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PROLINE CATALYZED ALDOL, MANNICH, PROLINE CATALYZED ALDOL, MANNICH, AND MICHAEL REACTIONS: AND MICHAEL REACTIONS: APPLICATION OF ASYMMETRIC ORGANOCATALYSIS APPLICATION OF ASYMMETRIC ORGANOCATALYSIS SANJIT SANYAL DEPARTMENT OF CHEMISTRY MICHIGAN STATE UNIVERSITY JANUARY 19, 2005

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  • PROLINE CATALYZED ALDOL, MANNICH,PROLINE CATALYZED ALDOL, MANNICH, AND MICHAEL REACTIONS: AND MICHAEL REACTIONS:

    APPLICATION OF ASYMMETRIC ORGANOCATALYSISAPPLICATION OF ASYMMETRIC ORGANOCATALYSIS

    SANJIT SANYALDEPARTMENT OF CHEMISTRYMICHIGAN STATE UNIVERSITY

    JANUARY 19, 2005

  • What is What is Organocatalysis?

    A field of chemistry that pays my mortgage and has gotten me many free dinners. - David W. C. Macmillan

  • What is What is Organocatalysis?

    A catalysis field wherein small organic molecules efficiently and selectively catalyze organic transformations. - David W. C. Macmillan

    Organocatalysis is the catalysis of a reaction with an organic small molecule. By accepted convention, organic small molecule means a molecule without a metal, and not a macromolecule like protein, nucleic acid, or polymer. - K. N. Houk

    Catalytic reactions mediated by small organic molecule in absence of metals or metal ions. - Carlos F. Barbas, III

  • Organocatalysts

    NFe

    RR

    RRR

    R12N

    Chiral DMAP (Gregory C. Fu)

    BOCHNO

    HN

    O

    NH O

    HN

    O

    NH O

    HN

    O

    NH O

    HN

    Oi-Pr

    i-PrOMe

    Me Ot-Bu

    Ph Met-BuO

    MeMeN N

    N

    NMe

    Trt

    Peptide-Based Catalyst (Scott J. Miller)

    (S)-2-methoxy-methyl -pyrrolidin (SMP)

    NH

    OMe

    5,5-dimethyl thiazoli-dinium-4-carboxylate (DTMC)

    NH

    S

    NH

    L-proline

    CO2H

    acetylquinineN

    NHAcO

    OMe

    N

    NH

    (-)-cinchonidinea cinchona alkaloid

    HO

    H2N

    O

    OH

    (S)-phenylalanine

    N

    ON

    Br

    H

    chiral quaternary ammonium salt

    fructose-derived chiral-ketone

    O

    OO

    O

    O

    O

  • Classification of Classification of Organocatalysts

    Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 16151621.

    Type-I : Activation of the reaction based on the nucleophilic/electrophilic properties of the catalyst.

    OO

    O

    3 mol % L-prolineDMF, 20 C, 20 h 100%

    O

    O OH1 2

    93% ee

    Type-II : Organic molecules that form reactive intermediates. The chiral catalyst is consumed in the reaction and requires regeneration in parallel catalytic cycle.

    Shu, L.; Shi, Y. J. Org. Chem. 2000, 65, 88078810.

    O

    OO

    O

    O

    O

    30% H2O2 (3 equiv.) CH3CN-K2CO33 4

    30 mol %R2R1 R3

    R2R1 R3

    O

  • Classification of Classification of Organocatalysts

    Type-III : Phase-transfer reactions. The chiral catalyst forms a host-guest complex with the substrate and shuttles between the standard organic solvent and a second phase.

    Corey, E. J.; Xu, F.; Noe, M. C. J. Am. Chem. Soc. 1997, 119, 1241412415.

    Catalytic Enantioselective Enolate Alkylation :

    NPh

    Ph OtBu

    OEtI N

    Ph

    Ph OtBu

    O

    H Et

    Catalyst (10 mol %) CsOHH2OCH2Cl2, -60 C, 30 h

    5 6

    N

    ON

    Br

    H

    Chiral quaternary ammonium salt

    Type-IV : Molecular-cavity-accelerated asymmetric transformations in which the catalyst may select between competing substrates, depending on size and structure criteria.

    HO

    NHN

    OHO

    OH

    O

    PolymerSellergren, B.; Karmalkar, R. N.; Shea, K. J. J. Org. Chem. 2000, 65, 40094027.

    O O

    BOCHN NO2 1. Polymer

    2. Nu

    O

    BOCHN NuOH

    NO27 8

    OH

  • Type-IType-I Activation of the reaction based on the nucleophilic/electrophilic properties of the catalyst.

    Background Information

    Direct Catalytic Asymmetric Aldol Reaction

    Direct Catalytic Asymmetric Mannich Reaction

    Direct Catalytic Asymmetric Michael Reaction

  • Background InformationBackground Information

    Bredig, G.; Fiske, P. S. Biochem. Z. 1912, 46, 723.

