Total Synthesis and Functional Characterization of Selenoneine

The N-α-trimethyl 2-selenohistidine selenoneine is the selenium isolog of the natural antioxidant ergothioneine. Sulfur-to-selenium substitutions are known to endow proteins and nucleic acids with special activities. In contrast, secondary metabolites that exploit selenium-specific chemistry are rare. Selenoneine therefore provides a unique opportunity to study how natural organoselenides interact with cellular processes. In this report we describe the chemical synthesis of selenoneine and other 2-selenoimidazoles. With synthetic selenoneine at hand we discovered a set of reactivities that distinguish selenoneine from ergothioneine, showing that the two compounds can fill distinct functional niches. Synthetic access to 2-selenoimidazoles should pave the way to explore the pharmaceutical potential and physiological function of this heretofore inaccessible class of compounds.