Fluoroglycoproteins by Copper-Free Strain-Promoted Azide–Alkyne Cycloaddition

This chapter describes a reliable two-step, metal-free protocol for the preparation of well-defined fluoroglycoproteins. It starts with a first alkylation step to chemoselectively install strained alkyne handles at cysteine residues followed by a second strain-promoted azide–alkyne cycloaddition using an inverse electron-demand Diels–Alder reaction. This proof-of-principle study that uses the apoptotic protein marker Annexin V enables the efficient metal-free incorporation of 2-deoxy-2-fluoro-glycopyranosyl azides into proteins and complements previous methods using Cu(I)-mediated azide–alkyne cycloadditions and thiol chemistry.