Selective Removal of the o‐Nitrophenylsulfenyl Protecting Group in Peptide Synthesis

Abstract 2‐Thiopyridone (2‐mercaptopyridine, 1 ) was found to be a very suitable reagent for removing the N α ‐o‐nitrophenylsulfenyl (NPS‐) group in both conventional and solid‐support peptide synthesis. A 3‐ to 5‐molar excess of the reagent together with an equivalent amount of glacial acetic acid in methanol, dimethylformamide, or methylene chloride produces the soluble, stable mixed disulfide, 2‐nitrophenyl 2‐pyridyl disulfide ( 2 ), and the N α ‐deprotected amino‐acid or peptide. The yields are quantitative in less than 5 min if all educts are dissolved, in about 20 to 30 min in solid‐support synthesis. No modifications of either the indole side‐chain of tryptophan or of a series of side‐chain protecting groups, in particular of the t ‐butyl type, are produced. No adverse side‐reactions (insoluble disulfides) were observed. The procedure is illustrated with a series of amino‐acid derivatives and with the solid‐support synthesis of [5‐leucine]‐enkephalin.