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

Abstract

The α-arylation of amino acids may be achieved by intramolecular nucleophilic aromatic substitution (SNAr) 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 SNAr 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 for 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).