Asymmetric Alkene Isomerization Approach to C4-Substituted Piperidines

Chiral C4-substituted piperidines are prominent motifs in pharmaceuticals, agrochemicals, and alkaloid natural products, yet broadly applicable strategies for their asymmetric synthesis and diversification remain underdeveloped. Here we report a catalytic enantioselective alkene-isomerization platform that converts readily accessible C4-substituted tetrahydropyridines into enantioenriched cyclic enamines and enamides. In this Rh-catalyzed process, positional migration of the alkene simultaneously establishes the C4 stereogenic center and generates a polarized enamine or enamide handle for downstream functionalization. The method accommodates diverse C4 substituents, including primary, secondary, and tertiary alkyl groups as well as aryl, heteroaryl, alkenyl, alkynyl, ester, carboxylic acid, and fluorinated motifs, delivering products in high yields and enantioselectivities. The resulting chiral enamines and enamides are versatile linchpins for the synthesis of 2,4-, 3,4-, and 2,3,4-substituted piperidines, bicyclic and polycyclic nitrogen heterocycles, medium-ring azepines, and acyclic stereodefined amide derivatives through regio- and stereoselective functionalization, cycloaddition, ring-expansion, and deconstructive transformations. Mechanistic studies support a Rh(I)-catalyzed and nitrogen lone pair-assisted hydride-transfer pathway. In this mechanism, enantioinduction originates from formation of a chiral catalyst–substrate complex, while the rate-limiting step involves rotation of the piperidine ring around the Rh(I)–C(allylic) bond. Overall, this work establishes asymmetric alkene isomerization of cyclic allylamines as a direct and modular entry to stereochemically rich C4-substituted piperidine architectures.