Quaternary amino acids, in which the α-carbon is fully substituted, have an important role as modifiers of peptide conformation and bioactivity, and as precursors of medicinally important compounds. For α-alkylated amino acids, synthesis by enantioselective alkylation of naturally occurring amino acids is routine. For α-arylated amino acids by contrast, there exists no general method allowing enantioselective α-arylation of naturally occurring amino acids. Here we describe the synthesis of quaternary α-aryl amino acids from enantiomerically enriched amino acid precursors by α-arylation without loss of stereochemical integrity. The method relies on the temporary formation of a second stereogenic centre in the <i>N</i>’-aryl urea derivative of an imidazolidinone. Formation of an enolate induces intramolecular, diastereoselective aryl transfer to give a product whose hydrolysis yields enantiomerically enriched quaternary amino acids, or, optionally, their hydantoin derivatives. The method uses readily available enantiopure amino acids as precursors and allows arylation with electron-rich, electron-poor and heterocyclic aryl substituents. It avoids the use of high value transition metals, and is practical and scalable, providing the opportunity to produce α-arylated quaternary amino acids in multi-gram quantities.

Asymmetric α-arylation of amino acids

255th National Meeting (2018)

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