Synthesis of chiral α-amino acids via Pd(II)-catalyzed enantioselective C-H arylation of α-aminoisobutyric acid

Non-natural chiral alpha,alpha-disubstituted alpha-amino acids (alpha,alpha-AAs) constitute an attractive alpha-aminoisobutyric acid (Aib) replacement for improving bioavailability of linear peptides as therapeutics due to the ability of these amino acids to induce the peptides to form helical structures. Enantioselective beta-C(sp(3))-H arylation of Aib could potentially provide a versatile one-step strategy for accessing diverse alpha,alpha-AAs, but the installation and removal of external directing groups was found in our previously reported work to reduce the efficiency of this approach. Herein we report a Pd(II)-catalyzed enantioselective C-H arylation of N-phthalyl-protected Aib enabled by a N-2,6-difluorobenzoyl aminoethyl phenyl thioether (MPAThio) ligand, affording alpha,alpha-AAs with up to 72% yield and 98% ee. Use of this newly developed chiral catalyst has also significantly improved enantioselective C(sp(3))-H arylation of cyclopropanecarboxylic acids by expanding the substrate scope to heterocyclic coupling partners and increasing enantioselectivity to 99% ee.