Bioinspired Diversification of Short Peptides via Tyrosine Umpolung

Herein, we report a bioinspired strategy for the selective modification of tyrosine residues in short peptides based on a formal umpolung of the phenolic side chain. Mild oxidation with a hypervalent iodine(V) reagent enables the in situ generation of ortho-quinone intermediates, effecting a polarity inversion. These electrophilic intermediates can be selectively intercepted by external nucleophiles, enabling diversification of tyrosine residues either through skeletal modification of the phenolic core into phenazine scaffolds, or via peripheral modifications through the formation of tyrosine-cysteine cross-links.