Breaking The Rule-Of-Five To Access Bridged Bicyclic Heteroaromatic Bioisosteres

This study introduces a novel visible light-mediated intramolecular [2+2] cycloaddition of aza-1,6-dienes, which challenges the traditional “rule-of-five” by enabling the selective formation of bridged bicycles instead of the typically favored fused bicycles. This breakthrough allows for the creation of 6-azabicyclo[3.1.1]heptanes (6-N-BCHeps), which are valuable as bioisosteric mimetics for nitrogen-containing aromatics and saturated six-membered ring heterocycles. The research represents the first general synthesis of substituted 6-N-BCHeps, allowing for substitution at every position around the ring. The study highlights the potential application of this scaffold in medicinal chemistry, as demonstrated by the physicochemical and pharmacological analysis of a 6-N-BCHep analogue of a piperazine-based drug. This methodology opens new avenues in chemical space exploration, with significant implications for drug discovery.