In recent years, the incorporation of greater saturation into pharmaceutical leads has become a major focus within drug discovery. It has been shown that increasing the sp³ character within a drug’s core often correlates to lower toxicity, leading to greater potential for advancing through clinical trials and approval. The 2-azanorbornane scaffold has been identified as a more rigid alternative to piperidine and pyrrolidine functionality within pharmaceuticals. In addition to this bioisosterism, this motif allows for a greater degree of possible substitution patterns, and derivatives of these scaffolds have been demonstrated as ligands for asymmetric transformations.
Bicyclic systems of this sort are particularly underexplored in medicinal chemistry and drug discovery. The synthesis of structurally complex 2-azanorbornanes has proven to be challenging for synthetic organic chemists, with the most precedented routes relying on thermally initiated aza-Diels-Alder reactions. The need to develop orthogonal approaches is critical due to the drawbacks and limitations associated with these strategies. Photochemical mediated processes offer a welcome alternative to these existing strategies, with previous studies in our lab detailing radical cascade reactions towards saturated bicycle synthesis. Herein, we describe adaptation of this protocol towards 2-azanorbornane synthesis, harnessing the power of the strain-driven homolysis of amine-radical-cations under mild conditions.
We have disclosed a scope of novel 2-azanorbornanes. The transformation results in the formation of two new C–C bonds and the precursor N-allyl,N-cyclopropylamines can be synthesized from readily available commercial precursors. Mechanistic studies indicate the intermediacy of an amine radical cation, adding to the impressive resumé of such intermediates in complex molecule synthesis.

Corey Stephenson

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