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

Abstract 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-azabicyclo3.1.1heptanes with facile substitution at every position around the ring. Exit vector analysis and comparison of the physicochemical and pharmacological properties of a 6-azabicyclo3.1.1heptane 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.