A Selective Synthesis of 2,2-Difluorobicyclo[1.1.1]pentane Analogues: “BCP-F₂”

Abstract

The bicyclo[1.1.1]pentane (BCP) motif has been utilized as bioisosteres in drug candidates to replace phenyl, <i>tert</i>-butyl, and alkynyl fragments in order to improve physicochemical properties. However, bceause of the difficulty of synthesis, most BCP analogues prepared only bear 1,3-"<i>para</i>"-substituents. We report the first selective synthesis of 2,2-difluorobicyclo[1.1.1]pentanes via difluorocarbene insertion into bicyclo[1.1.0]butanes. Moreover, this methodology should inspire future studies on synthesis of other "<i>ortho</i>/<i>meta</i>-substituted" BCPs via similar mechanisms.