Scaffold-Oriented Asymmetric Catalysis: Conformational Modulation of Transition State Multivalency during a Catalyst-Controlled Assembly of a Pharmaceutically Relevant Atropisomer

A new class of superbasic, bifunctional peptidyl guanidine catalysts is presented, which enable the organocatalytic, atroposelective synthesis of axially chiral quinazolinediones. Computational modeling unveiled the conformational modulation of the catalyst by a novel phenyl urea N-cap, that shape-shifts the structure into the active, folded state. A previously unanticipated noncovalent interaction involving a difluoroacetamide acting as a hybrid mono- or bidentate hydrogen bond donor emerged as a decisive control element inducing atroposelectivity. These discoveries spurred from a scaffold-oriented project inspired from a fascinating investigational BTK inhibitor featuring two stable chiral axes, and relies on a mechanistic framework that was foreign to the extant lexicon of asymmetric catalysis.