The application of a structurally simple, recyclable, and large-scale l-prolinamide catalyst for asymmetric aldol reactions

A highly efficient, bifunctional prolinamide catalyst, which consists of chiral proline and trans-cyclohexanediamine moieties, was prepared and evaluated in the direct asymmetric aldol reactions of various ketones and aldehydes. The catalyst displayed impressive catalytic activity toward heterocyclic ketones containing oxygen, sulfur, or nitrogen, which have not been sufficiently explored. The substrate scope also covered cyclic and acyclic ketones. With heterocyclic ketones or cyclohexanone, the aldol reactions gave products in high yields and with respectable enantioselectivities (87–99% ee) and diastereoselectivities (up to >99:1 anti/syn). The catalyst could be recycled and reused up to seven times resulting in good yields and with good selectivities. This catalyst is also efficient in large-scale reactions with the enantioselectivities remaining at the same level as in the experimental scale reactions.

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(R)-N-((1R,2R)-2-(3,4,5-Trimethoxybenzamido)cyclohexyl)pyrrolidine-2-carboxamideC21H31N3O5[α]D20 = −69.1 (c 0.3, CHCl3)Source of chirality: the precursorAbsolute configuration: (R)-N-(1R,2R)

(S)-3-((R)-Hydroxy(2-nitrophenyl)methyl)dihydro-2H-pyran-4(3H)-oneC12H13NO5[α]D20 = −7.3 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (3S,1′R)

(S)-3-((R)-Hydroxy(3-nitrophenyl)methyl)dihydro-2H-pyran-4(3H)-oneC12H13NO5[α]D20 = −7.9 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (3S,1′R)

(S)-3-((R)-Hydroxy(4-nitrophenyl)methyl)dihydro-2H-pyran-4(3H)-oneC12H13NO5[α]D20 = −18.1 (c 1.0, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (3S,1′R)

4-((R)-Hydroxy((S)-4-oxotetrahydro-2H-pyran-3-yl)methyl)benzonitrileC13H13NO3[α]D20 = −6.2 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (3S,1′R)

(S)-3-((R)-(4-Chlorophenyl)(hydroxy)methyl)dihydro-2H-pyran-4(3H)-oneC12H13ClO3[α]D20 = −7.8 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (3S,1′R)

(S)-3-((R)-(2-Chlorophenyl)(hydroxy)methyl)dihydro-2H-pyran-4(3H)-oneC12H13ClO3[α]D20 = −8.4 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (3S,1′R)

(S)-3-((R)-(4-Bromophenyl)(hydroxy)methyl)dihydro-2H-pyran-4(3H)-oneC12H13BrO3[α]D20 = −7.3 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (3S,1′R)

(S)-3-((R)-(3-Bromophenyl)(hydroxy)methyl)dihydro-2H-pyran-4(3H)-oneC12H13BrO3[α]D20 = −8.0 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (3S,1′R)

(S)-3-((R)-(4-Fluorophenyl)(hydroxy)methyl)dihydro-2H-pyran-4(3H)-oneC12H13FO3[α]D20 = −8.5 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (3S,1′R)

(S)-3-((R)-Hydroxy(p-tolyl)methyl)dihydro-2H-pyran-4(3H)-oneC13H16O3[α]D20 = −6.3 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (3S,1′R)

(S)-3-((R)-Hydroxy(phenyl)methyl)dihydro-2H-pyran-4(3H)-oneC12H14O3[α]D20 = −9.2 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (3S,1′R)

(S)-3-((R)-Furan-2-yl(hydroxy)methyl)dihydro-2H-pyran-4(3H)-oneC10H12O4[α]D20 = −10.2 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (3S,1′R)

(S)-3-((R)-Hydroxy(thiophen-2-yl)methyl)dihydro-2H-pyran-4(3H)-oneC10H12O3S[α]D20 = −9.8 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (3S,1′R)

(S)-3-((R)-Hydroxy(2-nitrophenyl)methyl)dihydro-2H-thiopyran-4(3H)-oneC12H13NO4S[α]D20 = +35.8 (c 1.0, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (3S,1′R)

(S)-3-((R)-Hydroxy(3-nitrophenyl)methyl)dihydro-2H-thiopyran-4(3H)-oneC12H13NO4S[α]D20 = +26.8 (c 0.8, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (3S,1′R)

(S)-3-((R)-Hydroxy(4-nitrophenyl)methyl)dihydro-2H-thiopyran-4(3H)-oneC12H13NO4S[α]D20 = +17.6 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (3S,1′R)

4-((R)-Hydroxy((S)-4-oxotetrahydro-2H-thiopyran-3-yl)methyl)benzonitrileC13H13NO2S[α]D20 = +14.2 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (3S,1′R)

(S)-3-((R)-(4-Fluorophenyl)(hydroxy)methyl)dihydro-2H-thiopyran-4(3H)-oneC12H13FO2S[α]D20 = +15.7 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (3S,1′R)

(S)-3-((R)-(4-Chlorophenyl)(hydroxy)methyl)dihydro-2H-thiopyran-4(3H)-oneC12H13ClO2S[α]D20 = +16.2 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (3S,1′R)

(S)-3-((R)-(2-Chlorophenyl)(hydroxy)methyl)dihydro-2H-thiopyran-4(3H)-oneC12H13ClO2S[α]D20 = +18.8 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (3S,1′R)

(S)-3-((R)-(4-Bromophenyl)(hydroxy)methyl)dihydro-2H-thiopyran-4(3H)-oneC12H13BrO2S[α]D20 = +20.4 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (3S,1′R)

(S)-3-((R)-(3-Bromophenyl)(hydroxy)methyl)dihydro-2H-thiopyran-4(3H)-oneC12H13BrO2S[α]D20 = +19.2 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (3S,1′R)

(S)-3-((R)-(2,4-Dichlorophenyl)(hydroxy)methyl)dihydro-2H-thiopyran-4(3H)-oneC12H12Cl2O2S[α]D20 = +24.5 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (3S,1′R)

(S)-3-((S)-1-Hydroxy-2-methylpropyl)dihydro-2H-thiopyran-4(3H)-oneC9H16O2S[α]D20 = −33.6 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (3S,1′S)

(S)-tert-Butyl 3-((R)-hydroxy(2-nitrophenyl)methyl)-4-oxopiperidine-1-carboxylateC17H22N2O6[α]D20 = −72.2 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (3S,1′R)

(S)-tert-Butyl 3-((R)-hydroxy(3-nitrophenyl)methyl)-4-oxopiperidine-1-carboxylateC17H22N2O6[α]D20 = −75.1 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (3S,1′R)

(S)-tert-Butyl 3-((R)-hydroxy(4-nitrophenyl)methyl)-4-oxopiperidine-1-carboxylateC17H22N2O6[α]D20 = −76.4 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (3S,1′R)

(S)-tert-Butyl 3-((R)-(4-fluorophenyl)(hydroxy)methyl)-4-oxopiperidine-1-carboxylateC17H22FNO4[α]D20 = −70.3 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (3S,1′R)

(S)-tert-Butyl 3-((R)-(4-chlorophenyl)(hydroxy)methyl)-4-oxopiperidine-1-carboxylateC17H22ClNO4[α]D20 = −68.5 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (3S,1′R)

(S)-tert-Butyl 3-((R)-(2-chlorophenyl)(hydroxy)methyl)-4-oxopiperidine-1-carboxylateC17H22ClNO4[α]D20 = −79.6 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (3S,1′R)

(S)-tert-Butyl 3-((R)-(4-bromophenyl)(hydroxy)methyl)-4-oxopiperidine-1-carboxylateC17H22BrNO4[α]D20 = −74.6 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (3S,1′R)

(S)-tert-Butyl 3-((R)-(3-bromophenyl)(hydroxy)methyl)-4-oxopiperidine-1-carboxylateC17H22BrNO4[α]D20 = −83.7 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (3S,1′R)

(S)-2-((R)-Hydroxy(2-nitrophenyl)methyl)cyclohexanoneC13H15NO4[α]D20 = +10.4 (c 1.0, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (2S,1′R)

(S)-2-((R)-Hydroxy(3-nitrophenyl)methyl)cyclohexanoneC13H15NO4[α]D20 = +12.6 (c 0.8, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (2S,1′R)

(S)-2-((R)-Hydroxy(4-nitrophenyl)methyl)cyclohexanoneC13H15NO4[α]D20 = +8.6 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (2S,1′R)

4-((R)-Hydroxy((S)-2-oxocyclohexyl)methyl)benzonitrileC14H15NO2[α]D20 = +9.4 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (2S,1′R)

(S)-2-((R)-Hydroxy(2-methoxyphenyl)methyl)cyclohexanoneC14H18O3[α]D20 = +11.4 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (2S,1′R)

(S)-2-((R)-Hydroxy(3-methoxyphenyl)methyl)cyclohexanoneC13H15NO4[α]D20 = +9.4 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (2S,1′R)

(S)-2-((R)-Hydroxy(4-methoxyphenyl)methyl)cyclohexanoneC14H18O3[α]D20 = +12.1 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (2S,1′R)

(S)-2-((R)-(4-Chlorophenyl)(hydroxy)methyl)cyclohexanoneC14H15ClO2[α]D20 = +15.3 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (2S,1′R)

(S)-2-((R)-(4-Bromophenyl)(hydroxy)methyl)cyclohexanoneC13H15BrO2[α]D20 = +18.2 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (2S,1′R)

(S)-2-((R)-(4-Fluorophenyl)(hydroxy)methyl)cyclohexanoneC13H15FO2[α]D20 = +11.5 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (2S,1′R)

(S)-2-((R)-Hydroxy(4-nitrophenyl)methyl)cyclopentanoneC12H13NO4[α]D20 = +15.1 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (2S,1′R)

(R)-4-Hydroxy-4-(4-nitrophenyl)butan-2-oneC10H11NO4[α]D20 = +18.4 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (4R)

(1R,2S)-1-Hydroxy-2-methyl-1-(4-nitrophenyl)pentan-3-oneC12H15NO4[α]D20 = +20.1 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (1R,2S)