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  • Samarium(II) Iodide Mediated Cyclizations in Natural Product SynthesisThe Kagan Reagent Part II

    An Evans Group Afternoon SeminarKeith Fandrick

    Seminar outline:-Introduction and Background-Intramolecular Barbier Reaction-Intramolecular Reformatsky Reaction-Radical Alkene and Alkyne Cyclizations-Carbonyl-Alkene Reductive Cyclizations-Intramolecular Pinacol Couplings-Intramolecular Reductive Couplings of Carbonyls and Hydrazones-Total Synthetic endeavors utilizing mutiple SmI2 cyclizations

    Primary ReferencesProcter, D. J. Chem. Rev. 2004, 3371.Krief, A. Chem. Rev. 1999, 745.Molander, G. Chem. Rev. 1996, 307.Molander, G. Chem. Rev. 1992, 29.Curran, D. R. Synlett 1992, 943. Rajapakse, H. Evans Group Seminar 1998

  • SmI2 Discovery and BackgroundIntroduction

    -Samarium diiodide was first reported by Kagan in 1977. Kagan reported the preliminary deoxygenation of epoxides and sulfoxides, chemoselective reduction of aldehydes in the presence of ketones, dehalogenations, and couplings between ketones and alkyl halides. (Kagan, H. B. Nouv. J. Chim. 1977, 5. Kagan, H. B. J. Am. Chem. Soc. 1980, 2693)

    -Samarium diiodide is the subject of >20 reviews and >850 publications.

    -Samarium diiodide is commercially available as an anhydrous powder (5g, $185) or as a 0.1 M solution in THF (100mL, $32). (Aldrich catalog 2003-2004)

    -Samarium diiodide can be prepared from Sm metal and CH2I2, ICH2CH2I, or I2.

    -Reactions are generally performed with an excess of samarium diiodide, degassed reagents and solvents, and in dry THF containing an antioxidant.

    -Catalytic amounts of SmI2 can be used with the addition of mischmetall (alloy of lanthanides [La 33%, Ce 50%, Nd 12%, Pr 4%, Sm and other lanthanides 1%] to regenerate SmI2. The use of catalytic amounts of Sm(II) and mischmetall is more cost effective. The alloy is unreactive to carbonyls and simple to use.

    -The normal work-up usually requires acidic conditions. However, Rochelle's salt and potassium carbonate can be used for acid sensitive substrates. (Little D. J. Org. Chem. 1996, 3240)

    -THF appears to be the proton source for the termination of radical cascades. If a second reduction with additional equivalent of SmI2 occurs the proton source is generally the alcoholic co-solvent. (Curran D. P. J. Am. Chem. Soc. 1988, 5046)

    -Samarium diiodide chemoselectively reduces: organic halides, carbonyls, -hetero-sustituted carbonyls, cyclopropyl ketones, epoxides, amine oxides, sulfoxides, phosphine oxides, sulfones, sulfonates, nitro, nitroso, and azo compounds, allyl acetates, and isoxazoles.

    Krief, A. Chem. Rev. 1999, 745.

  • -2.25

    -2

    -1.75

    -1.5

    -1.25

    -10 1 2 3 4 5 6 7

    Equiv of HMPA relative to Samarium Diiodide

    Oxi

    datio

    n Po

    tent

    ial

    SmI2 Reduction Potential

    -Samarium diiodide is a polyvalent single electron reducing agent.

    -The reduction potential (Eo) of Sm+2/Sm+3

    in water is -1.55 V compared to Nao/Na+1 of -2.77 V.

    -The reduction potential of SmI2 can be increased by the addition of HMPA, and LiBror LiCl.

    -The addition of transition metal increasesthe rate of several SmI2 reactions.(Kagan, H. B. Synlett 1996, 633)

    -Changes in protic solvents can alterthe rates of SmI2 mediated reactions andin some cases alter the mechanism.

