A Novel Method for the Protection and Activation of Histidine

The yield and purity of synthetic peptides were greatly related to the amino acid protection and activation during the synthesis process. Therefore, the amino acid protection and activation are the most important steps in peptide synthesis. By using tetrahydrofuran as the solvent, 9-fluorenylmethoxycarbonyl as protection group, 2-(7-azobenzotri- azol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) as condensation reagent an amino protected histidine ester was given. In this article a novel synthesis method for N-(9- fluorenylmethoxycarbonyl)-histidine active ester was established. The reaction conditions for preparing this active ester were optimized. The experimental results indicated that solvents and active reagents had remarkable effects on the yield of active ester. The best conditions for preparing the active ester was a ratio of n (Fmoc-His-OH): n (HATU) = 1:1.2 with THF used as the solvent at room temperature. The yield of the final product was about 80% with a purity of over 85%. This simple method would provide fundamentals for the synthesis of other protected amino acid active esters.