2-Hydroxy-3-[(S)-prolinamido]pinanes as novel bifunctional organocatalysts for asymmetric aldol reactions in aqueous media

Novel (S)-prolinamides with stereoisomeric 2-hydroxy-3-aminopinane units have been synthesized. In the presence of (1R,2R,3S,5R)-2-hydroxy-3-[(S)-prolinamido]pinane (5 mol %) cyclic ketones reacted with (hetero-)aromatic aldehydes in aqueous media to afford chiral aldols in high yields. The reaction had moderate to high diastereo- (dr up to 91/9) and enantioselectivities (up to 83% ee).

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(S)-Benzyl 2-((1S,2S,3R,5S)-2-hydroxy-2,6,6-trimethylbicyclo[3.1.1]heptan-3-ylcarbamoyl)-pyrrolidine-1-carboxylateC23H32N2O4[α]D23=-24.25 (c 1.0, CHCl3)Source of chirality: (S)-proline and (1S,2S,3R,5S)-2-hydroxy-3-amino-2,6,6-trimethylbicyclo[3.1.1]heptaneAbsolute configuration: (2S,1′S,2′S,3′R,5′S)

(S)-Benzyl 2-((1R,2R,3S,5R)-2-hydroxy-2,6,6-trimethylbicyclo[3.1.1]heptan-3-ylcarbamoyl)-pyrrolidine-1-carboxylateC23H32N2O4[α]D24=-86.95 (c 1.0, CHCl3)Source of chirality: (S)-proline and (1R,2R,3S,5R)-2-hydroxy-3-amino-2,6,6-trimethylbicyclo[3.1.1]heptaneAbsolute configuration: (2S,1′R,2′R,3′S,5′R)

(S)-Benzyl 2-((1S,2S,3S,5S)-2-hydroxy-2,6,6-trimethylbicyclo[3.1.1]heptan-3-ylcarbamoyl)-pyrrolidine-1-carboxylateC23H32N2O4[α]D23=-79.85 (c 1.0, CHCl3)Source of chirality: (S)-proline and (1S,2S,3S,5S)-2-hydroxy-3-amino-2,6,6-trimethylbicyclo[3.1.1]heptaneAbsolute configuration: (2S,1′S,2′S,3′S,5′S)

(S)-Benzyl 2-((1R,2R,3R,5R)-2-hydroxy-2,6,6-trimethylbicyclo[3.1.1]heptan-3-ylcarbamoyl)-pyrrolidine-1-carboxylateC23H32N2O4[α]D24=-54.35 (c 2.0, CHCl3)Source of chirality: (S)-proline and (1R,2R,3R,5R)-2-hydroxy-3-amino-2,6,6-trimethylbicyclo[3.1.1]heptaneAbsolute configuration: (2S,1′R,2′R,3′R,5′R)

(S)-N-((1S,2S,3R,5S)-2-Hydroxy-2,6,6-trimethylbicyclo[3.1.1]heptan-3-yl)-pyrrolidine-2-carboxamideC15H26N2O2[α]D24=-32.25 (c 1.0, CHCl3)Source of chirality: (S)-proline and (1S,2S,3R,5S)-2-hydroxy-3-amino-2,6,6-trimethylbicyclo[3.1.1]heptaneAbsolute configuration: (2S,1′S,2′S,3′R,5′S)

(S)-N-((1R,2R,3S,5R)-2-Hydroxy-2,6,6-trimethylbicyclo[3.1.1]heptan-3-yl)-pyrrolidine-2-carboxamideC15H26N2O2[α]D24=-39.45 (c 1.0, CHCl3)Source of chirality: (S)-proline and (1R,2R,3S,5R)-2-hydroxy-3-amino-2,6,6-trimethylbicyclo[3.1.1]heptaneAbsolute configuration: (2S,1′R,2′R,3′S,5′R)

(S)-N-((1S,2S,3S,5S)-2-Hydroxy-2,6,6-trimethylbicyclo[3.1.1]heptan-3-yl)-pyrrolidine-2-carboxamideC15H26N2O2[α]D25=-62.4 (c 1.0, CHCl3)Source of chirality: (S)-proline and (1S,2S,3S,5S)-2-hydroxy-3-amino-2,6,6-trimethylbicyclo[3.1.1]heptaneAbsolute configuration: (2S,1′S,2′S,3′S,5′S)

(S)-N-((1R,2R,3R,5R)-2-Hydroxy-2,6,6-trimethylbicyclo[3.1.1]heptan-3-yl)-pyrrolidine-2-carboxamideC15H26N2O2[α]D25=-8.93 (c 2.0, CHCl3)Source of chirality: (S)-proline and (1R,2R,3R,5R)-2-hydroxy-3-amino-2,6,6-trimethylbicyclo[3.1.1]heptaneAbsolute configuration: (2S,1′R,2′R,3′R,5′R)