Fluorodibenzocyclooctynes: A Trackable Click Reagent with Enhanced Reactivity

Bioorthogonal reactions have widespread applications in biological systems, and development of new bioorthogonal reactions has been of great interest over the past two decades. In this work, the design and synthesis of a family of fluorinated dibenzocyclooctynes (FDIBOs) are reported. The electron-deficient nature of fluorine atoms significantly accelerated the reaction of cyclooctynes in 1,3-dipolar cycloadditions, with either benzyl azide or ethyl diazoacetate, compared to conventional dibenzocyclooctyne (DIBO). In addition, FDIBOs showed unique trackable properties owing to the high NMR sensitivity of the naturally abundant F-19 isotope. Biological molecules, including a monosaccharide, a peptide, and a protein, were tested with FDIBOs, and these reactions could be easily monitored by F-19 NMR spectroscopy to evaluate the progress of the conjugation reactions. In addition, labeling of live cells was also demonstrated with metabolically modified bacteria to expand the possible applications of FDIBOs.