Synthesis of chiral α-amino acids via Pd(ii)-catalyzed enantioselective C–H arylation of α-aminoisobutyric acid†
Abstract
Non-natural chiral α,α-disubstituted α-amino acids (α,α-AAs) constitute an attractive α-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 β-C(sp3)–H arylation of Aib could potentially provide a versatile one-step strategy for accessing diverse α,α-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 α,α-AAs with up to 72% yield and 98% ee. Use of this newly developed chiral catalyst has also significantly improved enantioselective C(sp3)–H arylation of cyclopropanecarboxylic acids by expanding the substrate scope to heterocyclic coupling partners and increasing enantioselectivity to 99% ee.