A LIQUID PHASE SYNTHESIS OF ENKEPHALINES

The total synthses of methionine-enkephalin (H-Tyr-Gly-Gly-Phe-Met-OH) and leucine-enkephalin(H-Tyr-Gly-Gly-Phe-Leu-OH) are described. Treatment of L-tyrosine with benzyl chloroformate afforded N, O-dicarbobenzoxy derivative, which was coupled with ethyl glycyl-glycinate under the action of EEDQ in methanol to give dicarboben zoxy tripeptide ester. Cbz-Tyr-Gly-Gly-OH was formed on hydrolysis of both ester linkage with methanolic sodium hydroxide. This tripeptide was coupled with Phe-MetOMe and Phe-Leu-OMe respectively under the action of DCC. Hydrolysis of tbe condensation products with sodium hydroxide could not afford pure products. Thus the compounds were decarbobenzoxylated and then hydrolyzed. Methionine-enkephal in and ieucine-enkephalin were isolated by means of chromatography on LH-20 sephadex. Thepentapeptides produced transient analgesia following intracerebroventricular administration to mice.