Non-natural chiral α,α-disubstituted α-amino acids (α,α-AAs) are attractive Aib (α-aminoisobutyric acid) replacement for improving bioavailability of linear peptides as therapeutics due to their ability to induce helix structure. Enantioselective β-C(sp3)–H arylation of Aib could potentially provide a versatile one-step strategy for accessing diverse α,α-AAs, however, the installation and removal of external directing groups in our previous report has reduced the efficiency of this approach. Herein we report Pd(II)-catalyzed enantioselective C–H arylation of N-phthalyl protected Aib enabled by N-2,6-difluorobenzoyl aminoethyl phenyl thioether (MPAThio) ligand, affording α,α-AAs with up to 72% yield and 98% ee. This newly developed chiral catalyst has also significantly improved enantioselective C(sp3)–H arylation of cyclopropanecarboxylic acids by expanding to heterocyclic coupling partners and increasing enantioselectivity to 99% ee.

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