Synthesis of Asp-based lactam cyclic peptides using an amide-bonded diaminodiacid to prevent aspartimide formation

Asp-based lactam cyclic peptides are considered promising drug candidates. However, using Fmoc solid-phase peptide synthesis (Fmoc-SPPS) for these peptides also causes aspartimide formation, resulting in low yields or even failure to obtain the target peptides. Here, we developed a diaminodiacid containing an amide bond as a beta-carboxyl-protecting group for Asp to avoid aspartimide formation. The practicality of this diaminodiacid has been illustrated by the synthesis of lactam cyclic peptide cyclo[Lys9,Asp13] KIIIA7-14 and 1Y. A diaminodiacid (DADA) containing an amide bond can be used in Fmoc solid-phase peptide synthesis (SPPS) of an Asp-based lactam cyclic peptide with no aspartimide formation.