Convergent synthesis and protein binding of vicinal difluorides by stereodivergent C–C bond formation

Abstract

Vicinal difluorides adopt defined conformations due to the electronic properties of fluorine. Therefore, they could be valuable for controlling the constellation of functional groups about acyclic C–C bonds in organic molecules if all stereoisomers of the difluorides could be synthesized. However, stereoselective synthesis of vicinal difluorides has been cumbersome. The location of functional groups within organic molecules is important because it influences function, particularly biological function. We report a catalytic synthesis of acyclic vicinal difluoride stereoisomers by C–C bond formation between two monofluoro units, along with crystallographic and computational data showing that the gauche relationship of two fluorides causes substituents to occupy defined positions about the C(sp³)–C(sp³) bond. Photoreactive chemical probes tethered to vicinal difluorides showed that difluorides bind more strongly than the analogous monofluorides, which possess less defined conformations, and that individual stereoisomers of the difluorides bind distinctly to the human proteome.