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<p>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.</p>

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Photoinduced polarity-mismatched transformations of isoquinolines into naphthalenes

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年2月9日

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  • Congcong Zhang,
  • Jianing Zhang,
  • Yu Lan,
  • Yunlong Qin,
  • Zerong Guo,
  • Wenjing Zhang,
  • Qilin Wang

摘要

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.