A General and Modular Approach to BCP Alkylamines via Multicomponent Difunctionalization of [1.1.1]Propellane

Over the past decade, bicyclo[1.1.1]pentane (BCP) motifs have come to the fore as valuable pharmaceutical bioisosteres of para-disubstituted benzenes. However, the limited approaches and requisite multistep syntheses of useful BCP building blocks are hampering early discovery research in medicinal chemistry. Herein we report the development of a modular strategy for the divergent preparation of functionalized BCP alkylamines. In this process, a general method to introduce fluoroalkyl groups to BCP scaffolds using readily available and easy-to-handle fluoroalkyl sulfinate salts was also developed. Moreover, this strategy can also be extended to S-centered radicals for incorporation of sulfones and thioethers into the BCP core. Overall, this multicomponent strategy enables rapid construction of BCP-type bioisosteres for applications in drug discovery.

Automated summary

Over the past decade, the bicycle[1.1.1]pentane (BCP) motifs have been proven to be valuable bioisosteres of para-disubstituted benzenes in pharmaceuticals. However, the limited approaches and complex syntheses of BCP building blocks are hindering early discovery research in medicinal chemistry. In this study, a modular strategy for preparing functionalized BCP alkylamines was developed, which includes a general method for introducing fluoroalkyl groups to BCP scaffolds using readily available fluoroalkyl sulfinate salts. Furthermore, this strategy can also be extended to incorporate sulfones and thioethers into the BCP core using S-centered radicals. Overall, this multicomponent strategy allows for rapid construction of BCP-type bioisosteres for drug discovery applications.