Catalytic Kinetic Resolution of Disubstituted Piperidines by Enantioselective Acylation: Synthetic Utility and Mechanistic Insights

The catalytic kinetic resolution
of cyclic amines with achiral
N-heterocyclic carbenes and chiral hydroxamic acids has emerged as
a promising method to obtain enantio-enriched amines with high selectivity
factors. In this report, we describe the catalytic kinetic resolution
of disubstituted piperdines with practical selectivity factors (s, up to 52) in which we uncovered an unexpected and pronounced
conformational effect resulting in disparate reactivity and selectivity
between the cis- and trans-substituted piperidine isomers. Detailed
experimental and computational studies of the kinetic resolution of
various disubstituted piperidines revealed a strong preference for
the acylation of conformers in which the α-substituent occupies
the axial position. This work provides further experimental and computational
support for the concerted 7-member transition state model for acyl
transfer reagents and expands the scope and functional group tolerance
of the secondary amine kinetic resolution.