Inverse Electron-Demand Diels–Alder Bioorthogonal Reactions

Bioorthogonal reactions have been widely used over the last 10 years for imaging, detection, diagnostics, drug delivery, and biomaterials. Tetrazine reactions are a recently developed class of inverse electron-demand Diels–Alder reactions used in bioorthogonal applications. Given their rapid tunable reaction rate and highly fluorogenic properties, tetrazine bioorthogonal reactions have come to be considered highly attractive tools for elucidating biological functions and messages in vitro and in vivo. In this chapter, we present recent advances expanding the scope of precursor reactivity and we introduce new biomedical methodology based on bioorthogonal tetrazine chemistry. We specifically highlight novel applications for different kinds of biomolecules, including nucleic acid, protein, antibodies, lipids, glycans, and bioactive small molecules, in the areas of imaging, detection, and diagnostics. We also briefly present other recently developed inverse electron-demand Diels–Alder bioorthogonal reactions. Lastly, we consider future directions and potential roles that inverse electron-demand Diels–Alder reactions may play in the fields of bioorthogonal and biomedical chemistry.