Safety‐catch linkers for Fmoc solid‐phase synthesis of peptide thioesters and hydrazides by amide‐to‐imide activation

The use of C‐terminal peptide thioesters and hydrazides in synthetic protein chemistry has inspired the search for optimal solid‐phase peptide synthesis (SPPS) strategies for their assembly. However, peptide thioesters are not directly accessible by conventional Fmoc‐SPPS owing to the nucleophilicity of the secondary amine required for Fmoc removal. Here, we report the mild and effective activation of the pGlu linker and a new safety‐catch linker that was used for the convenient synthesis of peptide thioesters and hydrazides via efficient amide‐to‐imide activation followed by nucleophilic displacement. A new safety‐catch linker that allows for the convenient, mild, and epimerization‐free synthesis of C‐terminal peptide thioesters and hydrazides via efficient on resin amide‐to‐imide activation followed by nucleophilic displacement was developed.