No 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).

No abstract

In order to assess the potential of sPLA-X as a therapeutic target for atherosclerosis, novel sPLA inhibitors with improved type X selectivity are required. To achieve the objective of identifying such compounds, we embarked on a lead generation effort that resulted in the identification of a novel series of indole-2-carboxamides as selective sPLA2-X inhibitors with excellent potential for further optimization.

A stereodivergent synthesis of four diastereomeric 2,3,4,5-tetrafluoropentanols is disclosed. X-ray crystallographic analysis reveals conformations that manifest sequential stereoelectronic gauche effects (σC–H/C → σC–F*), thereby generating topological diversity via subtle C­(sp3)–H to C­(sp3)–F exchange. Two representative tetrafluoro arrays have been incorporated into truncated analogues of Gilenya for the management of relapsing remitting multiple sclerosis. These closely similar multivicinal fluoroalkanes have notably different physicochemical profiles and were found to be stable in the presence of human microsomes.