Temporary serine protection in solid phase synthesis of LH-RH analogs.

Methodology for the large-scale, solid-phase synthesis of nafarelin, I, an LH-RH agonist and RS-26306, III, and LH-RH antagonist, is described. N alpha-Boc protected amino acids were used in the synthesis. The only side-chain-protected amino acids required were BocHis(Tos)-OH and BocSer(t-Bu)-OH. The use of temporary protection on serine eliminates the formation of bis-serine derivatives (II and IV), which presents a major limitation to the use of minimal protection schemes for large-scale synthesis. Using this approach, the side-chain protecting groups are cleaved during the synthesis, and HF deprotection in a separate step is not required.