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A Selective Synthesis of 2,2-Difluorobicyclo[1.1.1]pentane Analogues: "BCP-F2"
Xiaoshen Ma1, David L Sloman1, Yongxin Han1
1Department of Discovery Chemistry , Merck & Co., Inc. , 33 Avenue Louis Pasteur , Boston , Massachusetts 02115 , United States.
Abstract:
The bicyclo[1.1.1]pentane (BCP) motif has been utilized as bioisosteres in drug candidates to replace phenyl, tert-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-"para"-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 "ortho/meta-substituted" BCPs via similar mechanisms.