Enantioselective Organocatalytic Aminomethylation of Aldehydes:A Role for Ionic Interactions and Efficient Access to beta~2-Amino Acids

摘要

The Mannich reaction,in which an enol or enolate attacks an imine or an iminium ion,is a powerful tool for introducing aminoalkyl fragments into organic molecules.Imines derived from aryl aldehydes have been common substrates in recent efforts to develop asymmetric organocatalytic versions of this reaction;these substrates necessarily provide Mannich adducts containing aryl substituents adjacent to nitrogen.Our attention was drawn to formaldehyde-derived substrates because beta-amino aldehydes from such substrates can be used to generate beta~2-amino acids,which are valuable building blocks for beta-peptide foldamers and other targets.Many routes to enantioenriched beta~2-amino acids have been described;most involve chiral auxiliaries,and few are amenable to large-scale synthesis.Here we report an enantioselective organocatalytic method for aminomethylation of aldehydes,which leads to a new and efficient synthesis of beta~2-amino acids (Scheme 1).Our observa-tions provide evidence that non-H-bonded ionic interactions at the Mannich reaction transition state can influence stereochemical outcome.