On-Resin Selenopeptide Catalysts: Synthesis and Applications of Enzyme-Mimetic Reactions and Cyclization of Unsaturated Carboxylic Acids

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Selenium reagents are useful for selenoenzyme-mimicking reactions, as well as for organic synthesis. However, the reaction waste containing selenium frequently smells unpleasant and exhibits serious toxicity. Herein, we have developed new-type on-resin selenium reagents, H-UXX···-PAM (5) and Ac-(X)U*XX···-PAM (6), where U and U* represent selenocysteine (U) and p-methoxybenzyl (PMB)-protected U, respectively, as recyclable catalysts, in which U-containing peptide chains are linked to the polystyrene resin PAM. Synthesized on-resin selenopeptides 5a–g with a variable amino acid sequence were evaluated for their glutathione peroxidase (GPx)-like activity using the UV and 1H NMR methods, using the reaction between dithiothreitol (DTTred) and H2O2 in methanol. It was found that the intramolecular interaction between U and a basic amino acid residue, such as histidine (H) and lysine (K), enhances peroxidase activity through the formation of an NH···Se hydrogen bond. On the other hand, the catalytic activity of 6a–d was evaluated in the oxidative cyclization of β,γ-unsaturated acids (7) into α,β-unsaturated lactones (8). Although the yield of 8 was significantly decreased after second- or third-round reaction, due to detachment of the selenium moiety from the resin, the results demonstrated reusability, as well as a substrate scope of 6 as a catalyst. Since U is a natural amino acid, on-resin selenopeptides are potential targets as novel-type green redox catalysts.