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  • A1,3 Strain and the Anomeric Effect

    Michael Shaghafi Chem. Topics Feb. 6, 2012

  • Introduction: Definition of A1,3 Strain

    H H

    R

    Rotation about σ-bond between α-stereocenter and olefin is associated with an energetic cost (steric/van der Waals interaction).

    RLRm Rm

    H

    R

    HRL RL

    H

    R

    RmH

    1

    3

    3 3

    1 1

    RL H

    R

    HRm H

    H

    R

    RmRL 3

    1

    Rotation about allylic stereocenter to a lower energy confirmation = A1,3 strain minimization.

    H

    H

    R

    Rm

    RL 1 3

    Confirmational preferences based upon minimization of A1,3 strain can differentiate diastereofacial faces of pro-chiral nucleophiles and electrophiles (i.e. π-bonds).

    - Can lead to diastereoselective reactions if significant differences in steric bulk are realized between R, Rm, and RL.

    E+

    E+

  • Energy Differences Upon Sigma-Bond Rotation

    Hoffmann, R. W. Chem. Rev. 1989, 89, 1841–1880.

    H

    CH3 CH3

    H H

    CH3 H

    CH3

    0 kcal/mol + 0.73 kcal/mol

    ab initio calculations: MP2-6-31G (Houk)

    H

    H

    CH3 CH3

    > + 2.0 kcal/mol

    Mono-substituted olefins:

    CH3

    CH3 CH3

    H CH3

    CH3 H

    CH3

    0 kcal/mol + > 4.0 kcal/mol

    CH3

    H

    CH3 CH3

    > + 3.44 kcal/mol

    Z-substituted olefins:

  • A Warm-Up: Hydroboration

    Hoffmann, R. W. Chem. Rev. 1989, 89, 1841–1880.

    CH3

    H PhMe2Si

    Me

    OH

    ds = 50 %

    H PhMe2Si

    Me

    CH3

    OH ds = 95 %

    CH3

    H PhMe2Si

    Me 1. BH3

    2. [O]

    H PhMe2Si

    Me

    CH3

    1. BH3

    2. [O]

    CH3

    H H3C

    (CH2)7=

    1. BH3

    2. [O]

    CH3

    H H3C

    OH

    ds = 90 %

  • Diastereoselective Epoxidation of Olefins: A Classical Case

    Hoffmann, R. W. Chem. Rev. 1989, 89, 1841–1880.

    OH

    O Ph

    H O O

    O

    Cl

    H

    OBn

    OH

    m-CPBA

    OBn m-CPBAOH

    OBn m-CPBAOH

    OBn m-CPBAOH

    SiMe3

    OBn

    OH

    O ds = > 97 %

    OBn O OH ds = > 96 %

    OBn O OH ds = 60 %

    OBn O OH

    SiMe3

    ds = > 95 %

  • Diastereoselective Epoxidation of Olefins: Allylic Silanes and Siloxyethers

    Hoffmann, R. W. Chem. Rev. 1989, 89, 1841–1880.

    O R3Si

    O OH

    Ar

    SiMe2Ph

    PhMe2Si

    m-CPBA

    m-CPBA

    PhMe2Si O PhMe2Si O+

    61 : 39

    PhMe2Si O PhMe2Si O+

    > 95 : 5

    R

    t-BuMe2SiO m-CPBA OH R

    t-BuMe2SiO

    OH O

    Ti(Oi-Pr)4 t-BuOOH

    R

    t-BuMe2SiO

    OH O

    R t-BuMe2SiO

    O

    H

    Minimized A1,3 Strain

    O H O

    Ar O H

    mCPBA Coordination

    No Coordination: Attack from less hindered face

    ds = > 94 %

    ds = > 90 %

  • Classical Synthetic Example: Kishi’s Total Synthesis of Monensin

    Schmid, G.; Fukuyama, T.; Kishi, Y. J. Am. Chem. Soc. 1979, 101, 260–262.

    Ar

    O Et

    H C3H5

    H

    HOH2C

    Ar

    O Et

    H C3H5

    H

    HOH2C

    O

    mCPBA, NaHCO3 DCM, rt

    quant., sole product OAr H Et OH

    H

    steps

    OAr H Et OH H

    O Ar

    H Et O

    H

    H Br

    NBS, MeCN

    rt

    57 %

    Single Diastereomer

    OAr H Et OH H

    H

    Br

  • Diastereoselective Epoxidation of Olefins: A Recent Application to Library Synthesis

    Coombs, T.C.; Lushington, G. H.; Douglas, J.; Aube, J. Angew. Chem. Int. Ed. 2011, 50, 2734–2737.

    NH

    H H

    Ar N

    Ar H

    OO R

    1,3-diaxial minimization A1,3 minimization

  • Diastereoselective Epoxidation of Olefins: A Recent Application to Library Synthesis

    Coombs, T.C.; Lushington, G. H.; Douglas, J.; Aube, J. Angew. Chem. Int. Ed. 2011, 50, 2734–2737.

  • A1,3 Control in Cycloadditions: A Classical Example

    Hoffmann, R. W. Chem. Rev. 1989, 89, 1841–1880.

  • Roush: Total Synthesis of Spinosyn A

    Winbush, S. M.; Mergott, D.J.; Roush, W. R. J. Org. Chem. 2008, 73, 1818–1829.

  • A1,3 Control in Cycloadditions: Roush Synthesis of Spinosyn A

    Winbush, S. M.; Mergott, D.J.; Roush, W. R. J. Org. Chem. 2008, 73, 1818–1829.