    N

    NH

    (-)-CinchonidineA cinchona alkaloid

    HOCHO1. HCN, Catalyst, CHCl3, rt, 24 h

    2. 4N H2SO4, 8.7%COOH

    OH

    8.9% ee9 (-)-10

    Pracejus, H. Justus Liebigs Ann. Chem. 1960, 634, 9-29.

    AcetylquinineN

    NHAcO

    OMe

    Catalyst

    1 mol % Catalyst, toluene

    110 C, 90%C O

    Ph

    MeMeOH MeO

    MeO

    Ph

    74% ee (R)

    11 12

  • Background InformationBackground Information

    Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem. Int. Ed. 1971, 10, 496497.

    Hajos-Parrish-Eder-Sauer-Wiechert Reaction

    Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 16151621.

    NH

    Catalyst

    L-proline

    CO2H

    NH

    Catalyst

    L-proline

    CO2H47 mol % catalyst, 1N HClO4

    CH3CN, 80 C, 25 h 83%

    O

    O

    Me

    O O

    O

    71% ee13 1514

    OO

    O

    3 mol % catalystDMF, 20 C, 20 h 100%

    O

    O OH

    p -TsOHPhH, 15 min 99%

    O

    O

    1695% ee

    1 293% ee

  • Why Why ProlineProline??

    Proline is an optically active pyrrolidine derivative.

    OO

    O O

    O OH1 ()-2

    NH

    DMF, rt

    Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615-1621.

    H2N

    pyrrolidinium camphorsulphonic acid

    O3S ONH

    O

    O H

    Lproline

    Asymmetric carbon is in the same molecule next to the functional groups.

  • Why Why ProlineProline??

    The isoelectric point of proline is at pH 6.30.

    The optically active reagent should attach itself at more than one point to a symmetrical compound. (Ogstones hypothesis)

    NH

    O

    O HLproline O

    N O

    OOH

    Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615-1621. Ogstone, A. G. Nature. 1958, 181, 14621465.

  • Why Why ProlineProline??

    Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 16151621.

    OO

    O O

    O OH1 2

    Solvent, rt

    pyrrolidine derivatives

    2-(S)-trans-4-hydroxyproline

    ()-2-piperidinecarboxylic acid

    (S)-(+)-prolinol

    12.1%73% ee

    59%14% ee

    No Reaction

    (S)-proline ethyl ester N-methylproline

    traceRacemic

    48%Racemic

    100%93% ee

    NH

    L-proline

    CO2H

    NMe

    CO2H

    NH

    HO

    NH

    OHHO

    O

    HN

    HO

    O NH

    CO2Et

    (S)-azetidine-2-carboxylic acid

    51% 64% ee

    HN O

    OH

    37%19% ee

    (S)phenylalanineH2N

    O

    OH

  • How How Proline Proline WorksWorks

    Some passive or dynamic interaction is necessary to translate the chiral information via the organization of the transition state for the organocatalyzed enantioselective transformation.

    Hydrophobic, Van der Waals, and electrostatic interactions can be considered as passive interactions.

    Dynamic binding refers to interactions between catalysts and substrates at the reaction centers, e.g. hydrogen bonding.

  • OO

    NHO2C

    Enamine IntermediateO

    N OH

    OO

    B

    Enaminium-catalyzed mechanism

    OH

    HON

    O

    HO

    O

    Carbinolamine Intermediate

    O

    NO H O H

    OH O

    ANucleophilic substitution mechanism

    How How Proline Proline WorksWorks

    Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 16151621.

    OO

    N

    Enamine Intermediate

    OO

    O CO2HNH

    CO2H

    O

    18O

    -H2O16

    O

    N

    CO2 H2O18

    (exs.)O

    18ONH

    CO2H

    -H2O16

    OHOH

  • RR1

    OH , R2NH

    -R2NH, H3OR

    R1

    NR2 H , R2NH

    -R2NH, H3OR

    R1

    NR2

    R2CHO-R2CHO

    RR1

    NR2

    R2O

    RR1

    NR2

    R2OH

    H , R2NH

    -R2NH, H3O

    How How Proline Proline WorksWorks

    Puchot, C.; Samuel, O.; Dunach, E.; Zhao, S.; Agami, C.; Kagan, H. B. J. Am. Chem. Soc. 1986, 108, 23532357.

    OO

    NHO2C

    Enamine Intermediate O

    N OO

    OH

    NH

    O OH

    CDual proline enaminium-catalyzed mechanism

    Nonlinear Effect Study in the Hajos-Parrish Reaction by Agami & et. al.

