Chiral Piperidines from Acyclic Amines via Enantioselective, Radical-Mediated δ C-H Cyanation

Piperidines are the most prevalent heterocycle found in medicines. Yet, although they are often chiral, there remain no robust methods for their asymmetric syntheses. To solve this challenge, we have interrupted the century-old Hofmann-Loffler-Freytag (HLF) reaction to afford this privileged heterocycle. The catalytic, regio-, and enantioselective delta C-H cyanation of acyclic amines described here, incorporates a carbonyl equivalent selectively at the delta position. This delta C-H cyanation is enabled by a chiral Cu catalyst, which both initiates and terminates intramolecular hydrogen atom transfer (HAT) by an N-centered radical relay mechanism. The broad scope and utility of this highly enantioselective method for delta C-C formation is presented, as well as conversion of the resulting enantioenriched delta-amino nitriles to a family of chiral piperidines. Experiments probing the chemo-, regio-, and enantio-selectivity of this HAT mechanism are also included to enable extension to other stereoselective delta C-H functionalizations.