Synthesis of Unprotected Cyclic Peptide Methylene Dithioacetals by Rhodium-Catalyzed Oxidation of Methanol to Formaldehyde

In the presence of a rhodium catalyst, unprotected peptide dithiols possessing two cysteine residues are efficiently converted to their corresponding cyclic methylene dithioacetals in a mixed solvent of methanol and water (4:1) under an oxygen atmosphere (1 atm). The slow formation of formaldehyde inhibits side reactions by maintaining its concentration at a low level, which is a key feature of this reaction. This method can be applied to peptide dithiols containing amino acids such as Gly, Ala, Ser, Lys, Met, Phe, Tyr, and His and provides cyclic methylene dithioacetals without being affected by other functional groups. Primary alcohols, such as ethanol and isopropanol, can also be employed. Oxytocin can be cyclized to provide a cyclic methylene dithioacetal.