    % ee of KetolA

    % ee of proline

    O

    O OHKetol-A

  • How How Proline Proline WorksWorks

    Allemann, C.; Gordillo, R.; Clemente, F. R.; Cheong, P. H.; Houk, K. N. Acc. Chem. Res. 2004, 37, 558569 & references cited therein.

    O

    N O

    OO H

    D

    Carboxylic acid-catalyzed enamine mechanism

    OO

    NHO2C

    Enamine Intermediate

    0 Kcal/mol

    O

    NO H O H

    OH O

    ANucleophilic substitution mechanism

    37.9 Kcal/mol

    O

    N OH

    OO

    B

    Enaminium-catalyzed mechanism

    30.5 Kcal/mol

    O

    N OO

    OH

    NH

    O OH

    CDual proline enaminium-catalyzed mechanism

    30.5 Kcal/mol

  • Linh, H.; Bahmanyar, S.; Houk, K. N.; List, B. J. Am. Chem. Soc. 2003, 125, 1617.

    How How Proline Proline WorksWorks

    % ee of 3

    % ee of proline

    Absence of Nonlinear Effect in Hajos-Parrish-Eder-Sauer-Wiechert Reaction: (Observed by K. N. Houk and coworkers)

    OO

    O

    (S)-ProlineO

    O

    O

    O

    31 2

    n a (n = 1)b (n = 2)

    -H2O

    nOH n

  • % ee of 16

    % ee of proline

    How How Proline Proline WorksWorks

    Nonlinear Effect Study by Agami & et. al.

    % ee of KetolA

    % ee of proline

    Nonlinear Effect Study by K. N. Houk & et. al.

    O

    N O

    OO H

    D

    Carboxylic acid-catalyzed enamine mechanism

    O

    N OO

    OH

    NH

    O OH

    CDual proline enaminium-catalyzed mechanism

    Linh, H.; Bahmanyar, S.; Houk, K. N.; List, B. J. Am. Chem. Soc. 2003, 125, 1617.Puchot, C.; Samuel, O.; Dunach, E.; Zhao, S.; Agami, C.; Kagan, H. B. J. Am. Chem. Soc. 1986, 108, 23532357.

  • How How Proline Proline WorksWorks

    O18incorporation study by Benzamin List and et. al.

    O

    N O

    OO H

    D

    Carboxylic acid-catalyzed enamine mechanism

    O

    NO H O H

    OH O

    ANucleophilic substitution mechanism

    List, B.; Hoang, L.; Martin, H. J. Proc. Natl. Acad. Sci. 2004, 101, 58395842.

    B C D

    O(S)-proline(25 mol %)

    3 vol % H2O18 in DMSO, Ar, 4 d

    18O 18O

    O

    O

    O

    OH

    O

    NCO2H

    O

    A (0.1 M) B, 40% C, 50% D, 10%

  • Type-IType-I

    Background Information Direct Catalytic Asymmetric Aldol Reaction

    Direct Catalytic Asymmetric Mannich Reaction

    Direct Catalytic Asymmetric Michael Reaction

    Activation of the reaction based on the nucleophilic/electrophilic properties of the catalyst.

  • List, B.; Lerner, R. A.; Barbas III, C. F. Org. Lett. 1999, 1, 5961.

    Aldol Aldol ReactionReaction

    Ab 38C2 : 94%L-proline : 83%

    O

    OO

    O

    O

    15Ab38C2: 96% eeL-proline: 71% ee

    List, B.; Lerner, R. A.; Barbas III, C. F. J. Am. Chem. Soc. 2000, 122, 23952396.

    OH

    NO2

    O

    20 vol % NO2

    ONH

    CO2H

    30 mol %

    DMSO, rt, 4 h68%

    OH

    1876% ee

    Ab 38C2, 90%

    >90% ee

    OH

    NO2

    O

    20 vol % NO2

    O OH

    17

  • Aldol Aldol ReactionReaction

    List, B.; Lerner, R. A.; Barbas III, C. F. J. Am. Chem. Soc. 2000, 122, 23952396.

    1

    2

    3

    4

    5

    < 10

    < 10

    55

    < 10

    < 10

    n. d.a

    n. d.

    40

    n. d.

    n. d.

    (L)-His, (L)-Val(L)-Tyr, (L)-Phe

    NH

    CO2H

    NH

    CO2H

    NH

    CONH2

    NHCO2H

    Yield% %eeEntry Catalyst Yield% %eeEntry Catalyst

    6

    7

    8

    9

    10

    S

    NH

    CO2H

    NH

    CO2H

    NH

    HO CO2H

    NH

    CO2HAcO

    NH

    CO2HHO

    67

    68

    85

    >50

    70

    73

    76

    78

    62b

    74

    aNot determinedbOpposite enantiomer

    OH

    NO2

    O

    20 vol % NO2

    OCatalyst (30 mol %)

    DMSO, rt,

    OH

    18

  • Aldol Aldol ReactionReaction

    Product Yield%

    68

    62

    74

    94

    54

    %ee

    76

    60

    65

    69

    77

    NO2

    O OH

    O OH

    O OH

    Br

    O OH Cl

    O OH

    O

    ArH

    O

    20 vol %Ar

    OCatalyst (30 mol %)

    DMSO, rt,

    OH

    List, B.; Lerner, R. A.; Barbas III, C. F. J. Am. Chem. Soc. 2000, 122, 23952396.

