Water-Tolerant Iminium Reactive Species for Tyrosine-Specific Functionalization

We report a novel, metal-free, and biocompatible method for tyrosine-specific functionalization using kinetically persistent iminium intermediates in aqueous media. By employing weakly coordinating anion-based ion-pair catalysts, this approach overcomes the inherent instability of iminium species in water, enabling efficient conjugation with phenolic compounds. The method showcases broad applicability, including the functionalization of pharmaceuticals, phenol-containing natural products, and tyrosine residues in biopolymers, all under mild and environmentally friendly conditions. Importantly, the approach preserves stereochemical integrity during biomolecule modifications and achieves high chemo- and regioselectivity. This work offers a versatile platform for biofunctionalization, with potential applications in drug discovery, therapeutic innovation, and biomolecular engineering.