Cyclization of disulfide-containing peptides in solid-phase synthesis.
Disulfide-containing peptides may be obtained in good yields and purities when oxidations are carried out on peptide chains anchored to polymeric supports used for solid-phase synthesis. Such approaches take advantage of the pseudo-dilution phenomenon which favors intramolecular processes. A variety of procedures have been demonstrated using the related model peptides Ac-Cys-Pro-D Val-Cys-NH2 and Ac-Pen-Pro-D Val-Cys-NH2 (which both readily assume a type II beta-turn conformation that becomes stabilized by a 14-membered disulfide-containing intramolecular ring), and oxytocin (conformationally mobile 20-membered disulfide ring). Both Boc and Fmoc were used for N alpha-amino protection, the beta-thiols of cysteine or penicillamine were blocked by S-acetamidomethyl (Acm), S-9-fluorenylmethyl (Fm), or S-trityl (Trt), and compatible anchoring linkages included HF-labile 4-methylbenzhydrylamide (MBHA), TFA-labile tris (alkoxy)benzylamide (PAL), and photolabile o-nitrobenzylamide (Nonb). Assemblies of linear sequences proceeded smoothly, and polymer-supported oxidations were carried out in a variety of ways either directly or after deblocking to the resin-bound dithiol. Chains were released from the support without substantial damage to the disulfide bridges, and overall yields were as high as 60-90%.
Albericio
F
F
Department of Chemistry, University of Minnesota, Minneapolis.
Hammer
R P
RP
García-Echeverría
C
C
Molins
M A
MA
Chang
J L
JL
Munson
M C
MC
Pons
M
M
Giralt
E
E
Barany
G
G
D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry; D004220:Disulfides / Q000138:chemical synthesis*; D005449:Fluorenes / Q000737:chemistry; D008969:Molecular Sequence Data; D010121:Oxytocin / Q000138:chemical synthesis; D010456:Peptides, Cyclic / Q000138:chemical synthesis*
D000596:Amino Acids; D004220:Disulfides; D005449:Fluorenes; C016456:N(alpha)-fluorenylmethyloxycarbonylamino acids; D010456:Peptides, Cyclic; D010121:Oxytocin