Bioisosteric design has become an essential approach in the development of drug molecules. Recent advancements in synthetic methodologies have enabled the rapid adoption of this strategy into drug discovery programs. Consequently, conceptionally innovative practices would be appreciated by the medicinal chemistry community. Here we report an expeditous synthetic method for synthesizing aryl difluoromethyl bicyclopentane (ADB) as a bioisostere of the benzophenone core. This approach involves the merger of light-driven C−F bond activation and strain-release chemistry under the catalysis of a newly designed N-anionic-based organic photocatalyst. This defluorinative coupling methodology enables the direct conversion of a wide variety of commercially available trifluoromethylaromatic C−F bonds (more than 70 examples) into the corresponding difluoromethyl bicyclo[1.1.1]pentanes (BCP) arenes/difluoromethyl BCP boronates in a single step. The strategy can also be applied to [3.1.1]and [4.1.1]propellane systems, providing access to analogues with different geometries. Moreover, we have successfully used this protocol to rapidly prepare ADB-substituted analogues of the bioactive molecule Adiporon. Biological testing has shown that the ADB scaffold has the potential to enhance the pharmacological properties of benzophenone-type drug candidates.

生物电子等排设计已成为药物分子开发的重要方法。合成方法学的最新进展使得该策略能够快速应用于药物发现计划中。因此，概念上的创新实践将受到药物化学界的赞赏。在这里，我们报告了一种快速合成方法，用于合成芳基二氟甲基双环戊烷（ADB）作为二苯甲酮核心的生物等排体。该方法涉及在新设计的N-阴离子有机光催化剂的催化下将光驱动的 C−F 键激活和应变释放化学相结合。这种脱氟偶联方法能够一步将多种市售三氟甲基芳香族 C−F 键（超过 70 个例子）直接转化为相应的二氟甲基双环[1.1.1]戊烷 (BCP) 芳烃/二氟甲基 BCP 硼酸酯。该策略还可以应用于[3.1.1]和[4.1.1]丙烷系统，提供不同几何形状的类似物。此外，我们已经成功地使用该方案快速制备生物活性分子 Adiporon 的 ADB 取代类似物。生物学测试表明，ADB支架具有增强二苯甲酮类候选药物药理特性的潜力。