The LARGEST library of Bicyclo[1.1.1]pentanes for Drug Discovery enabled by Light

In 2012, bicyclo[1.1.1]pentanes were demonstrated to be bioisosteres of the phenyl ring. Today, after more than a decade, the difficulty in their large-scale preparation is still a problem, that often outweighs the corresponding derivatives to becoming clinical candidates. Here, we report a practical general reaction that gives bicyclo[1.1.1]pentanes on mg- to kg-quantities using just light. No additional additives or catalysts are needed. Using this strategy, we have prepared >300 functionalized bicyclo[1.1.1]pentanes on a (multi)gram scale. So far, this is the most general and practical approach to bicyclo[1.1.1]pentanes. Many of these molecules, which were previously commercialized, are already being used in drug discovery by pharmaceutical companies Gilead Sciences, Hoffman-La Roche, Idorsia, Merck, Janssen Pharm., etc. This work should ease the transition of bicyclo[1.1.1]pentane-containing bioactive compounds to clinical candidates, and subsequently to drugs.