The Proline‐Catalyzed Double Mannich Reaction of Acetaldehyde with N‐Boc Imines

Abstract

Double-cross: Proline catalyzes the double Mannich reaction of acetaldehyde with N-Boc imines in excellent yields (up to 99 %; Boc = tert-butoxycarbonyl) and close to perfect diastereo- and enantioselectivities. Depending on the choice of catalysts, both the chiral, pseudo-C(2)-symmetric diastereomer and the corresponding meso compound can be prepared. Cross double Mannich reactions of acetaldehyde with two different imines are also demonstrated.

Recent advances on organocatalysed asymmetric Mannich reactions

“…List 19 introduced the one-pot catalytic asymmetric synthesis of pseudo-C 2 -symmetric β,β'-diaminoaldehydes with extremely high stereoselectivities, starting from acetaldehyde and either aromatic or aliphatic N-Boc imines (Scheme 4). The method was effectively extended to cross-Mannich reactions, furnishing β,β'-diamino aldehydes containing three adjacent stereogenic centers.…”

2.16 The Bimolecular and Intramolecular Mannich and Related Reactions

“…Initially formed a-unbranched aldehydes underwent a second Mannich reaction to furnish double-Mannich addition products with extremely high enantiomeric excesses (Scheme 96). 118 Aldimines derived from heteroaromatic aldehyde as well as aromatic aldehyde participated successfully in the reaction. An aldimine derived from aliphatic aldehyde also gave the adducts with excellent diastereo-and enantioselectivity in modest yield.…”

Recent progress in the asymmetric Mannich reaction

“…Thus, the area of enantioselective organocatalysis became a main focus of research. In 2000 List described firstly the L-proline catalysed Mannich reaction [23][24][25], this landmark discovery stimulated the rapid development of the asymmetric organocatalytic Mannich reactions.…”

“…List [25] introduced an efficient method for the one-pot catalytic asymmetric synthesis of pseudo-C2-symmetric β,β'diaminoaldehydes with extremely high stereoselectivities, starting from acetaldehyde and either aromatic or aliphatic N-Boc imines (Scheme 18). The method was extended to cross-Mannich reactions, furnishing β,β'-diamino aldehydes containing three adjacent stereogenic centers.…”