Direct asymmetric aldol reaction catalyzed by simple prolinamide phenols

Simple prolinamides 1a–f were synthesized, and their catalytic effects on the direct asymmetric aldol reactions in organic solvents and in water were evaluated. Prolinamide phenols 1a–d were found to be effective catalysts for the reaction of aromatic aldehydes with cyclohexanone in neat ketone and in water. The anti-aldol products were obtained with up to 98/2 anti/syn ratio and 96% ee in neat ketone, 98/2 anti/syn ratio and 99% ee in water, respectively.

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(S)-N-(2-Hydroxyphenyl)pyrrolidine-2-carboxamideC11H14N2O2[α]D20=-41.0 (c 1.41, EtOH)Source of chirality: (S)-prolineAbsolute configuration: (2S)

(2S,4R)-4-Hydroxy-N-(2-hydroxyphenyl)pyrrolidine-2-carboxamideC11H14N2O3[α]D20=-20.0 (c 1.36, EtOH)Source of chirality: (2S,4R)-4-hydroxyprolineAbsolute configuration: (2S,4R)

(S)-N-(3,5-Di-tert-butyl-2-hydroxyphenyl)pyrrolidine-2-carboxamideC19H30N2O2[α]D20=-36.8 (c 1.18, EtOH)Source of chirality: (S)-prolineAbsolute configuration: (2S)

(2S,4R)-4-Hydroxy-N-(3,5-di-tert-butyl-2-hydroxyphenyl)pyrrolidine-2-carboxamideC19H30N2O3[α]D20=-16.2 (c 1.07, EtOH)Source of chirality: (2S,4R)-4-hydroxyprolineAbsolute configuration: (2S,4R)

(S)-N-(2-Hydroxynaphthalen-1-yl)pyrrolidine-2-carboxamideC15H16N2O2[α]D20=-28.3 (c 0.64, MeOH)Source of chirality: (S)-prolineAbsolute configuration: (2S)

(S)-N-(2-(4-Methylphenylsulfonamido)phenyl)pyrrolidine-2-carboxamideC18H21N3O3S[α]D20=-60.8 (c 0.88, EtOH)Source of chirality: (S)-prolineAbsolute configuration: (2S)