Enantioselective Synthesis of Atropisomeric Anilides via Pd(II)-Catalyzed Asymmetric C–H Olefination

Atropisomeric
anilides have received tremendous attention as a
novel class of chiral compounds possessing restricted rotation around
an N-aryl chiral axis. However, in sharp contrast to the well-studied
synthesis of biaryl atropisomers, the catalytic asymmetric synthesis
of chiral anilides remains a daunting challenge, largely due to the
higher degree of rotational freedom compared to their biaryl counterparts.
Here we describe a highly efficient catalytic asymmetric synthesis
of atropisomeric anilides via Pd­(II)-catalyzed atroposelective C–H
olefination using readily available L-pyroglutamic
acid as a chiral ligand. A broad range of atropisomeric anilides were
prepared in high yields (up to 99% yield) and excellent stereoinduction
(up to >99% ee) under mild conditions. Experimental studies indicated
that the atropostability of those anilide atropisomers toward racemization
relies on both steric and electronic effects. Experimental and computational
studies were conducted to elucidate the reaction mechanism and rate-determining
step. DFT calculations revealed that the amino acid ligand distortion
is responsible for the enantioselectivity in the C–H bond activation
step. The potent applications of the anilide atropisomers as a new
type of chiral ligand in Rh­(III)-catalyzed asymmetric conjugate addition
and Lewis base catalysts in enantioselective allylation of aldehydes
have been demonstrated. This strategy could provide a straightforward
route to access atropisomeric anilides, one of the most challenging
types of axially chiral compounds.