Providing a New Aniline Bioisostere through the Photochemical Production of 1-Aminonorbornanes

This report describes the photochemical conversion of aminocyclopropanes into 1-aminonorbornanes via formal [3 + 2] cycloadditions initiated by homolytic fragmentation of amine radical cation intermediates. Aligning with the modern movement toward sp3-rich motifs in drug discovery, this strategy provides access to a diverse array of substitution patterns on this saturated carbocyclic framework while offering the robust functional-group tolerance (e.g., -OH, -NHBoc) necessary for further derivatization. Evaluating the metabolic stability of selected morpholine-based 1-aminonorbornanes demonstrated a low propensity for oxidative processing and no proclivity toward reactive metabolite formation, suggesting a potential bioisosteric role for 1-aminonorbornanes. Continuous-flow processing allowed for efficient operation on the gram scale, providing promise for translation to industrially relevant scales. This methodology only requires low loadings of a commercially available, visible-light-active photocatalyst and a simple salt; thus, it stays true to sustainability goals while readily delivering saturated building blocks that can reduce metabolic susceptibility within drug development programs. [Display omitted] •Strain-driven homolysis initiates radical cyclization sequence toward norbornane core•Robust functional-group tolerance provides readily modifiable building blocks•Unique modes of diastereocontrol afford enantiopure 1-aminonorbornanes•1-Aminonorbornanes are shown to offer improved metabolic stability over anilines Recent years have witnessed an increasing focus on saturated substructures within drug development as a result of the pharmacokinetic and toxicological benefits correlated with higher saturation content. However, the synthetic challenges presented by densely functionalized saturated architectures generally prohibit their evaluation. The abundance of anilines within high-throughput screening libraries is demonstrative of these competing needs. Anilines are prone to adverse metabolic processing, commonly necessitating re-engineering of a given drug lead to ameliorate CYP450 inhibition and/or glutathione adduction issues, but the ease with which these systems are prepared outweighs the toxicity risks. This article contributes to the need for aniline bioisosteres through the development of a robust, photochemical methodology that supplies 1-aminonorbornanes, saturated bicyclic ring systems that offer similar spatial occupancy to anilines while im