HEAD-TO-TAIL CYCLIZATION OF HEXAPEPTIDES USING DIFFERENT COUPLING REAGENTS

In the synthesis of cyclic hexapeptides the cyclization step was exami ned by using different procedures for activation. Three coupling metho ds were tested for 'head-to-tail'' cyclization of the resin-cleaved pe ptides in solution: (1) DPPA/NaHCO3; (2) TBTU/HOBt/DIEA and (3) HBTU/H OBt/DIEA. The best results were obtained by using TBTU. Reaction rates were 5 to 70 times faster with the TBTU procedure compared to the DPP A activation and generally complete conversions to cyclopeptides were observed. The kinetics of the cyclizations under high dilution conditi ons were monitored by HPLC. During the synthesis of the linear peptide s the formation of an aminosuccinimide was observed. This by-product w as characterized by electrospray MS and NMR.