Here, we present a series of fluorinated cationic reagents
that
enable rapid arylation of cysteine under mild conditions compatible
with proteins and peptides. The highly polarized C–F bond and
attractive nucleophile–electrophile Coulombic interactions
substantially accelerate cysteine arylation, leading to unusually
high rate constants on the order of 100 M–1·s–1 and allowing for equimolar labeling of substrates
at micromolar concentrations. The synthetic modularity of this approach
promotes the direct coupling of structurally diverse phenol-containing
functional motifs to cysteine residues of biomacromolecules with high
efficiency. This user-friendly chemistry enables fast bond formation
between commonly used bioconjugation partners, thus greatly streamlining
the synthetic chemistry workflow, and can be easily developed as convenient
kits for chemical biology and medicinal chemistry applications.
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