  • Proposed Enamine Mechanism

    List, B.; Lerner, R. A.; Barbas III, C. F. J. Am. Chem. Soc. 2000, 122, 23952396.

    Aldol Aldol ReactionReaction

    HN

    OHO HO

    N

    OHO H

    HO- HO N

    O

    HOH

    NO

    HOH

    N H

    H

    R O H

    re-facial attack

    RCHON

    O

    OH

    R

    OH

    NO

    OHOH

    R

    OH

    HHN

    OHO H

    R

    OOH

    OO

    N H

    R

    H O H

    si-facial attack

    OO

  • List, B.; Pojarliev, P.; Castello, C. Org. Lett. 2001, 3, 573574.

    Aldol Aldol ReactionReaction

    20 vol%

    (L)-proline 30 mol %

    DMSO, rt, 2-96 h

    O

    H

    O

    R R

    OHO

    19

    81

    Entry R Yield% %ee

    1 CH2R1 99

    4 p-O2NPh 68 76

    HR1

    OH , R2NH

    -R2NH, H3OH

    R1

    NR2 H , R2NH

    -R2NH, H3OH

    R1

    NR2

    R1CH2CHO-R1CH2CHO

    HR1

    NR2 O

    HR1

    NR2 OH H , R2NH

    -R2NH, H3O R1R1

  • Aldol Reactions of -Unsubstituted Aldehydes

    List, B.; Pojarliev, P.; Castello, C. Org. Lett. 2001, 3, 573574.

    Aldol Aldol ReactionReaction

    R = Yield% of 21 (22) %ee solventEntry

    1

    2

    3

    4

    5

    31 (38)29

    6770

    AcetoneCHCl3

    35 (40) 73 Acetone

    34 (35) 72 CHCl3

    34 (42)23 (46)

    7361

    AcetoneCHCl3

    22 (50) 36 CHCl3

    20 vol%

    (L)-proline10-20 mol %

    rt, 3-7 d

    O

    H R

    O

    R

    OHO

    R

    O

    21 22

  • Enone 29 is Formed Via Mannich Reaction-Elimination Sequence

    Aldol Aldol ReactionReaction

    List, B.; Pojarliev, P.; Castello, C. Org. Lett. 2001, 3, 573574.

    H R

    O

    R H

    N CO2

    N CO2H

    R

    OO

    R

    O

    R

    OH

    + Proline

    -H2O

    + Acetone

    - Proline

    + Acetone

    Proline

    21

    22

    O OH OTBS

    21d

    1. TBSCl, Imidazole2. KHMDS

    N

    N

    Cl

    TfTf

    57%

    LiCl, THFPd(PPh3)4 (2mol%) 95%

    SnBu3

    OTBS

    TBAF, THF 90%

    OTf

    23

    24

    L-proline (20 mol %)

    rt, 3 d20 vol%

    O

    H

    O

    Kg scale

    OH

    25(S)-Ispenol

  • Aldol Aldol ReactionReaction

    Gijsen, H. J. M.; Wong, C.-H. J. Am. Chem. Soc. 1994, 116, 84228423.

    HDERA O

    OH

    [DERA = 2-deoxyribose-5-phosphate aldolase]

    OHOH DERA OH OH

    2,4,6-trideoxyhexose

    O

    H

    O

    H

    O

    O O

    26

    Cordova, A.; Notz, W.; Barbas III, C. F. J. Org. Chem. 2002, 67, 301303.

    NO O

    H

    H

    MeHHO

    re-facial attack

    L-proline, THF

    0 C, 5 h(S)

    90% ee

    Me H

    O O

    H

    OH

    273 equiv. 10%

    Northrup, A. B.; Macmillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 67986799.

    H Me10 mol % (L)-proline

    DMF, 4 C 80%

    HMe

    OHMe

    2 equiv. 4:1 anti:syn, 99% ee

    O O

    28

  • Northrup, A. B.; Macmillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 67986799.

