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.

中文翻译：

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天冬酰胺的问题仍然存在：由于形成N末端哌嗪-2,5-二酮，导致芴基甲氧基羰基固相肽合成（Fmoc-SPPS）链终止。

天冬酰胺（Asi）的形成是肽合成中一个臭名昭著的副反应，在文献中已得到充分表征和描述。在这种情况下，我们观察到Fmoc-SPPS中大量链终止，同时合成了N末端Xaa-Asp-Yaa基序。该终止是由于哌嗪-2,5-二酮的形成引起的。我们使用线性模型肽研究了这一副反应，并独立合成了其哌嗪-2-5-二酮衍生物。粗线性肽中存在的副产物的核磁共振（NMR）数据表明，仅形成了六元环，而没有发现理论上可以想象的七元1,4-二氮杂-2,5-二酮。