Exploring physicochemical space via a bioisostere of the trifluoromethyl and ethyl groups (BITE): attenuating lipophilicity in fluorinated analogues of Gilenya® for multiple sclerosis

Abstract

The direct, catalytic vicinal difluorination of terminal alkenes via an I(I)/I(III) manifold was exploited to install a chiral, hybrid bioisostere of the CF₃ and Et groups (BITE) in Gilenya®; the first orally available drug for the clinical management of Multiple Sclerosis (MS). This subtle fluorination pattern allows lipophilicity (log D) to be tempered compared to the corresponding CF₃ and Et derivatives (CH₂CH₃ > CH₂CF₃ > CHFCH₂F).