  • A1,3 and Control in Addition to Nitrones

    Hoffmann, R. W. Chem. Rev. 1989, 89, 1841–1880.

    N O

    OH C5H11

    t-BuMe2SiO CH3

    N O

    OH C5H11

    t-BuMe2SiO CH3

    AcOH

    THF, –100 ºC ds = > 95 %

    N O

    OH C5H11

    LiO CH3

    N O

    OH C5H11

    HO CH3

    AcOH

    THF, –100 ºC ds = 80 %

    N O

    OH R

    PhSe CH3

    N O

    OH R

    PhSe CH3

    AcOH

    THF, –100 ºC

    R = Me, ds = 91 %

    = n-Bu, ds = 95 % = Ph, ds = 80 %

    N H3C

    O H

    N O

    H3C

    H

    Intramolecular [3+2] Only product

    55 %

  • Barbas Carbohydrate Synthesis: Asymmetric Organocatalytic Michael-Henry Reactions

    Uehara, H.; Imashiro, R.; Hernandez-Torres, G.; Barbas III, C. F. PNAS, 2010, 107, 20672– 20677.

    d.r. (6 + 5:7) = usually > 10:1; 36 % to 76 % yield (2 steps)!

  • Barbas Carbohydrate Synthesis: Model for Diastereoselectivity

    Uehara, H.; Imashiro, R.; Hernandez-Torres, G.; Barbas III, C. F. PNAS, 2010, 107, 20672–20677.

  • Introduction: The Anomeric Effect

    Kirby, A. J. Oxford Chemistry Primers: Stereoelectronic Effects 1996, Oxford University Press.!

    OH O

    HO

    HO HO

    OH OR

    O HO

    HO HO

    OR β-glucopyranose

    β α

    α-glucopyranose

    R = H 64 36:

    R = Me 33 : 67

    H

    R

    H

    H

    RH H

    O R

    H

    O HH

    RH H

    Steric Preference:

    Contra-Steric Preference: Anomeric Effect = Electrostatic Effect

    R = alkyl

    R = polar group - i.e. OMe, Halogen, OAc, etc.

  • Introduction: The Anomeric Effect

    Kirby, A. J. Oxford Chemistry Primers: Stereoelectronic Effects 1996, Oxford University Press.!

    OBzO BzO

    OBz X O

    OBz

    X BzO

    OBz X = F, Cl, Br

    Ph

    O Bz =

    OAc O

    AcO

    AcO AcO

    OAc OR

    O AcO

    AcO AcO

    OR β-glucopyranose

    β α

    α-glucopyranose

    R = OAc 14 86:

    R = Cl 6 : 94

  • Explaining the Anomeric Effect: Electrostatics

    O HH

    X

    nO σ*C–X O XH

    σ*C–XσC–C

    σ*C–Br

    nO

    ΔΕ σ*C–Cl σ*C–F

    σ*C–X

    ΔΕ

    σC–C

    Just considering electrostatics:

  • The Anomeric Effect is General and Predictable: Kishi’s Monesin Total Synthesis

    Kishi, Y. et. al. J. Am. Chem. Soc. 1979, 101, 262–263.

    O

    HO

    Me O Me

    HO2C Me

    Me

    Me

    H O O

    O H Et H

    Me

    H

    Me

    H HO CH2OH

    Me

    O

    OOH

    Me R1

    R2 Me

    From Degradation Studies followed by X-rayMonensin

    Spiroketalization

    Aldol Reaction

    O X

    Y

    OH Me

    H n-C6H13

    1:1 ratio of anomers 1:2

    CSA

    DCM, rt O

    HO Me Me

    n-C6H13 H

    OBn Me

    HO 10% Pd/C

    CH3OH, AcOH rt 1 X = O, Y = CH2

    2 X = CH2, Y = O

    O X

    Y

    OH Me

    H n-C6H13

    Only 1 (anomeric)

    OBn

    HO

    Me HO Me

    HO2C

    Me

    Me

    Me

    H O O

    O H Et H

    Me

    H

    Me

    H HO CH2OH

    Me O

    as above Monensin 53 %

  • Roush: Toward the Total Synthesis of Integramycin

    Sun, H.; Abbott, J. R.; Roush, W. R. Org. Lett. 2011, 13, 2734–2737.

    -  A1,3 minimization controls π-bond facial selectivity ! in the iodonium formation. ! -  Also formation of the doubly anomeric conformation! should drive the equilibrium!

    O O

    Me

    H

    Me

    TIPSO

    OTIPS

    Me

    I

    Iodoketalization O HO

    Me

    Me

    TIPSO

    OTIPS

    Me

    NIS

  • Stereoselectivity in Glycosidic Bond Formation: Radical Reactions

    Abe, H.; Shuto, S.; Matsuda, A. J. Am. Chem. Soc. 2001, 123, 11870–11882.

    O OPg

    (PgO)n O

    OPg

    (PgO)n

    X = D, CH2CH2CN, n-BuSnC3H6

    X α-selectivity dominates

    O R

    AcO AcO

    OAc nO SOMO

    SOMO σ*C2

    (anomeric stabilization) Studies by Giese

    Studies by Renaud S

    t-Bu O

    SePh

    Bu3SnD, AIBN

    Benzene, reflux

    S t-Bu

    O

    D SnBu3

    S t-Bu

    O

    S t-Bu

    O

    D

    Radical Cieplack Effect

  • Conformationally Locking in α-Glycosylation: α-Selective Substrates

    Abe, H.;