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<p>Skeletal editing via single-carbon atom insertion has recently emerged as a powerful tactic for the expansion of accessible chemical space for drug discovery. Despite advancements, enantioselective single-atom skeletal editing of saturated carbocycles, specifically bridged hydrocarbons, remains unexplored due to competing strain-induced ring-opening and isomerization processes. Here we report an enantioselective skeletal editing strategy that enables the direct insertion of metal carbenes into readily available bicyclo[1.1.0]butanes, using triftosylhydrazones as carbene precursors. This operationally simple method delivers enantiopure 1,2,2,3-tetrasubstituted bicyclo[1.1.1]pentanes featuring an all-carbon quaternary centre in high yields and excellent enantioselectivity. The postsynthetic transformations of the chiral bicyclo[1.1.1]pentanes into various functionalized derivatives are highly valued in medicinal chemistry, yet typically difficult to synthesize. Computational calculations support the proposed stepwise mechanism involving direct metal carbene addition across the highly strained C–C <i>σ</i>-bond of bicyclo[1.1.0]butanes and the origin of high enantioselectivity.</p><p></p>

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Enantioselective single-atom skeletal editing of bicyclo[1.1.0]butanes by carbene insertion

  • 期刊论文

  • 发表日期：

    2026年7月17日

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  • Yongquan Ning,
  • Shaopeng Liu,
  • Yixuan Wang,
  • Chenxu Wang,
  • Paramasivam Sivaguru,
  • Wei Song,
  • Jun Yang,
  • Weitao Zhang,
  • Xihe Bi

摘要

Skeletal editing via single-carbon atom insertion has recently emerged as a powerful tactic for the expansion of accessible chemical space for drug discovery. Despite advancements, enantioselective single-atom skeletal editing of saturated carbocycles, specifically bridged hydrocarbons, remains unexplored due to competing strain-induced ring-opening and isomerization processes. Here we report an enantioselective skeletal editing strategy that enables the direct insertion of metal carbenes into readily available bicyclo[1.1.0]butanes, using triftosylhydrazones as carbene precursors. This operationally simple method delivers enantiopure 1,2,2,3-tetrasubstituted bicyclo[1.1.1]pentanes featuring an all-carbon quaternary centre in high yields and excellent enantioselectivity. The postsynthetic transformations of the chiral bicyclo[1.1.1]pentanes into various functionalized derivatives are highly valued in medicinal chemistry, yet typically difficult to synthesize. Computational calculations support the proposed stepwise mechanism involving direct metal carbene addition across the highly strained C–C σ-bond of bicyclo[1.1.0]butanes and the origin of high enantioselectivity.