J. Am. Chem. Soc. 141, 18644–18648 (2019)

Bioorthogonal chemical reactions provide facile routes to generate modified biological molecules. Useful bioorthogonal reactions must be both efficient and chemoselective, utilize moieties rarely (if at all) found in natural biomolecules, and generate stable ligation products. In the interest of developing new reactions that generate minimal ligation moieties, Schäfer and Monaco et al. identified the bioorthogonal capacity for the reaction of isonitriles and chlorooximes to generate hydroxyimino amides. The authors demonstrated that this reaction is chemoselective, is robust at physiological pH and temperature, and accommodates a variety of appended moieties. Not only is the reaction compatible with aqueous conditions (unlike many organic reactions), but water is actually a necessary reagent both to activate the chlorooxime and to resolve the final intermediate. In addition, the reaction is compatible with living cells, as demonstrated by metabolic labeling of cell-surface glycans, and orthogonal to the commonly used strain-promoted azide–alkyne cycloaddition reaction, enabling dual labeling. With its selectivity, versatility, and small size, the isonitrile–chlorooxime ligation is a robust new addition to the bioorthogonal reaction toolbox.

Credit: ACS