Breaking the 'Rule-of-Five' to Access Bridged Bicyclic Heteroaromatic Bioisosteres

    February 2026 in “ Nature Synthesis ”
    Zexin Zhang, Kaichen Shu, Michael J. Tilby, Mark John P. Mandigma, Yiheng Guo, Jasper L. Tyler, Adam Noble, Varinder K. Aggarwal
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    Studysummary In this study, researchers introduced a visible-light-mediated intramolecular cycloaddition method that selectively forms 6-azabicyclo[3.1.1]heptanes, suggesting these structures could offer promising new scaffolds for drug discovery and medicinal chemistry.
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    The study introduces a novel visible-light-mediated intramolecular [2 + 2] cycloaddition of aza-1,6-dienes, which overcomes the limitations of the ‘rule-of-five’ by enabling the selective formation of bridged bicycles instead of the typically favored fused bicycles. This method allows for the creation of 6-azabicyclo[3.1.1]heptanes with substitution possible at every position around the ring. The research highlights the potential of these structures in medicinal chemistry by comparing the physicochemical and pharmacological properties of a 6-azabicyclo[3.1.1]heptane analogue to a piperazine-based drug. This approach opens up new chemical space, offering significant implications for drug discovery.
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