Direct Asymmetric <i>a</i><i>nti</i>-Mannich-Type Reactions Catalyzed by a Designed Amino Acid

TLDR

Mannich-type reactions typically yield syn-products, and anti-selective, enantioselective variants are difficult to achieve. The authors aim to develop a catalyst that delivers anti-Mannich products with high diastereo- and enantioselectivity at low loadings. They designed the (3R,5R)-5-methyl-3-pyrrolidinecarboxylic acid catalyst based on proline chemistry, confirmed by computational studies, and synthesized it for use with aldehydes and N‑PMP‑protected α‑imino esters. The catalyst gives anti-products in good yields with anti:syn ratios of 94:6 to 98:2 and enantiomeric excesses above 97 %.

Abstract

The development of catalysts for Mannich-type reactions that afford anti-products with excellent diastereo- and enantioselectivities under mild conditions and low catalyst loadings (1−5 mol %) is reported. Based on principles gained from the study of (S)-proline-catalyzed Mannich-type reactions that afford enantiomerically enriched syn-products, (3R,5R)-5-methyl-3-pyrrolidinecarboxylic acid (RR35) has been designed to catalyze the direct enantioselective anti-selective Mannich-type reactions. Computational studies of the above reaction using HF/6-31G* level of theory suggested that this design would be highly effective. The catalyst was subsequently synthesized and studied in organocatalytic Mannich-type reactions between unmodified aldehydes and N-PMP-protected α-imino esters. In accord with the design principles and in quantitative agreement with the theoretical predictions, reactions catalyzed by this catalyst afforded anti-products in good yields with excellent diastereo- and enantioselectivities (anti:syn 94:6 to 98:2, >97 to >99% ee).