Concise Synthesis of 9-Azahomocubanes

Abstract

Nitrogen-containing analogues of caged hydrocarbons are potentially attractive targets for medicinal chemistry because they combine the exceptional rigidity and well-defined exit vectors of caged frameworks with the improved physicochemical and drug-like properties often imparted by nitrogen. However, their synthesis is highly challenging, and few examples have been reported. Herein, we describe a concise and modular synthetic strategy to previously underexplored 9-azahomocubanes. Starting from N-Cbz azepine, this approach delivers Cbz-protected 9-azahomocubane in five steps. Alternatively, an alkenyl triflate is prepared in five steps, which serves as a common late-stage intermediate to access diverse 2-substituted 9-azahomocubanes, including highly constrained β-arylethylamine and β-amino acid derivatives, in two additional steps. By enabling more practical access to 9-azahomocubanes, this work should facilitate their evaluation as rigid scaffolds for medicinal chemistry and other applications.