A highly enantio- and diastereoselective direct aldol reaction in aqueous medium catalyzed by thiazolidine-based compounds

Taking l-aminoacids as starting materials, a new set of enantiopure thiazolidine-based organocatalysts were prepared using a simple synthetic approach and successfully applied in the asymmetric direct aldol reaction between various cyclic ketones and aldehydes in a saturated aqueous medium. The aldol adducts were obtained with excellent enantioselectivity (up to >99% ee) and diastereoselectivity (dr >20:1).

Figure optionsDownload as PowerPoint slide

(R)-N-((S)-1-Hydroxy-4-(methylthio)-1,1-diphenylbutan-2-yl)thiazolidine-4-carboxamideC21H26N2O2S2[α]D20 = −57 (c 1, CH2Cl2)Source of chirality: natural aminoacidAbsolute configuration: (R,S)

(R)-N-((R)-1-Hydroxy-3-mercapto-1,1-diphenylpropan-2-yl)thiazolidine-4-carboxamideC19H22N2O2S2[α]D20 = −151 (c 1, CH2Cl2)Source of chirality: natural aminoacidAbsolute configuration: (R,R)

(R)-N-((S)-1-Hydroxy-1,1,3-triphenylpropan-2-yl)-2,2-dimethylthiazolidine-4-carboxamideC27H30N2O2S[α]D20 = −98 (c 1, CH2Cl2)Source of chirality: natural aminoacidAbsolute configuration: (R,S)

(S)-2-((R)-Hydroxy(phenyl)methyl)cyclohexanoneC13H16O2ee = 99% and dr = 91:9[α]D25 = +18 (c 1, CHCl3)Source of chirality: organocatalytic asymmetric aldol additionAbsolute configuration: (S,R)

(S)-2-((R)-Hydroxy(p-tolyl)methyl)cyclohexanoneC14H18O2ee >99% and dr = 98:2.[α]D25 = +17 (c 0.2, CHCl3)Source of chirality: organocatalytic asymmetric aldol additionAbsolute configuration: (S,R)

(S)-2-((R)-Hydroxy(4-methoxyphenyl)methyl)cyclohexanoneC14H18O3ee = 98% and dr = 89:11[α]D25 = +25 (c 1, CHCl3)Source of chirality: organocatalytic asymmetric aldol additionAbsolute configuration: (S,R)

(S)-2-((R)-(4-Chlorophenyl)(hydroxy)methyl)cyclohexanoneC14H15ClO2ee = 99% and dr = 96:4[α]D25 = +20 (c 1, CHCl3)Source of chirality: organocatalytic asymmetric aldol additionAbsolute configuration: (S,R)

(S)-2-((R)-(4-Bromophenyl)(hydroxy)methyl)cyclohexanoneC14H15BrO2ee = 99% and dr = 98:2[α]D25 = +24 (c 1, CHCl3)Source of chirality: organocatalytic asymmetric aldol additionAbsolute configuration: (S,R)

4-((R)-Hydroxy((S)-2-oxocyclohexyl)methyl)benzonitrileC14H15NO2ee = 98% and dr = 96:4[α]D25 = +19 (c 1, CHCl3)Source of chirality: organocatalytic asymmetric aldol additionAbsolute configuration: (R,S)

(S)-2-((R)-Hydroxy(2-nitrophenyl)methyl)cyclohexanoneC13H15NO4ee >99% and dr = 98:2[α]D25 = +15 (c 1, CHCl3)Source of chirality: organocatalytic asymmetric aldol additionAbsolute configuration: (S,R)

(S)-2-((R)-Hydroxy(3-nitrophenyl)methyl)cyclohexanoneC13H15NO4ee = 98% and dr = 91:9[α]D25 = +26 (c 1, CHCl3)Source of chirality: organocatalytic asymmetric aldol additionAbsolute configuration: (S,R)

(S)-2-((R)-Hydroxy(4-nitrophenyl)methyl)cyclohexanoneC13H15NO4ee = 98% and dr = 91:9[α]D20 = +10 (c 1, CHCl3)Source of chirality: organocatalytic asymmetric aldol additionAbsolute configuration: (S,R)

(S)-2-((R)-Hydroxy(4-nitrophenyl)methyl)cyclopentanoneC12H13NO4ee = 90% and dr = 68:32[α]D25 = −25 (c 0.5, CHCl3)Source of chirality: organocatalytic asymmetric aldol additionAbsolute configuration: (S,R)