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<p>Bicyclo[2.1.1]hexanes are rigid bridged scaffolds with well-defined exit vectors that have been proposed as appropriate bioisosteres of phenyl rings. Although many racemic syntheses have recently emerged, access to single enantiomers of these skeletons remains a major challenge. Here we have developed an enantioselective copper-catalysed protoborylation to obtain 1,3-disubstituted bicyclo[2.1.1]hexanes as suitable mimics of <i>meta</i>-benzenes. The stereocontrolled formation of these bicyclic frameworks, which presents an elusive substitution pattern, was achieved through a desymmetrization of bicyclo[2.1.1]hex-2-enes. The obtained versatile enantioenriched building blocks have been incorporated into the structures of different drug analogues, leading to an improvement in solubility, metabolic stability and permeability in comparison with the parent drugs. Moreover, the drug analogues showed a retention of biological activity by targeting the same molecular receptors, which validates them as suitable <i>meta</i>-benzene bioisosteres.</p><p></p>

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Enantioselective synthesis of 1,3-bicyclo[2.1.1]hexanes as meta-benzene bioisosteres

  • 期刊论文

  • 发表日期：

    2026年4月23日

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  • Carla Pérez-Sánchez,
  • Pablo Garrido-García,
  • Daniel Fernández,
  • Silvia Ortega-Gutiérrez,
  • Mar Martín-Fontecha,
  • Daniel González-Pinardo,
  • Israel Fernández,
  • Thomas Rigotti,
  • Mariola Tortosa

摘要

Bicyclo[2.1.1]hexanes are rigid bridged scaffolds with well-defined exit vectors that have been proposed as appropriate bioisosteres of phenyl rings. Although many racemic syntheses have recently emerged, access to single enantiomers of these skeletons remains a major challenge. Here we have developed an enantioselective copper-catalysed protoborylation to obtain 1,3-disubstituted bicyclo[2.1.1]hexanes as suitable mimics of meta-benzenes. The stereocontrolled formation of these bicyclic frameworks, which presents an elusive substitution pattern, was achieved through a desymmetrization of bicyclo[2.1.1]hex-2-enes. The obtained versatile enantioenriched building blocks have been incorporated into the structures of different drug analogues, leading to an improvement in solubility, metabolic stability and permeability in comparison with the parent drugs. Moreover, the drug analogues showed a retention of biological activity by targeting the same molecular receptors, which validates them as suitable meta-benzene bioisosteres.