trans-4-Hydroxy-l-prolinamide as an efficient catalyst for direct asymmetric aldol reaction of acetone with isatins

Prolinamide (2S,4R)-4-hydroxy-N-((S)-1-phenylethyl)pyrrolidine-2-carboxamide was found to be an efficient organocatalyst (10 mol %) for the direct asymmetric aldol reactions of isatins with acetone at −35 °C in THF and afforded the product in 79% yield with 74% ee. We have generalised the methodology for the direct asymmetric aldol reaction between isatin derivatives and acetone, and the corresponding aldol products were obtained in high yields (up to 99%) and with moderate enantioselectivities (up to 80%). This method has been applied to the enantioselective synthesis of (S)-convolutamydine.

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(S)-N-Benzhydrylpyrrolidine-2 carboxamideC18H20N2O[α]D25 = −25.7 (c 0.605, MeOH)Absolute configuration: (S)Source of chirality: (S)-Proline

(2S,4R)-4-Hydroxy-N-((S)-1-(naphthalen-1-yl)ethyl)pyrrolidine-2-carboxamideC17H20N2O2[α]D25 = −24.0 (c 0.734, MeOH)Absolute configuration: (S)Source of chirality: (S)-Proline

(S)-3-Hydroxy-3-(2-oxopropyl)indolin-2-oneC11H11NO3[α]D25 = −32.0 (c 0.39, MeOH)Absolute configuration: (S)Source of chirality: (S)-Proline

(S)-3-Hydroxy-1-methyl-3-(2-oxopropyl)indolin-2-oneC12H13NO3[α]D25 = −18.2 (c 1.00, MeOH)Absolute configuration: (S)Source of chirality: (S)-Proline

(S)-1-Benzyl-3-hydroxy-3-(2-oxopropyl)indolin-2-oneC18H17NO3[α]D25 = −13.5 (c 1.2, MeOH)Absolute configuration: (S)Source of chirality: (S)-Proline

(S)-1-Allyl-3-hydroxy-3-(2-oxopropyl)indolin-2-oneC14H15NO3[α]D25 = −27.5 (c 0.35 MeOH)Absolute configuration: (S)Source of chirality: (S)-Proline

(S)-5-Fluoro-3-hydroxy-3-(2-oxopropyl)indolin-2-oneC11H10FNO3[α]D25 = −18.9 (c 0.38, MeOH)Absolute configuration: (S)Source of chirality: (S)-Proline

(S)-5-Chloro-3-hydroxy-3-(2-oxopropyl)indolin-2-oneC11H10ClNO3[α]D25 = −9.9 (c 0.50, MeOH)Absolute configuration: (S)Source of chirality: (S)-Proline

(S)-5-Bromo-3-hydroxy-3-(2-oxopropyl)indolin-2-oneC11H10BrNO3[α]D25 = −25.0 (c 1.11, MeOH)Absolute configuration: (S)Source of chirality: (S)-Proline

(S)-5-Nitro-3-hydroxy-3-(2-oxopropyl)indolin-2-oneC11H10N2O5[α]D25 = −12.8 (c 1.35, MeOH)Absolute configuration: (S)Source of chirality: (S)-Proline

(S)-3-Hydroxy-5-methoxy-3-(2-oxopropyl)indolin-2-oneC12H13NO4[α]D25 = −2.2 (c 1.05, MeOH)Absolute configuration: (S)Source of chirality: (S)-Proline

(S)-5,7-Dibromo-3-hydroxy-3-(2-oxopropyl)indolin-2-oneC11H9Br2NO3[α]D25 = −7.8 (c 0.26, MeOH)Absolute configuration: (S)Source of chirality: (S)-Proline