    Aldol Aldol ReactionReaction

    NO

    H

    H

    R2HHO

    anti

    H

    R1O

    NO

    H

    HH

    syn

    HR1

    OO

    H

    R2

    Entry R1 R2 Product Yielda% anti:syn %ee

    a combined yields of diastereomers

    1 Me i-Bu 88 3:1 97

    2 Me c-C6H11 87 14:1 99

    3 Me Ph 81 3:1 99

    4 Bn i-Pr 75 19:1 91

    H

    O

    Me

    OH

    H

    O

    Me

    OH

    H

    O

    Me

    OH

    H

    O

    Bn

    OH

    10 mol % L-Proilne

    DMF, 4 C, 11-26 hHR1

    H R2OO

    H R2O

    R1

    OH

    29

  • 3 steps, 22% overall yield Pihko, P. M.; Erikkila, A. Tetrahedron Lett. 2003, 44, 76077609.

    Aldol Aldol ReactionReaction

    O

    H

    O

    H

    L-proline (10 mol%) DMF, 40 h, 5 C

    H

    O

    with crudeTBSOTf, 2,6-lutidine Et2O/CH2Cl2 (1:1) 10 C, 2.5 h 61% (two steps)

    TBSO

    OEt

    BF3Et2O, CH2Cl2 -78 C, 65%

    EtO

    O OH48% HF, H2O, MeCN ( 1:2:17)

    4.5 h, rt, 55%

    O

    O

    HO

    (-)-Prelactone B

    OTBS

    OTBS

    3031

    3233

    O

    O

    HOEtO

    O OH OTBSTBSO

    OEt

    O

    H

    O

    H

    Lactonization

    (-)-Prelactone B

    Aldehyde-aldehyde crossed-aldol

    Mukaiyama aldol33

  • Aldol Aldol ReactionReactionA recent synthesis involves 8 steps, 33% overall yield

    Dias, C. L.; Steil, L. J.; Vasconcelos, V. A. Tetrahedron: Asymmetry. 2004, 15, 147150.

    MeH

    O

    NO

    OMe

    Bn

    O1. MgCl2, NaSbF6

    Et3N, TMSCl, rt2. MeOH, CF3CO2H 77%

    MeXc

    O

    Me

    OH

    dr 15:1

    Xc = NO

    O

    Bn

    H2, Pd/C

    EtOAc, 99%Me

    MeXc

    O

    Me

    OH

    1. TBSOTf, THF 2,6-Lutidine, 0 C

    2. LiBH4, H2O Et2O, 79% (2 steps)

    Me

    Me

    OH

    Me

    TBSOSwern

    -78 C, 95%Me

    Me

    O

    Me

    TBSO

    H

    Me

    Me Me

    TBSO O

    OtBu

    OHOTMS

    OtBu

    BF3.OEt2 CH2Cl2-78 C, 75%

    HCl/THF/H2O

    rt, 48 h, 77%

    O

    MeMe

    Me

    O

    OH

    (+)Prelactone B

    95:5aldehyde re-face attackFelkin/1,3-anti

    34

    33

  • an enantioselective aldol union of -oxyaldehyde substrates (Aldol 1). a diastereoselective aldol coupling between tri-oxy substituted butanals and an oxyaldehyde enolate (Aldol 2).

    Northrup, A. B.; Mangion, F. H.; Macmillan, D. W. C. Angew. Chem. Int. Ed. 2004, 43, 2152-2154.

    Aldol Aldol ReactionReaction

    Aldol 1 Aldol 2H

    OX

    O

    35

    H

    OOX

    H

    O

    OX

    OH

    OX

    H

    OOY O

    OYXOOH

    XO OH

    36 37

    Sakthivel, K.; Notz, W.; Bui, T.; Barbas III, C. F. J. Am. Chem. Soc. 2001, 123, 52605267.

    L-proline (20 mol %)

    DMSO, rt 62%

    anti:syn = >20:1, 99% ee

    OH

    O

    H

    O O OH

    OH38 39 40

  • R Solvent Yield% anti:syn ee (%)

    Ac DMF 0 - -Bn

    PMB

    MOM

    TBDPS

    TIPS

    TBS

    DMF 73 4:1 98

    DMF 64 4:1 97

    DMF 42 4:1 96

    DMF/Dioxane 61 9:1 96a

    DMSO 92 4:1 95

    Dioxane 62 3:1 88a

    aUsing 20 mol% catalystNorthrup, A. B.; Mangion, F. H.; Macmillan, D. W. C. Angew. Chem. Int. Ed. 2004, 43, 21522154.

    Aldol Aldol ReactionReactionStep 1: Organocatalytic Enantioselective Aldehyde Dimerization

    H

    OOR H

    O OH

    OR

    10 mol % L-prolinesolvent, rt, 24-48 h

    OR

  • Aldol Aldol ReactionReactionStep 2: Lewis Acid (LA) Mediated Mukaiyama AldolCarbohydrate Cyclization

    Northrup, A. B.; Macmillan, D. W. C. Science 2004, 305, 17521755.