    -Visible light increases the reduction potentialof SmI2. (Ogawa, A. J. Am. Chem. Soc. 1997, 2745)

    Krief, A. Chem. Rev. 1999, 745.

    UV-vis spectrum of SmI2 in THF

    Effects on the Eo of SmI2 with HMPA

  • SmI2 Barbier Reaction Basic Mechanism

    Sm

    I

    I

    HMPA

    HMPA

    HMPA

    HMPAOuter Sphere

    ETR-I+ Sm

    I

    I

    HMPA

    HMPA

    HMPA

    HMPA+ R

    + SmI

    I

    HMPA

    HMPA

    HMPA

    HMPA

    Outer Sphere ETSm

    I

    I

    HMPA

    HMPA

    HMPA

    HMPA+ R

    +-

    Sm

    R

    I

    HMPA

    HMPA

    HMPA

    HMPASm

    I

    I

    HMPA

    HMPA

    R

    HMPAorR' R'

    O

    R' R'R

    OSmInHMPAm

    H+R' R'R

    OH

    -Reduction of the ketone followed by substitution of alkyl-halide with ketyl-radical ruled out by Kagan, because the use of chiral alkyl-halides leads to racemic products.

    -The replacemed of HMPA with LiBr predominately leads to the Pinacol product via inner sphere electron transport/reduction of the ketone via formation of SmBr2.

    -Replacement of HMPA with HMDS leads to the formation of [Sm(HMDS)2]2, which has a redox potential inbetween SmI2 and [Sm(HMPA)6]I2. [Sm(HMDS)2]2 reacts faster with alkyl halides and ketones via change in mechanism towards an inner sphere ET process.

    Molander, G. J. Am. Chem. Soc. 1987, 6556. Curran, D. P. Synlett 1992, 943.Flowers, R. A. Org. Lett. 1999, 2133.Flowers, R. A. J. Am. Chem. Soc. 2000, 7718.Flowers, R. A. J. Am. Chem. Soc. 2002, 6895. Flowers, R. A. J. Am. Chem. Soc. 2002, 14663.Flowers, R. A. J. Am. Chem. Soc. 2004, 6891.

  • Intramolecular SmI2 Barbier ReactionsBasic Mechanism

    Me

    Me O

    Me

    I

    Me

    Me O

    Me Me

    Me O

    MeMe

    Me O

    Me

    Me

    Me O

    Me

    I2Sm

    Me

    Me

    Me

    OSmI2

    Me

    Me

    Me

    OH

    Me

    Me O

    Me

    SmI2

    Me

    Me

    Me

    OSmI2

    Me

    Me

    Me

    OH

    SmI2

    SmI2KSm

    KC

    SmI2

    H+

    H+

    H+

    Reactions performed with 2 equiv of SmI2 and 20 equiv of HMPA

    SmI2 (M) A B C D0.010.030.050.07

    64%42%27%20%

    21%42%55%59%

    11%11%13%15%

    4%5%5%6%

    A

    B

    C

    Me

    MeO

    Me

    D Curran, D. P. Tetrahedron 1997, 9023Krief, A. Chem. Rev. 1999, 745Molander, G. A. J. Org. Chem. 1991, 4112

