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Direct Organocatalytic Enantioselective Mannich Reactions of Ketimines: An Approach to Optically Active Quaternary α-Amino Acid Derivatives Wei Zhang, Steen Saaby, and Karl Anker Jorgensen The Danish National Research Foundation: Center for Catalysis Department of Chemistry, Aarhus University Angew. Chem. Int. Ed. 2004, 43, 4476-4478 Michael Rishel @ Wipf Group 1 9/13/2004

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  • Direct Organocatalytic Enantioselective MannichReactions of Ketimines: An Approach to Optically

    Active Quaternary α-Amino Acid Derivatives

    Wei Zhang, Steen Saaby, and Karl Anker Jorgensen

    The Danish National Research Foundation: Center for CatalysisDepartment of Chemistry, Aarhus University

    Angew. Chem. Int. Ed. 2004, 43, 4476-4478

    Michael Rishel @ Wipf Group 1 9/13/2004

  • The Mannich Reaction

    R1

    O

    R2H R3

    OR4NH2++

    R1

    R2

    X

    preformed enol equivalent

    preformedimine

    NR4

    R3Hindirect

    direct

    R1 R3

    R2

    O HNR4

    List, B.; Pojarliev, P.; Biller, W. T.; Martin, H. J.; J. Am. Chem. Soc. 2002, 124, 827-833.

    Michael Rishel @ Wipf Group 2 9/13/2004

  • Iminoesters as Useful Electrophiles in Mannich Reactions

    EtOH

    O

    O

    tosylisocyanate

    [AlCl3]

    p-methoxyaniline

    sieves

    EtOH

    N

    O

    Ts

    EtOH

    N

    O

    PMP

    Taggi, A. E.; Hafez, A. M.; Leckta, T. Acc. Chem. Res. 2003, 36, 10-19.

    EtOOH

    O

    OHPhCONH2

    EtOAcEtO

    OH

    O

    HN O

    EtOCl

    O

    HN Ooxalyl chloride

    α-haloglycine

    Michael Rishel @ Wipf Group 3 9/13/2004

  • Lewis Acid Catalyzed Mannich Reactions of α-Imino Esters

    OH

    NX

    O

    OLG

    HNX

    O

    -LG

    MP P

    MP P

    OH

    NX

    O

    MP

    P

    O

    HNX

    O

    HNu

    Nu

    Taggi, A. E.; Hafez, A. M.; Leckta, T. Acc. Chem. Res. 2003, 36, 10-19.

    Michael Rishel @ Wipf Group 4 9/13/2004

  • Chiral Lewis Acid Catalyzed Mannich Reactions - 1

    H

    O

    EtO

    NTs

    2-10 mol% cat.

    THFor CH2Cl2-78 oC to 0 oC

    R

    OTMS

    O

    EtO

    NHTs

    R

    O

    95%, 98%ee

    P

    P

    R'

    R'

    CuClO4

    R'

    R'

    "cat"

    R = Ar, AlkR' =p-Me-Ph

    (a) Ferraris, D.; Young, B.; Dudding, T.; Lectka, T. J. Am. Chem. Soc. 1998, 120, 4548-4549. (b) Ferraris, D.; Dudding, T.; Young,B.; Drury, W. J.; Lectka, T. J. Org. Chem. 1999, 64, 2168-2169. (c)Ferraris, D.; Young, B.; Cox, C.; Dudding, T.; Drury, W. J.; Ryzhkov, Lev.; Lectka, T. J. Am. Chem. Soc. 2002, 124, 67-77.

    Michael Rishel @ Wipf Group 5 9/13/2004

  • Chiral Lewis Acid Catalyzed Mannich Reactions - 2

    H

    O

    O

    NPMP

    5 mol% cat.

    DMF, 25 oC

    R

    OTMS

    O

    O

    NHPMP

    R

    O

    80-95%, 71-90%ee

    P

    P

    R'

    R'

    Pd

    R'

    R'P

    P

    R'

    R'

    Pd

    R'

    R'

    "cat"

    O

    O

    H

    H

    22TfO-

    R = ArR' =Tol

    (a) Hagiwara, E.; Fujii, A.; Sodeoka, M. J. Am. Chem. Soc. 1998, 120, 2474-2475. (b) Fujii, A.; Sodeoka, M.; 1999, 40, 8011-8014.

    Michael Rishel @ Wipf Group 6 9/13/2004

  • Chiral Lewis Acid Catalyzed Mannich Reactions - 3

    H

    O

    EtO

    N

    10 mol% cat.

