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 enables 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 preorganizes 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. Albeit of significative recent pharmaceutical interest, there is an almost complete absence of asymmetric methods to deliver enantioenriched, axially chiral N-aryl quinazolinediones. Posed with the challenge of establishing such a catalytic method, we developed a new class of superbasic bifunctional peptidyl guanidine catalysts. In addition, we carried out extensive computational modeling to dissect the role of the individual elements in governing the catalyst's activity and selectivity. image