    H

  • Me

    Intramolecular SmI2 Barbier ReactionsEunicellin and Muscone

    O

    O

    I

    Me

    Me SmI2, THF-78 oC to rt

    O

    MeOH

    O

    AcO

    AcO Me

    OAc

    OAcMeMeMe

    CH2

    Eunicellin

    Hoffman, M. R. Tetrahedron 1997, 4331

    88% Single Diastereomer

    SmI2, HMPATHF

    1) HgO, I2 PhH, hv, O oC 59%2) Bu3SnH-AIBN PhH, hv, 82%

    O

    Me

    90% Single Diatereomer(+/-) Muscone

    Suginome, H. Tetrahedron 1987, 3963

    O

    I

    Me Me

    OHH

    H

  • MeMe

    Intramolecular SmI2 Barbier ReactionsPolyoxypeptin A

    NTs

    I Me O

    ORNTs

    OHMe

    ORNTs

    MeOH

    ORSmI2 +

    R Yield A:BTBDPSTrH

    76%45%75%

    13:8731:6997:3

    THF, HMPA

    HNN

    N

    N

    N

    NH HN

    O

    Me

    O

    O

    N

    O

    OMeO

    OH

    H

    H

    MeOH

    Pr

    H

    iPrH

    Me

    HO

    OH H

    Me

    H

    OHO O

    OH

    Polyoxypeptin A

    OSmI2O

    H

    N H

    I

    OSmI2O

    H

    H

    Me

    N

    I

    TsTs

    Favored Disfavored

    Hamada, Y. Tetrahedron Letters 2002, 4695Procter D. Chem. Rev. 2004, 3371

    Hamada's Explanation

    OO

    Sm(III)(HMPA)n

    N

    I

    Ts

    H

    O

    Me

    N

    I

    Ts

    OP Sm(III)(HMPA)n

    HH

    Procter's Explanation

    -Mechanism might proceed through a bis-radical stucture

    A B

  • Intramolecular SmI2 Barbier CyclizationsSynthetic Studies Towards Variecolin

    Molander, G. Org. Lett. 2001, 2257For increased reaction rates with NiI2 see: Kagan, H. Synlett 1996, 633For increasing reducing ability of SmI2 with visible light see: Ogawa A. J. Am. Chem. Soc. 1997, 2745

    OMe

    I

    O

    Cl+

    SmI2, cat. NiI2THF, 72% OH

    OMe

    Cl

    1:1 Mixture of diastereomers due to racemic starting

    materials RuCl3, NaIO4MeCN, CCl4, H2O

    65%

    OCl

    O

    H

    H

    H

    O

    HO SmI2, NiI2hv, THF

    H

    Me

    MeH

    H

    H

    MeOHC

    O

    Me

    Me

    63%

    Variecolin

    Model of Intermediate A

    A

  • OSmInTHFm

    SmI2 Reformatsky reactionsBasic Mechanism

    OBr

    O

    O

    MePh

    2 equiv SmI2THF, -78 oC

  • O

    Me

    SmI2 Intramolecular Reformatsky reactions(+/-) Paeoniflorigenin and Paeoniflorin

    O

    O

    OH OTIPS

    H

    Me

    Cl

    NC

    Slow Additionof SmI2 (7 equiv)

    THF, -45 oC10h

    O

    OTIPS

    NC

    HO

    O

    MeO

    OH

    HO

    HOO

    MeO

    OH

    O

    HO

    O

    OHHO

    HOHO

    Paeoniflorin Paeoniflorigenin

    Chem 3D w/ MM2 energy minimization

    Corey, E. J. J. Am. Chem. Soc. 1993, 8871

    93% Single Diastereomer

    -Product of the cyclization is base sensitive. Retro-Aldol is observed upon treatment of product with Et3N.

  • O

    SmI2 Intramolecular Reformatsky reactionsUridine Derivatives

    Matsuda A. J. Org. Chem. 1997, 1368

    O N

    OTBSO

    O

    O

    N

    O

    OEt

    SmI2THF O

    N

    OTBS

    N

    O

    OEt

    OOH

    H

    OBr

    O N

    OTBS

    N

    O

    OEt

    OH

    OH

    H2N

    O

    Uridine Derivatives

    O

    O

    O

    I3Sm

    -Substrate is Base sensitive

    -Uridine Derivatives have been shown to be potent antitumor agents bothin vitro and in vivo

    Base

    OTBS

    Conditions Product Yieldsrt w/ Znrt0 oC-78 oC-78 oC w/ HMPA

    A

    C 22%A 71%A 75%A 90%A 76%, B 11%

    O N

    OTBSO

    AcO

    N

    O

    OEt

    NH

    N

    O

    OEt

    B C

    Product Distribution Plausible Tra

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