Department of Discovery Chemistry , Merck & Co., Inc. , 33 Avenue Louis Pasteur , Boston , Massachusetts 02115 , United States.
Org Lett. 2019 Sep 20;21(18):7199-7203. doi: 10.1021/acs.orglett.9b02026. Epub 2019 Jul 11.
The bicyclo[1.1.1]pentane (BCP) motif has been utilized as bioisosteres in drug candidates to replace phenyl, -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-""-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 "/-substituted" BCPs via similar mechanisms.
双环[1.1.1]戊烷（BCP）基序已被用作药物候选物中的生物等排体，以取代苯、-丁基和炔基片段，从而改善物理化学性质。然而，由于合成难度，大多数 BCP 类似物仅带有 1,3-""-取代基。我们报告了首例通过二氟卡宾插入双环[1.1.0]丁烷来选择性合成 2,2-二氟双环[1.1.1]戊烷。此外，这种方法应该会激发未来通过类似机制合成其他"/-取代"BCP 的研究。
