Breaking the “rule-of-five” to access Bridged Bicyclic Heteroaromatic Bioisosteres

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 provide an efficient route to these motifs but are governed by the “rule-of-five”, which dictates that five-membered rings are preferentially formed, therefore limiting access to alternative ring sizes. Herein, we introduce a visible light-mediated intramolecular [2+2] cycloaddition of aza-1,6-dienes that leverages radical stabilisation strategies to successfully challenge this paradigm and enable the selective formation of bridged bicycles over traditionally favoured fused bicycles. This provides previously elusive 6-azabicyclo[3.1.1]heptanes (6-N-BCHeps), which serve as bioisosteric mimetics for both nitrogen-containing aromatics and saturated six-membered ring heterocycles. Notably, this work represents the first general synthesis of substituted 6-N-BCHeps, enabling facile substitution at every position around the ring. Exit vector analysis and comparison of the physicochemical and pharmacological properties of a 6-N-BCHep analogue of a piperazine-based drug demonstrate the potential application of this scaffold in medicinal chemistry. The methodology offers a powerful strategy for exploring new chemical space, with broad implications for drug discovery and beyond.