Inert Complexes Unlock Ligand‐Accelerated Transition‐Metal Catalysis on Proteins

ABSTRACT Reactions that excel in small‐molecule settings typically require metal loadings far exceeding the number of protein reaction sites (often ≥10‐fold) once transplanted into proteinaceous media—conditions that are not truly “catalytic.” Here, we show that biologically inert metal–ligand complexes based on bathocuproine disulfonic acid disodium salt (BCS) overcome this barrier and enable ligand‐accelerated catalysis (LAC) on proteins under substoichiometric conditions. For example, Ni‐BCS effects complete deprotection of green fluorescent protein bearing N ε ‐propargyloxycarbonyl‐L‐lysine (GFP‐ProcLys) at 5 mol% catalyst with an observed turnover number (TON) ≈ 20, surpassing all previously reported metal‐catalyzed depropargylation reactions. Mechanistic studies indicate that an in situ Ni–H intermediate mediates multiple transformations on proteins, including reductive deuteration of terminal alkenes/alkynes and efficient decaging across diverse amino acid side chains. Likewise, Cu‐BCS enables copper(I)‐catalyzed azide‐alkyne cycloaddition (CuAAC) on proteins at 10 mol% with low residual copper and no protein oxidation, in sharp contrast to the benchmark Cu‐BTTAA (tris((1‐tert‐butyl‐1H‐1,2,3‐triazol‐4‐yl)methyl)amine) system. These outcomes stem from a screening strategy that prioritized metal–ligand stability, eliminating metal complexes susceptible to protein sequestration and selecting strongly coordinating, physiologically inert pairs. The resulting rational ligand‐design framework for protein‐level transition‐metal catalysis expands the frontier of protein chemistry and paves the way to translate advanced small‐molecule LAC strategies onto protein substrates for posttranslational mutagenesis.