Enantioselective Organocatalytic Aminomethylation of Aldehydes: A Role for Ionic Interactions and Efficient Access to β2-Amino Acids

Abstract

Organocatalytic Mannich addition of aldehydes to a formaldehyde-derived iminium species catalyzed by proline-derived chiral pyrrolidines provides β-amino aldehydes with ≥90% ee. Mechanistic analysis of the proline-catalyzed reactions suggests that non-hydrogen-bonded ionic interactions at the Mannich reaction transition state can influence stereochemical outcome. The β-amino aldehydes from our process bear a substituent adjacent to the carbonyl and can be efficiently converted to protected β²-amino acids, which are important building blocks for β-peptide foldamers that display useful biological activities.