Endomorphin-2 Synthesis

The tetrapeptide of endomorphin-2, a strong agonist of the u-acceptor with high affinity and selectivity, was synthesized from L-tyrosine, L-proline and L-phenylalanine by liquid phase condensation. The synthetic procedure includes the synthesis of two dipeptides first and coupling of the two dipeptides to the titled tetrapeptide. The Boc protected phenylalanine (Boc-Phe-OH) reacted with phenylalanine amide to give the first dipeptide Boc-Phe-Phe-NH₂ in 86% yield. The Boc and Bzl protected tyrosine (Boc-Tyr(Bzl)-OH) was allowed to react with proline methyl ester hydrochloride to form the second dipeptide Boc-Tyr(Bzl)-Pro-OMe in 42% yield. The Boc group on the first dipeptide and the protecting group of methyl ester on the other were then deprotected respectively. The tetrapeptide Boc-Tyr(Bzl)-Pro-Phe-Phe-NH₂ was obtained in 77% yield by coupling of the two deprotected dipeptides in DMF/CH₂Cl₂ in the presence of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDCI) and 1-hydroxybe-nztriazole(HOBt). Final deprotection of the Boc and Bzl group on tyrosine in the tetrapeptide in thioanisole-trifluoroacetic Acid gave endomorphin-2 TFA salt in 81% yield. Structures of the titled product and the intermediates were characterized by ¹H NMR, IR and MS.