Photoelectrochemical Catalyzed Site-Selective Tryptophan β-Position Functionalization

Site-specific bioconjugation methods offer exceptional uniformity in producing protein/peptide conjugates, thereby improving pharmacological properties. However, developing site-selective chemical modifications directly on natural amino acids, especially at the β-position, remains challenging. Here, we present a novel photoelectrochemical strategy for site-selective tryptophan β-position functionalization. Employing a 2,3-dichloro-5,6-dicyano-<i>p</i>-benzoquinone (DDQ)/<i>tert</i>-butyl nitrite (TBN) catalyst system under blue LED irradiation and electrochemical conditions, we achieved C(sp³)-H functionalization for activating the tryptophan β-position with nucleophiles. This resulted in a variety of conjugated peptides and proteins with outstanding selectivity. The in situ generation of the C-centered Trp-skatolyl cation by this protocol allows its reaction with nucleophiles to produce diverse functionalized products. Offering mild, eco-friendly conditions and enhanced selectivity, this method emerges as a promising tool for peptide and protein modification in pharmaceutical applications.