Solid-phase synthesis of tailed cyclic peptides: The use of alpha-allyl-protected aspartic acid leads to aspartimide and tetramethylguanidinium formation

This paper discusses the application of a method developed for cyclic peptide synthesis using allyl-based sidechain-protecting groups to obtain a so-called tailed cyclic peptide, a cyclic peptide bearing a side-chain anchoring tail. The method used for the synthesis of cyclo[-D-Val-Arg-Gly-Asp-Asp(-epsilon Ahx-Cys-NH2)-] incorporates the alpha-allyl-protected aspartic acid Fmoc-L-Asp-OA1. A major side reaction, resulting in aspartimide formation, was observed when Fmoc-L-Asp-OA1 was incorporated into the sequence at the N-terminus of 6-aminohexanoic acid (epsilon>Ahx). This side reaction leads to an aspartimidyl linear peptide with the same molecular weight as the expected cyclized peptide. Additionally, the undesired peptide contains a free amino terminus, which was responsible for further side reactions during the subsequent steps of the synthesis, mainly tetramethylguanidinium formation (M+98) in TBTU-induced cyclization, and acetylation (M+42).