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<p>Bicyclo[1.1.1]pentane (BCP) has emerged over the past decade as a valuable three-dimensional bioisostere for benzene, attracting considerable interest in pharmaceutical research for its ability to improve drug-like properties. Although [1.1.1]propellane has traditionally served as the key precursor to <i>mono</i>- and 1,3- disubstituted BCPs, the growing demand for multisubstituted and bridge-functionalized BCP derivatives has spurred the development of alternative, propellane-free synthetic strategies. Recent advances toward these highly strained and sterically hindered ring systems can be broadly organized into three mechanistic categories: intramolecular diradical couplings, carbene-mediated ring expansions, and two-electron disconnections. This Perspective highlights these emerging methodologies, assesses their scope and limitations, and offers an outlook on remaining synthetic challenges and their implications for medicinal chemistry.</p>

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Propellane-free access to bicyclo[1.1.1]pentanes

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年1月12日

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  • Chang Liu,
  • Wenyuan Li,
  • Renzhe Li,
  • Rohan R. Merchant,
  • Yuzuru Kanda,
  • Tian Qin

摘要

Bicyclo[1.1.1]pentane (BCP) has emerged over the past decade as a valuable three-dimensional bioisostere for benzene, attracting considerable interest in pharmaceutical research for its ability to improve drug-like properties. Although [1.1.1]propellane has traditionally served as the key precursor to mono- and 1,3- disubstituted BCPs, the growing demand for multisubstituted and bridge-functionalized BCP derivatives has spurred the development of alternative, propellane-free synthetic strategies. Recent advances toward these highly strained and sterically hindered ring systems can be broadly organized into three mechanistic categories: intramolecular diradical couplings, carbene-mediated ring expansions, and two-electron disconnections. This Perspective highlights these emerging methodologies, assesses their scope and limitations, and offers an outlook on remaining synthetic challenges and their implications for medicinal chemistry.