Alpha- and beta- aspartyl peptide ester formation via aspartimide ring opening.
The undesirable reaction of aspartimide formation has been proved to occur under both acid and base conditions in solid-phase peptide synthesis and is dependent on the beta-carboxyl protecting group, the acid or base used during the synthesis, as well as the peptide sequence. The hydrolysis of aspartimide-containing peptides, especially during HPLC purification, yields a mixture of alpha- and beta-aspartyl peptides that can not be purified easily. A previous study demonstrated that treatment of aspartimide-containing peptides with methanol in the presence of 2% diisopropylethylamine in solution leads to alpha- and beta-aspartyl peptide methyl esters. Taking advantage of these results and aiming at elucidating the optimal conditions for aspartimide ring opening, the effect of different types and concentrations of alcohols (primary and secondary) and bases (diisopropylethylamine, collidine, 4-pyrrolidinopyridine, 1-methyl-2-pyrrolidone, piperidine and KCN) was tested at various temperatures and reaction times. The best results were obtained with a combination of a primary alcohol and diisopropylethylamine, while aspartimide ring opening by secondary alcohols occurred only at high temperatures. The optimal conditions were also applied to solid-phase peptide synthesis.
Stathopoulos
Panagiotis
P
Department of Chemistry, University of Ioannina, GR-45110 Ioannina, Greece.
Papas
Serafim
S
Kostidis
Sarantos
S
Tsikaris
Vassilios
V
D000596:Amino Acids / Q000737:chemistry; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000737:chemistry; D004952:Esters / Q000138:chemical synthesis*; D005449:Fluorenes / Q000737:chemistry; D007094:Imides / Q000737:chemistry; D026581:Isoaspartic Acid / Q000737:chemistry*; D009842:Oligopeptides / Q000737:chemistry; D010455:Peptides / Q000138:chemical synthesis*; D021241:Spectrometry, Mass, Electrospray Ionization
D000596:Amino Acids; D004952:Esters; D005449:Fluorenes; D007094:Imides; D026581:Isoaspartic Acid; C016456:N(alpha)-fluorenylmethyloxycarbonylamino acids; D009842:Oligopeptides; D010455:Peptides; D001224:Aspartic Acid; C075871:aspartimide