    CH2Cl2, 25 oC

    R

    OTMS

    O

    EtO

    NH

    R

    O

    77-97%, 90-97%%ee

    O

    R1

    O

    R1

    NHCu

    NH

    TfO OTf

    PhPh

    "cat"

    R = Ar, OMe, SEtR' = Ar, Alk

    (a) Kobayashi, S.; Matsubara, R.; Kitagawa, H. Org. Lett. 2002, 4, 143-145. (b) Kobayashi, S.; Hamada, T.; Manabe, K. J. Am. Chem. Soc. 2002, 124, 5640-5641.

    Michael Rishel @ Wipf Group 7 9/13/2004

  • Chiral Lewis Acid Catalyzed Mannich Reactions - 4

    O

    PPh2N

    Ar

    OMeO

    OH

    +NH

    Ar

    OH

    O OMe

    1-5 mol% cat.

    THF, MS 3A,

    -20 oC, 2-24 h93-98%, 88/12-96/4 de,95-98% ee

    Et2Zn, 4eq

    OH

    OH

    "cat"

    HO

    HO

    O

    Matsunaga, S.; Kumagai, N.; Harada, S.; Shibasaki, M. J. Am. Chem. Soc.2003, 125, 4712-4713.

    Ph2P

    O

    Michael Rishel @ Wipf Group 8 9/13/2004

  • Mannich Reactions by Organocatalysis

    H

    O

    O

    NPMP

    DMSO, 25 oCO

    O

    NHPMP

    O

    47-86%, 11-99%ee, 19:1 dr

    O

    R2R1

    +

    NH

    OH

    O

    20 mol%

    R1 R22-20 h

    (a) List, B. J. Am. Chem. Soc. 2000, 122, 9336-9337. (b) Cordova, A.; Notz, W.; Zhong, G.; Betancort, J. M.; Barbas, C. F., III. J. Am. Chem. Soc. 2002, 124, 1842-1842.

    H

    O

    O

    NPMP

    DMSO, 25 oCO

    O

    NHPMP

    O

    44-78%, 74-92%ee, 5:1-19:1 dr

    O

    R

    +

    20 mol%

    R2-20 h

    H H

    NH

    OMe

    (a) Cordova, A.; Barbas, C. F. Tetrahedron Lett. 2002, 43, 7749-7752. (b) Notz, W.; Tanaka, F.; Barbas, C. F., III. Acc. Chem. Res. 2004, 37, 580-591.

    Proposed Transition States

    N

    H CO2EtR1

    PMPR2

    N

    O

    OH N

    OO R2

    N

    R1CO2Et

    PMP

    H

    N

    H CO2EtR

    H

    NMeO

    PMP N

    HMeO

    RN

    PMP

    CO2Et

    Michael Rishel @ Wipf Group 9 9/13/2004

  • The Scoop: Mannich Reactions Largely Restricted to IminesDerived From Aldehydes

    N

    O

    OEt

    R

    PG N

    O

    OEt

    R

    PG LA*LA* N

    O

    OEt

    R

    LA* PG

    Saaby, S.; Nakama, K.; Lie, M. A.; Hazell, R. G.; Jorgensen, K. A. Chem. Eur. J. 2003, 9, 6145-6154.

    • Imines bearing α-protons are susceptible to form enamines in the presence ofBronstead or Lewis acids.

    • The equilibrium of the flexible imine double bond is often shifted towards the Zisomer and thereby render difficult a constrained and rigid bidentate coordination to aLewis acid complex

    • A characteristic and fundamental problem related to the use of ketimine substrates issteric hindrance.

    • The disubstituted carbon atom of a prochiral ketimine double bond is much lessreactive than the analagous monosubstituted prochiral aldimine, owing to unfavorablesteric interactions during the CC bond forming step.

    Michael Rishel @ Wipf Group 10 9/13/2004

  • Intrinsic Protecting Groups: Their Role in ModulatingKetimine Reactivity

    “…By anchoring the nitrogenprotecting group by means ofan aryl substituent, the degreeof rotational freedom, as wellas possible imine double bondisomerization, is minimized,rendering a beneficialpreorganized structure forbidentate Lewis acid activation.Moreover, the problem ofenamine formation is alsocircumvented…”

    N

    Ar

    PG

    O

    OEtNO

    R

    O

    O

    OEtvs.

    N

    RO

    OEt

    O

    OMe

    Saaby, S.; Nakama, K.; Lie, M. A.; Hazell, R. G.; Jorgensen, K. A. Chem. Eur. J. 2003, 9, 6145-6154.

    OH

    R Hunig's base

    PMB-isocyanateO

    R

    O

    NHPMB

    formic acid

    NHO

    R

    O

    O

    OEtOH TFA (cat)

    Dean-Stark

    NO

    R

    O

    O

    OEt

    O

    O

    OEt

    O

    O

    OEt

    Michael Rishel @ Wipf Group 11 9/13/2004

  • Lewis Acid Catalyzed Ketimine Alkylation

    O

    OEt

    N

    5-10 mol% cat.