    H

    O OH

    H OAcOTMS

    OTIPSTIPSO

    MgBr2Et2O

    Et2O, -20 to 4 C

    O

    TIPSO

    OHTIPSO

    GlucoseOH

    OAc

    H

    O OH

    H OAcOTMS

    OTIPSTIPSO

    MgBr2Et2O

    CH2Cl2, -20 to 4 C

    O

    TIPSO

    TIPSO

    MannoseOH

    OAc

    OH

    H

    O OH

    H OAcOTMS

    OTIPSTIPSO

    TiCl4CH2Cl2, -78 to -40 C

    O

    TIPSO

    TIPSO

    AlloseOH

    OAc

    OH

    79% yield 10:1 dr, 95% ee

    87% yield> 19:1 dr, 95% ee

    97% yield> 19:1 dr, 95% ee

    42

    42

    42

    43

    43

    43

    44

    45

    46

    H

    O OH

    OXOXH OY

    OTMS

    H

    O

    OXOY

    OH OH

    OX

    TMS O

    XOOH

    OY

    OHXO

    oxocarbenium

    LA

    4 possible carbohydrates36 41 37

  • Type-IType-I Activation of the reaction based on the nucleophilic/electrophilic properties of the catalyst.

    Background Information Direct Catalytic Asymmetric Aldol Reaction

    Direct Catalytic Asymmetric Mannich Reaction

    Direct Catalytic Asymmetric Michael Reaction

  • Mannich Mannich ReactionReaction

    Two important requirements : The nucleophilic addition of the proline enamine must be faster to an imine than to an aldehyde.

    The imine formation with a primary amine must be faster than the competitive aldol reaction.

    R1O

    H R2O

    R3NH2

    R1O

    H R2NR3

    Direct

    Indirect

    Preformedenol equivalent

    Preformed imine

    R1 R2O NR3

    List, B. J. Am. Chem. Soc. 2000, 122, 93369337.

    R

    O OH

    OH R

    O

    H R

    NR1

    R1 R

    O NR1kaldol

    keqR1NH2

    -H2O

    kMannich

    O

  • Mannich Mannich ReactionReaction

    Yamasaki, S.; Iida, T.; Shibasaki, M. Tetrahedron Lett. 1999, 40, 307310.

    Ph OCH3Et2N Ph OCH3

    NEt2 (R)-ALB (30 mol %)La(OTf)3.nH2O (30 mo l%)

    toluene, 50 C, 18 h, MS 3 65%

    40% ee

    O O

    47

    OO

    OOAl

    Li

    (R)-AlLibis(binapthoxide) ((R)-ALB)

    48

    List, B. J. Am. Chem. Soc. 2000, 122, 93369337.

    L-proline (35 mol %)

    DMSO, rt, 12 h 50%

    94% ee

    O

    NO2

    CHO NH2

    OMe

    O HN

    OMe

    48 NO2

    syn:anti = 17:1, 65% ee

    L-proline (35 mol %)

    DMSO, rt, 12 h 57%

    ONH2

    OMe

    O HN

    49OH

    H

    O

    OMe

    OH

  • Mannich Mannich ReactionReaction

    List, B.; Pojarliev, P.; Biller, W. T.; Martin, H. J. J. Am. Chem. Soc. 2002, 124, 827833.

    NO

    HH

    HX

    N

    H

    R ArO

    N N

    HRAr

    HHO

    H

    O

    NCO2H

    X

    H

    R

    ON

    H

    H

    N

    MeO

    X

    H O

    R

    O

    R

    syn

    (E)-Imine Small (planar) R gives high ee

    Enamine si Imine si

    N

    H

    X

    H O

    O

    H Large Rgives high ee

    Enamine siAldehyde re

    anti

    O NHAr

    R

    O OH

    O

  • Mannich Mannich ReactionReaction

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

    R = Yield % dr %ee

    p-NO2C6H4 92 20:1 >99

    C6H5 83 9:1 93

    P-MeOC6H4 88 3:1 61

    10 vol%

    L-proline (20 mol %)

    DMSO, rt, 3-24 h

    ONH2

    OMe

    O HN

    OHH

    O

    R R

    OMe

    OH

    O

    OH

    RNH2(S)-Proline

    Sharpless AA

    H

    O

    R

    O

    R

    O

    ROH

    NHR

    50

  • Mannich Mannich ReactionReaction

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

    OHPh

    NHPMPCl3CO OCCl3

    O NPMP

    Ph

    (PMP = paramethoxyphenyl)

    76% ONBOC

    Ph1. CAN2. BOC2O

    80%

    CF3CO3H

    O NBOCO

    Ph

    87%

    NaBH4, EtOHHO Ph

    NHBOC 98%

    OO O

    O

    O

    O

    O

    O

    51 52

    5354

    Synthesis of -amino acid derivative from the syn-1,2-amino alcohol: an oxydative hydroxy ketone(glycol-type) cleavage. an oxidative removal of the aromatic nitrogen substituent.

