RESUMO
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.
Assuntos
Ligação de Hidrogênio , Conformação Molecular , Catálise , Estereoisomerismo , Quinazolinonas/química , Guanidina/química , Peptídeos/química , Modelos Moleculares , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Tirosina Quinase da Agamaglobulinemia/química , Tirosina Quinase da Agamaglobulinemia/metabolismoRESUMO
Mechanistic studies clarifying how chiral primary amines control the stereochemistry of vinylogous processes are rare. We report a density functional theory (DFT) computational study for the comprehension of the reaction mechanism of the vinylogous atroposelective desymmetrization of N-(2-t-butylaryl)maleimide catalyzed by 9-amino(9-deoxy)epi-quinine. Our results illustrate how the origin of the atroposelectivity was realized by the catalyst through steric and dispersion interactions. The role of N-Boc-l-Ph-glycine was crucial for the formation of a closed transition-state geometry and the activation of both reaction partners.