Synthesis of 2-Azanorbornanes via Strain-Release Formal Cycloadditions Initiated by Energy Transfer

Rigid bicycles are becoming more popular in the pharmaceutical industry because they allow for expansion to new and unique chemical spaces. This work describes a new strategy to construct 2-azanorbornanes, which can act as rigid piperidine/pyrrolidine scaffolds with well-defined exit vectors. To achieve the synthesis of 2-azanorbornanes, new strain-release reagent, azahousane, is introduced along with its photosensitized strain-release formal cycloaddition with alkenes. Furthermore, new reactivity between a housane and an imine is disclosed. Both strategies lead to various substituted 2-azanorbornanes with good selectivities. Strategies to prepare 2-azanorbornanes by photochemical strain-release formal cycloadditions is presented. The method involves the combination of azahousanes or housanes with alkenes or imines, respectively. The 2-azanorbornanes have defined exit vectors and represent new building blocks to enable drug development. The synthetic utilty of the products is also demonstrated.image