Bioinspired Selenium‐Nitrogen Exchange (SeNEx) Click Chemistry Suitable for Nanomole‐Scale Medicinal Chemistry and Bioconjugation

Abstract

Click chemistry is a powerful molecular assembly strategy for rapid functional discovery. The development of click reaction with new connecting linkage is of great importance for expanding the click chemistry toolbox. We report the first Selenium‐Nitrogen Exchange (SeNEx) click chemistry between benzoselenazolones and terminal alkynes (Se‐N to Se‐C), which is inspired by the biochemical SeNEx between Ebselen and cysteine (Cys) residue (Se‐N to Se‐S). The formed selenoalkyne connection is readily elaborated, thus endowing this chemistry with multidimensional molecular diversity. Besides, this reaction is characterized by modular, predictable, high‐yielding, fast kinetics (k2 ≥ 14.43 M‐1s‐1), excellent functional group compatibility, and working well at miniaturization (nanomole‐scale), opening up many interesting opportunities for organo‐Se synthesis and bioconjugation, as exemplified by sequential click chemistry (coupled with ruthenium‐catalyzed azide–alkyne cycloaddition (RuAAC) and sulfur‐fluoride exchange (SuFEx), seleno‐macrocycle synthesis, nanomole‐scale synthesis of Se‐containing natural product library and DNA‐encoded library (DEL), late‐stage peptide modification and ligation, and multiple functionalization of proteins. These results indicated that SeNEx is a useful strategy for new click chemistry development, and the established SeNEx chemistry will serve as a transformative platform in multidisciplinary fields such as synthetic chemistry, material science, chemical biology, medical chemistry, and drug discovery.