Manipulating the Click Reactivity of Dibenzoazacyclooctynes: From Azide Click Component to Caged Acylation Reagent by Silver Catalysis

Strain‐promoted azide–alkyne cycloaddition using dibenzoazacyclooctyne (DBCO) is widely applied in copper‐free bioorthogonal reactions. Reported here is the efficient acid‐promoted rearrangement and silver‐catalyzed amidation of DBCO, which alters its click reactivity robustly. In the switched click reaction, DBCO, as a caged acylation reagent, enables rapid peptide/protein modification after decaging facilitated by silver catalysts, rendering site‐specific conjugation of an IgG antibody by a Fc‐targeting peptide. Dibenzoazacyclooctyne (DBCO) is widely used in strain‐promoted copper‐free click reactions. Reported here is an efficient approach to render a switch in click reactivity of DBCO from azide to amine substrates by using silver catalysts, allowing robust conjugation to peptides, proteins, and living bacteriophages. Moreover, by harnessing the caged acylation reactivity of DBCO, site‐specific conjugation to an IgG antibody was achieved.