Total Synthesis of (+)-Resiniferatoxin via a Pyridinium Salt Photorearrangement

We report a total synthesis of (+)-resiniferatoxin (RTX) that leverages both the ground-state and excited-state reactivity of pyridinium to assemble its highly oxidized 5/7/6-fused tricyclic core. A key strategic element is the development of a practical protocol for the in situ formation of pyridinium trifluoromethanesulfonate salts via mild methylation of densely substituted pyridines, followed by a ring-contracting photorearrangement in either batch or continuous flow settings. Rapid, one-pot elaboration of the resulting aziridine intermediate provides gram-scale access to advanced intermediates, which represents a modular route to highly functionalized five-membered carbocycles embedded in fused-ring scaffolds, thereby facilitating biological studies and analog development of RTX.