Nickel-Catalyzed Asymmetric Alkene Hydrogenation of α,β-Unsaturated Esters: High-Throughput Experimentation-Enabled Reaction Discovery, Optimization, and Mechanistic Elucidation

A highly
active and enantioselective phosphine-nickel catalyst
for the asymmetric hydrogenation of α,β-unsaturated esters
has been discovered. The coordination chemistry and catalytic behavior
of nickel halide, acetate, and mixed halide-acetate with chiral bidentate
phosphines have been explored and deuterium labeling studies, the
method of continuous variation, nonlinear studies, and kinetic measurements
have provided mechanistic understanding. Activation of molecular hydrogen
by a trimeric (Me–DuPhos)3Ni3(OAc)5I complex was established as turnover limiting followed by
rapid conjugate addition of a nickel hydride and nonselective protonation
to release the substrate. In addition to reaction discovery and optimization,
the previously unreported utility high-throughput experimentation
for mechanistic elucidation is also described.