a structurally defined cation belongs at most to two classes, i.e. classes A and B or classes B and C. Thus, formation of class C products precludes class A as a source of cycloaddition and conversely, operation of a class A reaction makes it unlikely that products of class C are formed."

    Shimizu, N., JACS 1982, 104, 1330.

  • Early Uses of [4+3] Cycloadditions in Synthesis

    Examples of [4+3] adducts successfully implemented in synthesis: tropanoids, e.g. nezukone (1) tropane alkaloids, e.g. scopine (2) synthetic intermediates, e.g. Prelog-Djerassi lactone (3)

    O

    MeMe

    1

    MeN

    O

    2

    O

    Br

    Me

    O

    O

    Me

    OMe

    OMe

    Br

    OO

    Zn/Cu

    glyme Me

    O

    OMe

    53%OO

    Me Me

    Me

    CO2HH

    31: Noyori, R., Chem. Lett. 1975, 509.2: Noyori, R., JACS 1974, 96, 3336. 3: White, J.D., JACS 1979, 101, 226.

    Hoffmann, synthesis of Barbaralanes, 1976:

    O

    Me

    Me

    50% NaOH, CHCl3

    BnNEt3Cl50C, 50 h

    80%

    OCl

    Cl

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