Chemoselective Acylation of Fully Deprotected Hydrazino Acetyl Peptides. Application to the Synthesis of Lipopeptides

Fully deprotected N-terminal α-hydrazino acetyl peptides were synthesized and chemoselectively acylated on the hydrazine moiety with various fatty acid succinimidyl esters or N-(cholesterylcarbonyloxy) succinimide to give lipopeptides of high purity. The buffer and pH were adjusted in order to minimize the oxidation of the hydrazine moiety and to achieve the best conversion and selectivity. The acylation was performed in a citrate−phosphate buffer/2-methylpropan-2-ol mixture of pH 5.1. The pKa of the α-hydrazino acetyl group on our model peptide was found to be 6.45, i.e., about 2 units lower than the pKa of a glycyl residue. The reaction was subsequently applied to the synthesis of a 38AA peptide derivatized by a palmitoyl group.