cis-4-Pyrrolidin-1-yl-l-Proline: A Highly Stereoselective Organocatalyst for the Direct Aldol Reaction

Abstract

Modification of the pyrrolidinyl backbone of proline has not been quite successful for improving the catalytic efficiency and enantioselectivity. In this study, cis substitutions on the C4 position of proline with nitrogen-containing groups were found to have significant impacts on both the reactivity and selectivity of the catalyst for the direct aldol reaction of aromatic aldehydes with cyclohexanone. cis-4-Pyrrolidin-1-yl-l-proline exhibited dramatically improved reactivity, diastereo- and enantioselectivity compared with the parent l-proline, affording high isolated yields (up to 99%), excellent diastereoselectivities (>99:1 dr) and enantioselectivities (>99% ee). The presence of trifluoroacetic acid was found to be critical for the outstanding performance of this catalyst.