Simple amphiphilic isosteviol–proline conjugates as chiral catalysts for the direct asymmetric aldol reaction in the presence of water

Two novel amphiphilic catalysts 3 and 4 were synthesized by the condensation of isosteviol with l-proline in a one-pot process. With only 1 mol % loading, the catalyst 3 showed excellent activity (up to >99% yield) and stereoselectivity (up to 99:1 dr, >99% ee) for the direct aldol reaction of cyclohexanone and substituted benzaldehydes at room temperature in the presence of water. In addition, solvent effects, catalyst loading, substrate scope, temperature, and the influence of water on the reactions were investigated. These results demonstrate that the catalysts with a chiral concave and hydrophobic substituent in the 4-position of l-proline furnished high activity and stereoselectivity for the reaction.

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(2S,4R)-4-(ent-16′-Oxobeyeran-19′-carbonyl oxy)-prolineC25H37NO5[α]D20=-56.7 (c 0.13, CHCl3)Source of chirality: (2S,4R)-4-hydroxy-proline ent-16-ketobeyeran-19-oic acidAbsolute configuration: (2S,4R,19′R)

(2S,4R)-4-(ent-16′β-Hydroxybeyeran-19′-carbonyl oxy)-prolineC25H39NO5[α]D20=-50.0 (c 0.12, CH3OH)Source of chirality: (2S,4R)-4-hydroxy-proline ent-16′β-Hydroxybeyeran-19′-oic acidAbsolute configuration: (2S,4R,16′R,19′R)