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

ABSTRACT: 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 sp 3 -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 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.

SUBMITTER: Staveness D 

PROVIDER: S-EPMC6411061 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature