Thiyl Chemistry: Cysteine-Catalyzed Maleate Isomerization via Nucleophilic Addition versus Aqueous Thiyl Radical Processes

Enzymatic systems catalyze the E/Z isomerization of C=C double bonds by thiol-based cysteine residues efficiently, while artificial reactions with thiol-based molecules have remained stoichiometric, not catalytic. Herein, we report a catalytic isomerization of maleate to fumarate at benign temperatures using molecular catalysts based on cysteine and its analogs via chemical or photochemical radical activation. Kinetic analysis and DFT study support the aqueous thiyl radical-catalyzed reaction. The reaction is first-order with respect to the reactant, zero-order with respect to the thiol molecules, and first-order with respect to the radical initiator concentration. The catalytic turnover number of 2,500 and catalytic turnover frequency of 1.1 s‒1 have been achieved in the presence of thiyl radicals, and chemical “mutational” studies reveal the importance of both the thiol unit and the intramolecular adjacent groups for efficient catalysis.