Base‐Controlled Switchable Umpolung Phosphorylation of Tyrosine, Cysteine, and Tryptophan by CHCl 3 ‐Assisted Phosphonium Salt Catalysis

Chemical post‐modification of peptides is a powerful approach for enabling structural diversification and rapid derivatization during the development of peptide therapeutics. In particular, tyrosine phosphorylation is a key regulatory mechanism in many cellular functions. Furthermore, phosphorylated tyrosine is a fundamental structural unit present in bioactive peptides and their lead compounds. Herein, we report a highly efficient DBU–CHCl 3 ‐mediated umpolung phosphorylation of tyrosine in short peptides using H‐phosphine oxides as electrophilic phosphoryl donors in both solution and solid phases. The method shows base‐controlled selectivity and is applicable to cysteine, and tryptophan using Cs 2 CO 3 as base. The reaction involves base‐promoted carbene generation from CHCl 3 under phosphonium salt catalysis to form an electrophilic phosphorus species that underwent nucleophilic attack by amino acids, enabling umpolung phosphorylation through O─P, S─P, and N─P bond formation. Furthermore, the strategy has been successfully applied to biomolecule‐amino acid conjugates, yielding phosphorylated conjugates in good efficiency.