A one-pot photocatalytic triazole-based linkerology for PROTACs

Proteolysis-targeting chimeras (PROTACs) are a powerful approach for targeted protein degradation. One of the current bottlenecks for developing PROTACs is the lack of an operationally simple linkerology to rapidly construct PROTACs with various linkers. The classic convergent synthesis strategy by coupling pre-assembled linkers with two ligands stepwise commonly needs at least four steps to give the final target PROTACs, which results in low total yields with long reaction times (several days) and tedious operations. Here, we develop an efficient photocatalytic one-pot linkerology for the rapid coupling of analogs of PROTACs containing triazole-based linkers without any linker-pre-assembled procedure. The reaction was completed within 4 h with up to 95% yields at room temperature. Easily accessible cyclic ethers are directly used as linker precursors to furnish the one-pot fashion, including alkenyl, polyethylene glycol (PEG), ketone, and cyclohexane chains. The study provides a highly efficient, step-economic, operationally simple, and environmentally friendly one-pot linkerology for PROTAC drug discovery.