Photoinduced polarity-mismatched transformations of isoquinolines into naphthalenes
Congcong Zhang, Jianing Zhang, Yu Lan, Yunlong Qin, Zerong GUO, Wenjing Zhang, Qilin Wang
Abstract
Isosteric replacement is an important strategy for lead optimization in drug-development paradigms. However, it is usually restricted to cost- and labor-intensive de novo syntheses. We here report a photochemical photosensitizer-free skeletal-editing strategy to directly transform easily accessible isoquinolines into synthetically challenging naphthalene derivatives in a single operation. Directed by density functional theory calculations, the key factor enabling the (4 + 2) cycloaddition between two polarity-mismatched species was harnessing photonic energy to overcome fundamental electronic hurdles by the combination of isoquinolinium carbonate as the electron-donor-acceptor complex. The high compatibility of this methodology was expanded to late-stage functionalization of commercial drugs, thus enriching optimization libraries. Importantly, value-adding access to valuable polycyclic aromatic hydrocarbons, numerous ligands and drug analogies is also demonstrated. Isosteric replacement, an important tactic in drug-lead optimization, typically demands bespoke synthesis. Here, the authors report a photochemical skeletal-editing method that converts readily available isoquinolines into otherwise difficult naphthalene derivatives in a single step.