ArticleJournal of peptide science : an official publication of the European Peptide Society2019
The aspartimide problem persists: Fluorenylmethyloxycarbonyl-solid-phase peptide synthesis (Fmoc-SPPS) chain termination due to formation of N-terminal piperazine-2,5-diones.
Article in Journal of peptide science : an official publication of the European Peptide Society, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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8 citing papers in PubMed.
- Reversing Lanmodulin's Metal-Binding Sequence in Short Peptides Surprisingly Increases the Lanthanide Affinity.Angewandte Chemie (International ed. in English) · 2025Article
- Aspartimide Formation and Its Prevention in Fmoc Chemistry Solid Phase Peptide Synthesis.Chembiochem : a European journal of chemical biology · 2025Review
- Unveiling the Oxazolidine Character of Pseudoproline Derivatives by Automated Flow Peptide Chemistry.International journal of molecular sciences · 2024Article
- Dipropylamine for 9-Fluorenylmethyloxycarbonyl (Fmoc) Deprotection with Reduced Aspartimide Formation in Solid-Phase Peptide Synthesis.ACS omega · 2023Article
- Lanmodulin peptides - unravelling the binding of the EF-Hand loop sequences stripped from the structural corset.Inorganic chemistry frontiers · 2022Article
- Design and Synthesis of Brain Penetrant Glycopeptide Analogues of PACAP With Neuroprotective Potential for Traumatic Brain Injury and Parkinsonism.Frontiers in drug discovery · 2022Article
- Sustainable Peptide Synthesis Enabled by a Transient Protecting Group.Angewandte Chemie (International ed. in English) · 2020Article
- The aspartimide problem persists: Fluorenylmethyloxycarbonyl-solid-phase peptide synthesis (Fmoc-SPPS) chain termination due to formation of N-terminal piperazine-2,5-diones.Journal of peptide science : an official publication of the European Peptide Society · 2019Article
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5 authors.
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Abstract
Aspartimide (Asi) formation is a notorious side reaction in peptide synthesis that is well characterized and described in literature. In this context, we observed significant amounts of chain termination in Fmoc-SPPS while synthesizing the N-terminal Xaa-Asp-Yaa motif. This termination was caused by the formation of piperazine-2,5-diones. We investigated this side reaction using a linear model peptide and independently synthesizing its piperazine-2,5-dione derivative. Nuclear magnetic resonance (NMR) data of the side product present in the crude linear peptide proves that exclusively the six-membered ring is formed whereas the theoretically conceivable seven-membered 1,4-diazepine-2,5-dione is not found. We propose a mechanism where nucleophilic attack of the N-terminal amino function takes place at the α-carbon of the carbonyl group of the corresponding Asi intermediate. In addition, we systematically investigated the impact of (a) different adjacent amino acid residues, (b) backbone protection, and (c) side chain protection of flanking amino acids. The side reaction is directly related to the Asi intermediate. Hence, hindering or avoiding Asi formation reduces or completely suppresses this side reaction.
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