Morpholine Prevents the Formation of Aspartimide from β-allyl ester aspartic acid during Fmoc Cleavage in SPPS of Stapled Peptides

Despite significant advancements in peptide chemistry, the persistent occurrence of aspartimide formation during peptide synthesis is a stumbling block, especially in stapled peptide through Lys-Asp lactamization. This obstacle not only results in low yields but also necessitates expensive purification processes and can render certain peptide sequences unattainable. In this context, the method proposed in this work utilizes morpholine to effectively address the issue and successfully achieve the synthesis of a challenging aspartimide-prone peptide sequence. The efficacy of morpholine in preventing aspartimide formation is emphasized, presenting a versatile solution applicable to peptides containing β-allyl ester aspartic acid for stapling peptide synthesis. Graphical Abstract: (Figure presented.)