Breaking The Rule-Of-Five To Access Bridged Bicyclic Heteroaromatic Bioisosteres
May 2025
Studysummary This study introduces a novel visible light-mediated intramolecular [2+2] cycloaddition process that forms 6-azabicyclo[3.1.1]heptanes, offering a new synthesis route for bioisosteric mimetics used in drug discovery, potentially expanding medicinal chemistry applications beyond traditional limitations.
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This preprint introduces a novel method for synthesizing bridged bicyclic heteroaromatic bioisosteres, challenging the traditional "rule-of-five" that favors five-membered rings. By employing a visible light-mediated intramolecular [2+2] cycloaddition of aza-1,6-dienes, the study successfully forms 6-azabicyclo[3.1.1]heptanes (6-N-BCHeps), which can mimic nitrogen-containing aromatics and saturated six-membered ring heterocycles. This method allows for substitution at every position around the ring, offering new opportunities in medicinal chemistry. The study highlights the potential of 6-N-BCHeps as analogues for existing drugs, suggesting significant implications for drug discovery.
