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<p>Replacing benzene rings with C(<i>sp</i><sup>3</sup>)-rich bioisosteres to yield compounds with improved drug-like properties is an attractive strategy in medicinal chemistry. While many caged hydrocarbons have been validated as bioisosteres of <i>ortho</i>- and <i>meta</i>-disubstituted benzenes, 3D analogues of 1,2,4-trisubstituted benzenes—the second most prevalent benzenoid pattern in drugs—remain elusive because vector fidelity and enantioselective access are still formidable challenges. Here we report a practical route to (enantiomerically pure) 2-thiabicyclo[3.1.1]heptanes (thia-BCHeps) by cycloadditions of bicyclo[1.1.0]butanes with 1,4-dithiane-2,5-diol. This method produces cycloadducts with two and three exit vectors, which serve as promising bioisosteres for <i>ortho</i>-substituted and 1,2,4-trisubstituted benzenes, respectively. Moreover, the cycloadducts can be transformed into a diverse chemical space, including 1,5-disubstituted thiabicyclo[3.1.1]heptenes. Crystallographic analysis and a comparison of the pharmacokinetic properties, along with an evaluation of the biological activity of diflunisal, salicylanilide and the anticancer drug sonidegib, in relation to their 3D thia-BCHep analogues, demonstrate that the thia-BCHeps obtained can provide new surrogates for 1,2,4-trisubstituted, <i>meta-</i> and <i>ortho</i>-substituted benzene rings in drug discovery programmes.</p><p></p>

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Collective synthesis of 1,2,4-trisubstituted, meta- and ortho-substituted arene bioisosteres from bicyclobutanes

  • 期刊论文

  • 发表日期：

    2026年3月3日

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  • Feng Wu,
  • Ji-Jie Wang,
  • Yuanjiu Xiao,
  • Quanxin Peng,
  • Yu-Jie Li,
  • Keren Peng,
  • Qianlan Han,
  • Mengran Wei,
  • Yu Qian,
  • Wei Zhang,
  • Guoqiang Wang,
  • Jian-Jun Feng

摘要

Replacing benzene rings with C(sp3)-rich bioisosteres to yield compounds with improved drug-like properties is an attractive strategy in medicinal chemistry. While many caged hydrocarbons have been validated as bioisosteres of ortho- and meta-disubstituted benzenes, 3D analogues of 1,2,4-trisubstituted benzenes—the second most prevalent benzenoid pattern in drugs—remain elusive because vector fidelity and enantioselective access are still formidable challenges. Here we report a practical route to (enantiomerically pure) 2-thiabicyclo[3.1.1]heptanes (thia-BCHeps) by cycloadditions of bicyclo[1.1.0]butanes with 1,4-dithiane-2,5-diol. This method produces cycloadducts with two and three exit vectors, which serve as promising bioisosteres for ortho-substituted and 1,2,4-trisubstituted benzenes, respectively. Moreover, the cycloadducts can be transformed into a diverse chemical space, including 1,5-disubstituted thiabicyclo[3.1.1]heptenes. Crystallographic analysis and a comparison of the pharmacokinetic properties, along with an evaluation of the biological activity of diflunisal, salicylanilide and the anticancer drug sonidegib, in relation to their 3D thia-BCHep analogues, demonstrate that the thia-BCHeps obtained can provide new surrogates for 1,2,4-trisubstituted, meta- and ortho-substituted benzene rings in drug discovery programmes.