Diastereo- and Enantioselective Reductive Mannich-type Reaction of α,β-Unsaturated Carboxylic Acids to Ketimines: A Direct Entry to Unprotected β2,3,3 -Amino Acids

Abstract

Stereoselective construction of unprotected β-amino acids is a significant challenge owing to the lack of methods for the catalytic generation of highly enantioenriched carboxylic acid enolates. In this study, a novel copper-catalyzed diastereo- and enantioselective reductive Mannich-type reaction of α,β-unsaturated carboxylic acids was developed, which provides a direct and scalable synthetic method for enantioenriched β^2,3,3 -amino acids with vicinal stereogenic centers. The protocol features in situ generation of transiently protected carboxylic acids by a hydrosilane and their diastereo- and enantioselective reductive coupling with ketimines. The synthetic utility of this process was demonstrated by a gram-scale reaction and the transformation of β-amino acids.

Keywords: amino acids; asymmetric catalysis; carboxylic acids; copper; reductive Mannich-type reaction.

Scheme 1

Unprotected β‐amino acid synthesis via (Mukaiyama) Mannich‐type reactions.

Figure 1

Proposed catalytic cycle.

Scheme 2

Reaction compatibility with acrylates.

Scheme 3

Synthetic utility.