Chiral and Regenerable NAD(P)H Models Enabled Biomimetic Asymmetric Reduction: Design, Synthesis, Scope, and Mechanistic Studies

The
coenzyme NAD­(P)H plays an important role in electron as well
as proton transmission in the cell. Thus, a variety of NAD­(P)H models
have been involved in biomimetic reduction, such as stoichiometric
Hantzsch esters and achiral regenerable dihydrophenantheridine. However,
the development of a general and new-generation biomimetic asymmetric
reduction is still a long-term challenge. Herein, a series of chiral
and regenerable NAD­(P)H models with central, axial, and planar chiralities
have been designed and applied in biomimetic asymmetric reduction
using hydrogen gas as a terminal reductant. Combining chiral NAD­(P)­H
models with achiral transfer catalysts such as Brønsted acids
and Lewis acids, the substrate scope could be also expanded to imines,
heteroaromatics, and electron-deficient tetrasubstituted alkenes with
up to 99% yield and 99% enantiomeric excess (ee). The mechanism of
chiral regenerable NAD­(P)H models was investigated as well. Isotope-labeling
reactions indicated that chiral NAD­(P)H models were regenerated by
the ruthenium complex under hydrogen gas first, and then the hydride
of NAD­(P)H models was transferred to unsaturated bonds in the presence
of transfer catalysts. In addition, density functional theory calculations
were also carried out to give further insight into the transition
states for the corresponding transfer catalysts.