    OHR

    HNOxidation

    HO2C R

    PMPO NH2

  • Mannich Mannich ReactionReaction

    Cordova, A.; Notz, W.; Zhong, G.; Betancort, J. M.; Barbas III, C. F. J. Am. Chem. Soc. 2002, 124, 18421843.

    CO2Et

    NHPMP L-proline(20 mol %)

    DMSO, 2 h, rt 82%

    95% ee

    O

    H CO2Et

    N

    55 56

    OPMP

    (S)

    L-proline (5 mol %)

    [bmim]BF4, rt, 48 h 30%OH

    HOH

    OH

    >99% ee

    OO O

    58

    Chowdari, N. S.; Ramachary, D. B.; Barbas III, C. F. Synlett 2003, 19061909.

    N N BF4-

    [bmim = 1-butyl-3-methylimidazolium]

    [bmim]BF4 =

    55

    L-proline (5 mol %)

    [bmim]BF4, rt, 30 min 99%

    CO2Et

    NHPMP

    >99% ee

    O O

    57

    H CO2Et

    NPMP

    For an excellent review on room temperature ionic liquids in organic synthesis, seeWelton, T. Chem. Rev. 1999, 99, 20712084.

  • Mannich Mannich ReactionReaction

    H H CO2Et

    NHPMP L-proline (20 mol %)

    DMSO, 8 h, rt 80%iPr iPr

    syn: anti = 10:1, 87% ee2 equiv.

    O O

    59

    H CO2Et

    NPMP

    55

    Corodova, A.; Watanabe, S.; Tanaka, F.; Notz, W.; Barbas III, C. F. J. Am. Chem. Soc. 2002, 124, 18661867.

    Catalyst Time(h) Yield% syn:anti %eesyn (anti)

    (L)-Proline 3 88 32:1 >99 (31)

    SMP 22 40

  • Mannich Mannich ReactionReaction

    Corodova,A.; Barbas, C. F. Tetrahedron Lett. 2002, 77497752.

    N

    CO2EtH

    PMP NO

    OH

    H

    R

    transition state for Proline-catalyzed Mannich reaction

    N

    HR

    CO2Et

    NOMe

    H

    transition state for SMP-catalyzed Mannich reaction

    PMP

    Chowdari, N.S.; Suri. J. T.; Barbas III, C. F. Org. Lett. 2004, 25072510.

    L-proline(30 mol %)

    DMSO, rt, 6 h

    H CO2Et

    HNPMP

    98% ee

    NaClO2NaH2PO4

    rt, 2 h 90%

    1. NaClO2 NaH2PO4 2 h, rt2. NaOH3. HCl5 min, 80%

    HO CO2Et

    HNPMP

    NPMP

    CO2Et

    OO

    O

    O63

    64

    65

    H CO2Et

    NPMP

    55 94%

    H

  • Activation of the reaction based on the nucleophilic/electrophilic properties of the catalyst.

    Type-IType-I

    Background Information Direct Catalytic Asymmetric Aldol Reaction

    Direct Catalytic Asymmetric Mannich Reaction

    Direct Catalytic Asymmetric Michael Reaction

  • Michael ReactionMichael Reaction

    Role of chiral amine in previous catalytic asymmetric Michael reaction: activate the Michael acceptor via formation of an iminium species (I) act as a base forming a complex with enolate to react with the acceptor (II) activation of ketone donors through formation of an enamine intermediate (III)

    Betancort, J. M.; Sakthivel, R. T.; Barbas, C. F. Tetrahedron Lett. 2001, 42, 44414444.

    O

    NuMichael addition

    O

    Nu

    Nu = active methylene center, e.g., malonic acid ester -keto esters, nitroalkanes, etc.

    NR2R'

    Nu

    I

    O

    R' EWG

    II

    NR2

    R' EWG

    III

    :HNR3

  • Michael ReactionMichael Reaction

    Yamaguchi, M.; Igarashi, Y.; Reddy, R. S.; Shiraishi, T.; Hirama, M. Tetrahedron. 1997, 32, 11223-11236.

    ONO2

    NH

    CO2Rb

    5 mol %

    24 h, CHCl3, rt 81%

    O

    NO2

    59 % ee65

    (R)

    Hanessian, S.; Pham, V. Org. Lett. 2000, 2, 29752978.

    ONO2

    NH

    CO2H

    5 mol %

    additive, CHCl3, rt 88%

    O

    NO2(R)

    93 % ee

    HN

    NH

    trans-2,5-dimethylpiperazine

    additive =

    66

  • Michael ReactionMichael Reaction

    Entry Product Yield dr (syn: anti) eea

    1

    2

    3

    4

    5

    6

    97% 7%

    10%3:185%

    95% 20:1 23%

    n. d.bn. d.

    n. d. n. d.

