Remote substituent effects on the stereoselectivity and organocatalytic activity of densely substituted unnatural proline esters in aldol reactions

Abstract

The organocatalytic activities of highly substituted proline esters obtained through asymmetric [3+2] cycloadditions of azomethine ylides derived from glycine iminoesters have been analyzed by 19F NMR and through kinetic isotope effects. Kinetic rate constants have been determined for unnatural proline esters incorporating different substituents. It has been found that exo-L and endo-L unnatural proline methyl esters yield opposite enantiomers in aldol reactions between cyclic ketones and aromatic aldehydes. The combined results reported in this study show subtle and remote effects that determine the organocatalytic behavior of these synthetic but readily available amino acid derivatives. These data can be used as design criteria for the development of new pyrrolidine-based organocatalysts. Densely substituted enantiopure proline esters obtained through [3+2] cycloadditions catalyze aldol reactions. These synthetic organocatalysts produce different enantiomeric aldol adducts depending on the stereochemical dispositions of the substituents at distal positions with respect to the catalytic site. Design criteria are proposed for this kind of organocatalysts.