Synthesis of [1, 6‐cyclo(Acetyl‐1‐L‐glutamic acid, 2‐D‐phenylalanine, 3‐D‐tryptophan, 6‐D‐lysine)] luteinizing hormone‐releasing hormone on poly‐N‐acrylylpyrrolidine resin

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Abstract
The protected peptide, Ac-Glu(OBut)-D-Phe-D-Trp-Ser(But)-Tyr(But)-D-Lys(Z)-Leu-Arg(Tos)-Pro-Gly-NH2 was synthesized in a stepwise manner on a resin of poly-N-acrylylpyrrolidine using both acid cleavable Nα-tert.-butyloxy-carbonyl and base cleavable Nα-fluorenylmethyloxycarbonyl protecting groups. After cleavage by ammonolysis in methanol, the tert.-butyl and benzyloxy-carbonyl side-chain protecting groups were cleaved with CF3-CO2H-thioanisole and the 1–6 amide ring formed by cyclization with diphenylphosphorylazide, after which the remaining tosyl protecting group was cleaved in HF-anisole. [1,6-Cyclo (Ac-Glu1, D-Phe2, D-Trp3, D-Lys6] LH-RH exhibited less than 10% of the antiovulatory potency of [D1, D-Phe2, D-Trp3,6] LH-RH, a potent linear antagonist.