    87%

    92% 20:1 10%

    85%

    List, B.; Pojarliev, P.; Martin, H. J. Org. Lett. 2001, 3, 24232425. aee of syn diastereomer

    bnot determined

    ONO2

    Ph

    ONO2

    Ph

    ONO2

    Ph

    ONO2

    iPr

    ONO2

    Ph

    SO NO2

    O

    R R1

    20 vol%

    R3 NO2

    R2L-proline (15 mol %)

    DMSO, rt, 2-24 h

    O

    R R1

    R2

    R3NO2

    67 68

  • Michael ReactionMichael Reaction

    a 0.5 mL ofSolvent/mmol of nitrostyerene

    Enders, D.; Seki, A. Synlett 2001, 2629.

    EntryProline (equiv.) Solvent Conditions Yield%a %ee

    1

    2

    3

    4

    5

    6

    7

    8

    9

    10

    11

    0.50.5

    0.5

    0.5

    0.2

    0.5

    0.5

    0.5

    1.5

    0.5

    0.5

    DMSOMeCN

    DMF

    DMSO

    DMSO

    MeOH

    EtOH

    i-PrOH

    MeOH

    MeOH

    MeOHa

    rt, 1.5 drt, 4 d

    rt, 7 d

    15 C, 2 d

    rt, 3 d

    rt, 3 d

    rt, 3 d

    rt, 3 d

    rt, 3 d

    rt, 3 d

    rt, 3 d

    606

    46

    62

    57

    70

    32

    39

    77

    68

    70

    5460

    47

    5458

    71

    73

    66

    73

    75

    76

    O

    Ph NO2(L)-proline O

    NO2Ph

    69

  • Michael ReactionMichael Reaction

    Enders, D.; Seki, A. Synlett 2001, 2629.

    acombined yield of both diastereomers, b5mL solvent/mmol of 2, c0.5mL solvent/mmol of 2

    R1R2

    O

    Ph NO2(0.21.5 equiv.)

    MeOH, rtR1

    ONO2

    R2

    Ph

    70 71 72

    L-proline

    EntryProline (equiv.) Time (d) Yield%a %eede (%)72

    1

    2

    3

    4

    5

    6

    syn 0.2b 4 74 88 76

    syn 1.5c 3 81 90 73

    (S,R) 0.2b 8 44 80 76

    (S,R) 1.5c 3 83 80 72

    (S,R) 0.2b 4 79 94 57

    (S,R) 1.5c 2 99 97 47

    R1 R2

    Et Me

    Et Me

    Ph(CH2)2 Me

    Ph(CH2)2 Me

    (CH2)4

    (CH2)4

  • Michael ReactionMichael Reaction

    Proposed transition state

    Enders, D.; Seki, A. Synlett 2001, 2629.

    NO

    OR1

    R2

    N O

    O

    H

    Betancort, J. M.; Barbas III, C. F. Org. Lett., 2001, 3, 37373740.

    NH N

    OCatalyst

    R R' time yield% dr(syn/anti)

    %ee(syn)

    H Ph 3 h 85 90/10 56

    iPrCF3

    3 d 77 98/2 78

    R CHO NO2R' Catalyst 20 mol %

    THF, rtOHC NO2

    R'

    R73

  • Michael ReactionMichael Reaction

    Alexakis, A.; Andrey, O. Org. Lett. 2002, 4, 36113614.

    NH

    N

    (R,R)Catalyst

    H

    O

    NO2Ph

    Catalyst (15 mol %)HCl (15 mol %)

    CHCl3, 25 C, 2 d 71%

    NO2O

    H

    Ph

    83% ee(syn: anti) = 95:5

    74

    Betancort, J. M.; Barbas III, C. F. Org. Lett. 2004, 6, 25272530.

    NH

    N

    Catalyst

    H

    O

    NO2Ph

    Catalyst (0.3 equiv) TFA (0.3 equiv)

    2-PrOH, 4 C, 48 h 87%

    NO2O

    H

    Ph

    80% ee

    NO2Ph

    Catalyst (0.3 equiv) TFA (0.3 equiv)

    2-PrOH, 4 C, 24 h 93%

    NO2O

    H

    Ph

    91% ee

    O

    H

    75

    76

  • ConclusionConclusion

    Proline is nontoxic, inexpensive (1gm/$5), and readily available in both enantiomeric forms.

    Eliminating the protection-deprotection and oxidation state adjustment steps, proline-catalyzed aldol reactions can shorten the path of total synthesis.

    Products from proline-catalyzed Mannich reactions are useful in terms of both biological and chemical aspects and are complements of Sharpless-AA.

    The reactions do not require inert conditions and are run at room temperature or at lower temperatures.

    Organocatalysis is emerging as a complement to metal catalysis.

    It constitutes the tip of the iceberg of a novel catalytic principle, of which the entire scope still remains to be fully uncovered. Benjamin List