A novel method for the asymmetric synthesis of alpha,alpha-disubstituted alkylamines via Grignard additions to ketimines

The design of practical methods to prepare optically pure alpha,alpha-disubstituted alkylamines remains an important challenge. We now report a new and efficient method for the asymmetric synthesis of alpha,alpha-disubstituted amines 2 where R-3 is a nitrogen-containing heterocycle. The method utilizes the diasteroselective addition of a Grignard reagent to ketimine 1, followed by an oxidative cleavage of the chiral auxiliary to afford the target amines 2 in high enantiomeric excess. A model involving chelation of the imine and heterocyclic nitrogen with Mg is proposed to rationalize the observed diastereoselectivity.