Asymmetric Intramolecular α-Arylation of Polar Amino Acids Bearing β-Leaving Groups

The α-arylation of amino acids may be achieved by intramolecular nucleophilic aromatic substitution (S_NAr) reactions of amino-acid derived enolates, but for amino acids bearing β-leaving groups, such reactions are complicated by competing E1cB elimination of the β-substituent. In this paper we report an approach to the arylation of the polar amino acids serine, cysteine, diaminopropionic acid, and allothreonine by inducing intramolecular S_NAr reactions of heterocycles, which the heteroatom substituent is stereoelectronically protected from elimination by incorporating it into the ring system of N-carbamoyl oxazolidines, thiazolidines, or imidazolidines. The sequence comprises the diastereoselective formation of a heterocyclic urea followed by an intramolecular N-to-C aryl migration, yielding bicyclic hydantoins that can be further hydrolysed to afford quaternary α-aryl amino acids. The method is practical and scalable, avoids the use of transition metals or chiral auxiliaries, and provides the opportunity to access a variety of α-arylated products bearing electronically diverse benzenoid or heterocyclic substituents (35 examples).