    CH2Cl2, -78 oC

    OR1

    OTMSO

    O

    R R2

    +

    H2O 5-20 mol%

    NHO

    O

    R

    CO2Et

    CO2RR2

    NO

    N N

    O

    Ph Ph

    Zn

    2

    2 OTf-

    Saaby, S.; Nakama, K.; Lie, M. A.; Hazell, R. G.; Jorgensen, K. A. Chem. Eur. J. 2003, 9, 6145-6154.

    cat.

    Boc2O, DMAP

    MeCN, RT, 17 h

    Cs2CO3MeOH, RT, 2h O O

    CO2EtBocHN

    RR2

    Michael Rishel @ Wipf Group 12 9/13/2004

  • O

    OEt

    N OO

    O

    + NHO

    O

    CO2Et

    CHOiPr

    iPr

    H

    chiral amine

    1a 2a

    +

    4a

    NHO

    O

    CO2Et

    CHOiPr

    3a

    Table 1: Direct organocatalytic asymetric Mannich reaction of ketimine 1a with 2a.

    Entry Catalyst(mol%)

    T[ºC]

    2a[equiv]

    Solvent Yield[a][%]

    3a/4a[b] ee[c][%]

    1 5a (30) 0 5 CH2Cl2 84 1:8 822 5b (30) 0 5 CH2Cl2 11 >20:1 73 5c (30) 0 5 CH2Cl2 trace >20:1 –4 5d (30) 0 5 CH2Cl2 39 >20:1 805 5e (5) 0 5 CH2Cl2 56 15:1 866 5e (5) 0 5 CH2Cl2 73 2:1 887 5e (5) 0 5 Et2O 74 19:1 908 5e (5) 0 2 Et2O 99 >20:1 919 5e (5) -24 2 Et2O 51 17:1 9210 5e (2) 0 2 Et2O 93 18:1 91[a] Combined yield of the two isolated diastereomeric products. [b] The diastereomericratio was determined by 1H NMR spectroscopic analysis of the crude product mixture.[c] The ee of the major product was determined by HPLC on a Daicel Chiralpak AScolumn.

    NH

    CO2H NH

    CO2Me NH

    Ph

    OHPh N

    H

    Ar

    OHAr

    Ar = 3,5 xylyl

    NH

    N

    5a 5b 5c 5d 5e

    Zhang, W.; Saaby, S.; Jorgensen, K. A. Angew. Chem. Int. Ed. 2004, 43, 4476-4478

    Michael Rishel @ Wipf Group 13 9/13/2004

  • O

    OEt

    N OO

    O

    +

    R4H

    1a-f 2a R4 = iPr

    2b R4 = Me

    2c R4 = allyl

    NHO

    O

    CO2Et

    CHO

    R4

    3a-h

    R1

    R2

    R3

    5e (5 mol%)

    0 oC, 20 h

    Table 2. Reaction of ketimines 1a-f with aldehydes 2a-c under the optimized reactionconditions

    Entry Imine Solvent R1 R2 R3 R4 Product Yield[%][a]

    3/4[b] ee[%][c]

    1 1a Et2O H H H iPr 3a 99 >20:1 912 1b Et2O H H Me iPr 3b 98 6:1 893 1c Et2O H H OMe iPr 3c 95 9:1 864 1d Et2O H H F iPr 3d 97 19:1 835 1e Et2O H OMe H iPr 3e 90 >20:1 876 1f Et2O –C4H4– H iPr 3f 93 >20:1 847 1a CH2Cl2 H H H Me 3g 72 5:1 958 1a CH2Cl2 H H H allyl 3h 82 4:1 98[a] Combined yield of the two isolated diastereomeric products. [b] The diastereomericratio was determined by 1H NMR spectroscopic analysis of the crude product. [c] The eevalue of the major product (with R configuration at the quaternary center) wasdetermined by HPLC on a Chiral stationary phase (see Supporting Information fordetails).

    Zhang, W.; Saaby, S.; Jorgensen, K. A. Angew. Chem. Int. Ed. 2004, 43, 4476-4478

    Michael Rishel @ Wipf Group 14 9/13/2004

  • Conclusions

    • The first organocatalytic, enantioselective Mannich reaction ofketimines and unmodified aldehydes based on the concept of intrinsicprotecting group anchoring has been reported.

    • Catalysis is achieved by the addition of simple chiral amines (2-5mol%) providing optically active quaternary α-amino acid derivativesin high yields (72-99%) and good optical purities (83-98% ee).

    • Through careful selection of the amine catalyst, the diastereoselectivityof the reaction can be controlled.

    Michael Rishel @ Wipf Group 15 9/13/2004