title: Preventing aspartimide formation in Fmoc SPPS of Asp-Gly containing peptides--practical aspects of new trialkylcarbinol based protecting groups.
abstract: In our efforts to develop a universal solution to the problem of aspartimide formation in Fmoc SPPS, we investigated the application of our new β-trialkylmethyl protected aspartic acid building blocks to the synthesis of peptides containing the Asp-Gly motif. The N(α)-Fmoc aspartic acid β-tri-(ethyl/propyl/butyl)methyl esters were used in the synthesis of the classic model peptide scorpion toxin II (VKDGYI), and their effectiveness in minimising aspartimide formation during extended piperidine treatments was evaluated. Furthermore, we compared their efficacy against that of the commonly used approach of adding acids to the Fmoc deprotection solution. Finally, we applied our aspartic acid building blocks to the stepwise Fmoc SPPS of teduglutide, a human GLP-2 analogue, whose synthesis is made challenging by extensive aspartimide formation. In all experiments, our approach led to almost complete reduction of aspartimide formation with accompanied suppression of aspartic acid epimerisation.
authors.affiliation: Merck & Cie, Im Laternenacker 5, 8200, Schaffhausen, Switzerland.
authors.forename: Raymond
authors.initials: R
authors.lastname: Behrendt
authors.affiliation: Merck & Cie, Im Laternenacker 5, 8200, Schaffhausen, Switzerland.
authors.forename: Simon
authors.initials: S
authors.lastname: Huber
authors.affiliation: Merck Chemicals Ltd., Padge Road, Beeston, NG9 2JR, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: White
mesh_terms: D000438:Alcohols / Q000737:chemistry; D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry; D001224:Aspartic Acid / Q000737:chemistry; D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry; D005449:Fluorenes / Q000737:chemistry; D005998:Glycine / Q000737:chemistry; D008969:Molecular Sequence Data; D060327:Solid-Phase Synthesis Techniques
chemical_list: D000438:Alcohols; D000596:Amino Acids; D004151:Dipeptides; D005449:Fluorenes; C016456:N(alpha)-fluorenylmethyloxycarbonylamino acids; D001224:Aspartic Acid; C017033:aspartylglycine; D005998:Glycine
keywords: Aspartimide formation; Fmoc solid-phase peptide synthesis; aspartic acid β-trialkylmethyl ester; epimerisation; glucagon-like peptide 2; racemisation