LAUSR

Native chemical ligation (NCL) requires the constant development of methods that facilitate the efficient synthesis of C‐terminal peptide thioesters, which are key intermediates in NCL. After testing several resins and linkers, we have developed a solid support on the Rink and chlorotrityl chloride resins based on the attachment of o‐phenylenediamine (PheDA), with and without an electron withdrawing group. These linkers enable the synthesis of C‐terminus o‐aminoanilide peptides without overacylation when the glycine is the first amino acid in the synthesis or when we have a glycine‐rich sequence. Upon treatment with NaNO2, the glycine o‐aminoanilide peptides produce C‐terminus benzotriazole (Bt) peptides. The C‐terminus‐Bt peptides undergo thiol exchange, yielding thioester peptides, which can then be used in an NCL reaction. The linkers attached to the Rink and CT resins efficiently avoid overacylation in the synthesis of glycine‐rich sequences, increasing the yield and purity of these sequences.