Palladium-catalyzed regio- and enantioselective migratory allylic C(sp3)-H functionalization

Transition metal-catalyzed asymmetric allylic substitution with a suitably pre-stored leaving group in the substrate is widely used in organic synthesis. In contrast, the enantioselective allylic C(sp(3))-H functionalization is more straightforward but far less explored. Here we report a catalytic protocol for the long-standing challenging enantioselective allylic C(sp(3))-H functionalization. Through palladium hydride-catalyzed chain-walking and allylic substitution, allylic C-H functionalization of a wide range of acyclic nonconjugated dienes is achieved in high yields (up to 93% yield), high enantioselectivities (up to 98:2 er), and with 100% atom efficiency. Exploring the reactivity of substrates with varying pK(a) values uncovers a reasonable scope of nucleophiles and potential factors controlling the reaction. A set of efficient downstream transformations to enantiopure skeletons showcase the practical value of the methodology. Mechanistic experiments corroborate the PdH-catalyzed asymmetric migratory allylic substitution process. Alkene isomerizations and asymmetric C-H functionalizations have been independently studied, but their combination in one protocol is uncommon. Here the authors show a palladium-catalyzed method to iteratively "walk" a terminal alkene along a carbon chain to a position next to styrenes where a soft nucleophile is added asymmetrically.