Efficient solution phase synthesis of [1-(beta-mercapto-beta, beta-cyclopentamethylenepropionic acid)- 2-(O-ethyl-D-tyrosine)-4-valine-9-desglycine]arginine vasopressin.
A convergent synthesis of the peptide [1-(beta-mercapto-beta, beta-cyclopentamethylenepropionic acid)- 2-(O-ethyl-D-tyrosine)-4-valine-9-desglycine]arginine vasopressin (1), based on the classical solution phase method, was developed. The molecule is assembled by a 3 + 4 coupling via the azide method; then the disulfide bridge is installed by iodine treatment of the bis-acetamidomethyl protected thiols, and the terminal arginine amide added by a 7 + 1 coupling. The method has been used to prepare gram quantities of 1 in more than 98% purity and in 13% yield (based on tetrapeptide intermediate 13) after a single stage purification. The method appears to be particularly suitable for the large scale preparation of 1 and other vasopressin congeners. A novel, albeit low level, transfer of acetamidomethyl group from the sulfur of cysteine to the asparagine amide side-chain was detected following hydrogen chloride treatment of Boc-containing intermediates.
Mendelson
W L
WL
Synthetic Chemistry Department, Smith Kline & French Laboratories, King of Prussia, Pennsylvania.
Tickner
A M
AM
Holmes
M M
MM
Lantos
I
I
D000595:Amino Acid Sequence; D001127:Arginine Vasopressin / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D001386:Azides; D055598:Chemical Phenomena; D002621:Chemistry; D004220:Disulfides; D007455:Iodine; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000138:chemical synthesis; D012996:Solutions; D013438:Sulfhydryl Compounds; D014667:Vasopressins / Q000037:antagonists & inhibitors*
D001386:Azides; D004220:Disulfides; D009842:Oligopeptides; D012996:Solutions; D013438:Sulfhydryl Compounds; D014667:Vasopressins; D001127:Arginine Vasopressin; C050890:1-((beta-mercapto-beta)beta cyclopentamethylenepropionic acid)-2-(O-ethyl-Tyr)-4-Val-9-des-Gly-arginine vasopressin; D007455:Iodine