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.
Institute of Organic Chemistry, Syntex Research, Palo Alto, California.
H B
HB
Arzeno
W
W
Bingenheimer
R
R
Blanchette
D J
DJ
Morgans
J
J
Robinson
D000595:Amino Acid Sequence; D005563:Formic Acid Esters / Q000737:chemistry; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000138:chemical synthesis; D008969:Molecular Sequence Data; D017274:Nafarelin / Q000138:chemical synthesis*; D012694:Serine / Q000737:chemistry*
D005563:Formic Acid Esters; C000345:t-butyloxycarbonyl group; D017274:Nafarelin; D007987:Gonadotropin-Releasing Hormone; D012694:Serine; C061018:ganirelix