Fluorine-containing 6-Azabicyclo[3.1.1]heptanes: Bicyclic Piperidine Analogs for Drug Discovery

Abstract

Convenient synthetic approaches to a series of fluorinated bicyclic piperidine analogs (including 3-fluoro-, 3,3-difluoro-, 3-carboxy-3-fluoro-, and 3-trifluoromethyl-substituted 6-azabicyclo­[3.1.1]heptanes) were proposed. Using commercially available fluorination agents, the target building blocks were prepared in gram to decagram scale in a single run. Evaluation of pKa and LogP values revealed the importance of the fluorine-containing substituent and methylene bridge relative disposition for the compound’s physicochemical properties. Analysis of molecular structure using the exit vector plot (EVP) approach revealed negligible change in molecules conformation upon fluorination.