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<p>Bioisosteric replacement of aromatic and heteroaromatic rings with bridged bicyclic hydrocarbons is an important strategy in drug discovery. Intramolecular [2+2] cycloadditions of unconjugated dienes can provide a route to such motifs but are governed by the ‘rule-of-five’, which dictates that five-membered rings are preferentially formed, limiting access to alternative ring sizes. Here we introduce a visible-light-mediated intramolecular [2 + 2] cycloaddition of aza-1,6-dienes that leverages radical stabilization strategies to enable the selective formation of bridged bicycles over typically favoured fused bicycles. This approach generates previously elusive 6-azabicyclo[3.1.1]heptanes with facile substitution at every position around the ring. Exit vector analysis and comparison of the physicochemical and pharmacological properties of a 6-azabicyclo[3.1.1]heptane analogue of a piperazine-based drug demonstrate the potential application of this scaffold in medicinal chemistry. The methodology enables access to new chemical space, with implications for drug discovery and beyond.</p><p></p>

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Breaking the ‘rule-of-five’ to access bridged bicyclic heteroaromatic bioisosteres

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年2月11日

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  • Ze-Xin Zhang,
  • KaiChen Shu,
  • Michael J. Tilby,
  • Mark John P. Mandigma,
  • Yiheng Guo,
  • Jasper L. Tyler,
  • Adam Noble,
  • Varinder K. Aggarwal

摘要

Bioisosteric replacement of aromatic and heteroaromatic rings with bridged bicyclic hydrocarbons is an important strategy in drug discovery. Intramolecular [2+2] cycloadditions of unconjugated dienes can provide a route to such motifs but are governed by the ‘rule-of-five’, which dictates that five-membered rings are preferentially formed, limiting access to alternative ring sizes. Here we introduce a visible-light-mediated intramolecular [2 + 2] cycloaddition of aza-1,6-dienes that leverages radical stabilization strategies to enable the selective formation of bridged bicycles over typically favoured fused bicycles. This approach generates previously elusive 6-azabicyclo[3.1.1]heptanes with facile substitution at every position around the ring. Exit vector analysis and comparison of the physicochemical and pharmacological properties of a 6-azabicyclo[3.1.1]heptane analogue of a piperazine-based drug demonstrate the potential application of this scaffold in medicinal chemistry. The methodology enables access to new chemical space, with implications for drug discovery and beyond.