Solvent-effects tuning the catalytic reactivity of prolinamides in asymmetric aldol reactions

Novel prolinamides were prepared and applied as organocatalysts in the asymmetric aldol reaction. Stable imidazolidinones were formed between prolinamides and aromatic aldehydes in organic solvents. It was found that aqueous conditions can significantly suppress the formation of the unwanted imidazolidinone intermediate and improve the catalytic activity of the prolinamides. As a consequence, high chemical yields (up to 99%) and good diastereoselectivity (up to >20:1 dr) and enantioselectivity (up to 95% ee) were achieved in 2-Me-THF or brine. This strategy could serve as a general solution to enhance the performance of prolinamides as organocatalysts.

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(S)-N-(2-(p-Dodecylsulfonamido)phenyl)prolinamideC29H43N3O3S[α]D25 = −18.0 (c 0.5, CHCl3)Source of chirality: chiral poolAbsolute configuration: (S)

(S)-N-(2-Dodecylamidophenyl)prolinamideC23H37N3O2[α]D25 = −34.5 (c 0.5, CHCl3)Source of chirality: chiral poolAbsolute configuration: (S)

(S)-N-(2-Benzylaminephenyl)prolinamideC18H21N3O[α]D25 = −57.0 (c 0.5, CHCl3)Source of chirality: chiral poolAbsolute configuration: (S)

(S)-N-(2-Aminephenyl)prolinamideC11H15N3O[α]D25 = −55.5 (c 0.5, CHCl3)Source of chirality: chiral poolAbsolute configuration: (S)

(3R,7aS)-Hexahydro-2-(2-benzylaminephenyl)-3-(4-bromophenyl)-1H-pyrrolo[1,2-c]imidazol-1-oneC25H24BrN3O[α]D25 = +39.5 (c 0.4, CH2Cl2)Source of chirality: chiral poolAbsolute configuration: (3R,7aS)

(2S,1′R)-2-(Hydroxy-(2-nitro4-bromophenyl)methyl)cyclohexan-1-oneC13H14BrNO4[α]D25 = +23.4 (c 0.4, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2S,1′R)