Natural amino acid salt catalyzed aldol reactions of isatins with ketones: highly enantioselective construction of 3-alkyl-3-hydroxyindolin-2-ones

The asymmetric synthesis of 3-alkyl-3-hydroxyindolin-2-ones via direct aldol reaction of isatin with ketones catalyzed by natural amino acid salts is described, in which the phenylalanine lithium salt was found to be the best catalyst. This strategy was then applied to a variety of isatin and ketone substrates and the corresponding aldol products were obtained in excellent yields (up to 97%) with good to excellent enantioselectivities (up to 90%).

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(S)-3-Hydroxy-3-(2-oxopropyl)indolin-2-oneC11H13NO370% ee[α]D25 = −11.0 (c 1.0, MeOH) determined by HPLCThe absolute configuration was determined by comparison of the rotation with previously reported valuesAbsolute configuration: (S)

(S)-3-Hydroxy-1-methyl-3-(2-oxopropyl)indolin-2-oneC12H13NO381% ee[α]D25 = −15.2 (c 2.4, MeOH) determined by HPLCThe absolute configuration was determined by comparison of the rotation with previously reported valuesAbsolute configuration: (S)

(S)-1-Benzyl-3-hydroxy-3-(2-oxopropyl)indolin-2-oneC18H17NO387% ee[α]D25 = −16.4 (c 2.8, MeOH) determined by HPLCThe absolute configuration was determined by comparison of the rotation with previously reported valuesAbsolute configuration: (S)

(S)-3-Hydroxy-1-(4-methoxybenzyl)-3-(2-oxopropyl)indolin-2-oneC19H19NO487% ee[α]D25 = −16.3 (c 3.7, MeOH) determined by HPLCThe absolute configuration was determined by comparison of the rotation with previously reported valuesAbsolute configuration: (S)

(S)-3-Hydroxy-5-methyl-3-(2-oxopropyl)indolin-2-oneC12H13NO366% ee[α]D25 = −13.0 (c 1.0, MeOH) determined by HPLCThe absolute configuration was determined by comparison of the rotation with previously reported valuesAbsolute configuration: (S)

(S)-5-Fluoro-3-hydroxy-3-(2-oxopropyl)indolin-2-oneC11H10FNO377% ee[α]D25 = −17.0 (c 1.0, MeOH) determined by HPLCThe absolute configuration was determined by comparison of the rotation with previously reported valuesAbsolute configuration: (S)

(S)-5-Chloro-3-hydroxy-3-(2-oxopropyl)indolin-2-oneC11H10ClNO378% ee[α]D25 = −22.0 (c 1.0, MeOH) determined by HPLCThe absolute configuration was determined by comparison of the rotation with previously reported valuesAbsolute configuration: (S)