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<p><i>para</i>-Cyclophane scaffolds, characterized by their 1,4-disubstituted benzene frameworks, represent a structurally unique and biologically important class of compounds. Despite their extensive presence in natural products and bioactive molecules, the synthesis of highly strained <i>para</i>-cyclophanes remains challenging through conventional ring-closing strategies and alternative approaches. Here we report a facile preparation of <i>para</i>-cyclophanes containing bent 1,4-disubstituted benzene subunits via a N-arylation–ring-expansion [5,5]-sigmatropic rearrangement between cyclic tertiary amines and aryne intermediates. These scaffolds occupy a distinctive chemical space, with structural analyses revealing a remarkably high degree of angular distortion on the 1,4-disubstituted benzene rings. Notably, the rearrangement step not only exhibits diverse reaction modes in response to the location of the substituents but also demonstrates an intriguing point-to-planar chirality transfer. Density functional theory calculations provide mechanistic insights into both the diastereoselective control and the point-to-planar chirality transfer process.</p><p></p>

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Synthesis of highly strained para-cyclophanes via ring-expansion [5,5]-sigmatropic rearrangement reaction

  • 期刊论文

  • 发表日期：

    2025年7月21日

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  • Zhonghong Chen,
  • Weihao Yang,
  • Maomao Jia,
  • Jiarong Shi,
  • Jiyang Li,
  • Haohua Chen,
  • Yang Li

摘要

para-Cyclophane scaffolds, characterized by their 1,4-disubstituted benzene frameworks, represent a structurally unique and biologically important class of compounds. Despite their extensive presence in natural products and bioactive molecules, the synthesis of highly strained para-cyclophanes remains challenging through conventional ring-closing strategies and alternative approaches. Here we report a facile preparation of para-cyclophanes containing bent 1,4-disubstituted benzene subunits via a N-arylation–ring-expansion [5,5]-sigmatropic rearrangement between cyclic tertiary amines and aryne intermediates. These scaffolds occupy a distinctive chemical space, with structural analyses revealing a remarkably high degree of angular distortion on the 1,4-disubstituted benzene rings. Notably, the rearrangement step not only exhibits diverse reaction modes in response to the location of the substituents but also demonstrates an intriguing point-to-planar chirality transfer. Density functional theory calculations provide mechanistic insights into both the diastereoselective control and the point-to-planar chirality transfer process.