A general synthesis of complex bicyclo[1.1.1]pentanes via a multi-component cascade atom transfer radical addition

The replacement of arenes with bicyclo[1.1.1]pentane (BCP) motif in bioactive compounds has emerged as a promising approach to obtain drug candidates with improved physicochemical and pharmacokinetic properties. Despite the recent surge of numerous reports on BCP synthesis, there remains an urgent need for versatile synthetic strategies that utilize multiple reaction components to create drug-like BCPs. Herein, we disclose a general strategy for the synthesis of complex BCP scaffolds through a visible light-triggered cascade atom transfer radical addition (CATRA). This CATRA reaction is a one-step three-component radical process that is operationally simple, insensitive to air and moisture, and makes use of simple alkenes, readily available alkyl iodides, and [1.1.1]propellane as starting materials. This method is mechanistically intriguing, involving a photoredox catalytic cycle and radical chain processes. This CATRA strategy is amenable to gram-scale synthesis, and it has been used to rapidly prepare BCP analogues of a number of bioactive molecules, including indobufen, butetamate, and butamirate, among others. This study provides chemists with new possibilities for facile replacement of the para-substituted phenyl rings in promising bioactive compounds with a bioisosteric 1,3-disubstituted BCP, thereby potentially accelerating the discovery of drug molecules with enhanced pharmacological profiles.