Potassium tert-butoxide mediated stereoselective/direct Mannich reaction of α-substituted-γ-lactams with in situ generated aryl N-silyl imines

Abstract

A potassium tert-butoxide (KOt-Bu)-mediated Mannich reaction between α-substituted-γ-lactams and N-silyl imines is reported. N-silyl imines are generated in situ from readily available aryl nitriles and directly combined with the lactams, without preformation of the lactam enolate, to afford the α-quaternary center-bearing Mannich bases in high yield and with high diastereoselectivity (24 examples). This reaction is shown to be catalytic with respect to KOt-Bu and the catalytic mechanism has been investigated using density functional theory calculations. The computational investigations suggest that the diastereoselectivity is controlled by explicit interactions between a binuclear potassium complex and both the imine nitrogen and the enolate oxygen atoms in the selectivity-determining transition states. The Mannich products are shown to be useful in accessing novel spirocyclic pyrrolidines.