Abstract
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(sp3)-H functionalization is more straightforward but far less explored. Here we report a catalytic protocol for the long-standing challenging enantioselective allylic C(sp3)-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 pKa 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.
Highlights
Transition metal-catalyzed asymmetric allylic substitution with a suitably pre-stored leaving group in the substrate is widely used in organic synthesis
Efficient strategies are still highly desired for enantioselective allylic C−H functionalization, especially for functionalization with inert allylic C−H
Reported a Ni-catalyzed asymmetric hydrocyanation of skipped dienes, providing allyl nitriles via inner-sphere reductive elimination[33]. Inspired by these elegant studies, we envisioned that with a remote olefin unit prestored in a target allyl compound, the combination of metal hydride-catalyzed[50,51] alkene migration to indirectly realize the allylic C−H activation followed by ƞ3-allylation might provide a conceptually different strategy to the challenging allylic C−H functionalization[42,43,44,45,46,47,48,49]
Summary
Transition metal-catalyzed asymmetric allylic substitution with a suitably pre-stored leaving group in the substrate is widely used in organic synthesis. 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. Reported a Ni-catalyzed asymmetric hydrocyanation of skipped dienes, providing allyl nitriles via inner-sphere reductive elimination[33] Inspired by these elegant studies, we envisioned that with a remote olefin unit prestored in a target allyl compound, the combination of metal hydride-catalyzed[50,51] alkene migration to indirectly realize the allylic C−H activation followed by ƞ3-allylation might provide a conceptually different strategy to the challenging allylic C−H functionalization[42,43,44,45,46,47,48,49]. Mechanistic studies further provide evidence for the designed migratory allylation strategy
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