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.