A New Efficient Method for S–CH2–S Bond Formation and Its Application to a Djenkolic Acid-Containing Cyclic Enkephalin Analog

An efficient methylene insertion reaction to construct an S–CH2–S bridge between two cysteine residues occurred when the thiol-protecting dimethylphosphinothioyl (Mpt) group of Z–Cys(Mpt)–OMe was removed with tetrabutylammonium fluoride hydrate in CH2Cl2. The thiol-free form gave similar results, albeit the yields were somewhat lower. In both cases, the best yields were obtained using 2 molar amounts of the reagent. Higher amounts of the reagent reduced the yield because of dehydroalanine formation. In the case of penicillamine, the thiol-free form was better in reactivity than the S-Mpt form, which required double the amount of the reagent to give the same yield. The reaction was successfully used in a synthesis of a cyclic enkephalin analog with the S–CH2–S bridge.