STUDIES ON LACTAM FORMATION DURING COUPLING PROCEDURES OF N-ALPHA-N-OMEGA-PROTECTED ARGININE DERIVATIVES

We evaluated the quantity of delta-lactam generated during the synthes is of arginine-containing dipeptides using Z-Arg(Tos)-OH, Boc-Arg(Tos) -OH, Fmoc-Arg(Boc)(2)-OH and Fmoc-Arg(Pmc)-OH and assayed several carb oxyl-activating procedures for coupling the protected arginines to dif ferent amino components. We observed significant amounts of delta-lact am during the synthesis of Z-Arg(Tos)-methyl ester and Z-Arg(Tos)-amid e, as well as of Boc-Arg(Tos)-chloromethyl ketone. The mixed anhydride coupling procedure and the di-Boc-protecting guanidino group induced more delta-lactam formation than any other coupling of N-G-protection method. The amide, benzyl, 4-(NO2)-benzyl and methyl alpha-carboxyl-pr otected amino acids generated more delta-lactam than did those protect ed by tert-butyl or N2H2-Boc. So far it has not been possible to propo se a general mechanism for delta-lactam formation or a process that co mpletely abolishes it. Therefore, this side reaction should be conside red almost inevitable. Its minimization requires examination of argini ne-containing peptides in each specific synthesis.