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.
Zhang et al. (Wed,) studied this question.