Asymmetric Synthesis of Quaternary Hydantoins via a Palladium-Catalyzed Aza-Heck Cyclization

An asymmetric, palladium-catalyzed aza-Heck cyclization
to prepare
enantioenriched 5,5-disubstituted hydantoins (quaternary hydantoins),
which are medicinally important compounds but are classically challenging
to prepare, is reported. The required substrates can be prepared readily
from α,β-unsaturated amides in a single operation, and
aza-Heck cyclization provides a wide range of topologically complex,
highly substituted, pharmaceutically relevant hydantoins. The capacity
of this method to impact the synthesis of drug substances is demonstrated
by the first asymmetric synthesis of the anticonvulsant (R)-mephenytoin.