Importance of favourable non-covalent contacts in the stereoselective synthesis of tetrasubstituted chromanones

Abstract

Automated transition state (TS) structure computations for a recently reported Pd-catalysed conjugated addition of arylboronic acids to 2-substituted chromones (D. Baek, H. Ryu, J. Y. Ryu, J. Lee, B. M. Stoltz and S. Hong, Chem. Sci., 2020, 11, 4602–4607) reveal unexpected conformations of the key stereodifferentiating benzyl group on the pyridine-dihydroisoquinoline (PyDHIQ) ligand. Detailed analysis shows that stereoselectivity is determined primarily by favourable non-covalent contacts between this benzyl group and the substrates, combined with torsional strain in the primary TS structure leading to the minor stereoisomer. This finding should inform further use and analysis of PyDHIQ and related ligands in other stereoselective transformations.