Chiral Piperidines from Acyclic Amines Via Enantioselective, Radical-Mediated δ C-H Cyanation
194 Pages Posted: 1 Aug 2019 Publication Status: PublishedMore...
Piperidines are the most prevalent heterocyclic core found in medicines. Yet, while these structures often contain chiral substituents, there are no robust methods for the synthesis of enantioenriched, substituted piperidines. Current approaches rely on the reduction of pyridines or C-H functionalizations to afford racemic mixtures that must then be resolved. To solve this challenge, we proposed an adaptation of the century-old Hofmann-Löffler-Freytag (HLF) reaction may afford this privileged heterocycle. This approach would require interruption of the regioselective δ C-H amination of acyclic amines to instead incorporate a carbonyl equivalent at the δ position. Moreover, this C-C bond would need to be installed with high stereoselectivity (>90% enantiomeric excess) for the first time. To this end, a catalytic method for remote, enantioselective C-C formation has been developed. This δ C-H cyanation of amines is enabled by a chiral Cu catalyst, which both initiates and terminates an intramolecular hydrogen atom transfer (HAT) mechanism. The broad scope and utility of this catalytic method for enantioselective δ C-C formation by an N-centered radical relay is presented, as well as the conversion of the resulting enantioenriched d 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 δ C-H functionalizations in a stereoselective fashion.
Keywords: radical chemistry, asymmetric catalysis, heterocycle synthesis
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