Systematic evaluation of a few proline derivatives as catalysts for a direct aldol reaction

A series of pyrrolidine derivatives were prepared and examined as catalysts for an aldol reaction. Structural variations in these molecules involved altering the sterics at the α-position, the position of the carbonyl group, and the acidities of the hydrogen bonding sites. The effect of these factors on catalytic activity and enantioselectivity was studied. The experimental results revealed that additional sterics at the α-position were detrimental. However, no correlation was found between the catalytic activity and N–H acidity.

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(R)-(2-Benzylpyrrolidin-2-yl)methanolC12H17NO[α]D25=+20.5 (c 1.27, CHCl3)Source of chirality: (R)-2-benzylpyrrolidine-2- carboxylic acidAbsolute configuration: (R)

(S)-N-(Pyrrolidin-2-ylmethyl)benzamideC12H16N2O[α]D25=+29.0 (c 1.0, CHCl3)Source of chirality: l-prolineAbsolute configuration: (S)

(S)-N-(Pyrrolidin-2-ylmethyl)pivalamideC10H20N2O[α]D25=+8.85 (c 1.21, CHCl3)Source of chirality: l-prolineAbsolute configuration: (S)

(S)-Benzyl 2-((2-(methoxycarbonyl)phenyl)carbamoyl)pyrrolidine-1-carboxylateC21H22N2O5[α]D25=-133.3 (c 1.23, CHCl3)Source of chirality: l-prolineAbsolute configuration: (S)

(S)-2-(Pyrrolidine-2-carboxamido)benzoic acidC12H14N2O3[α]D25=-84.5 (c 1.04, H2O)Source of chirality: Starting materialAbsolute configuration: (S)