Formation of a Disulfide Bridge on the Resin during Solid-Phase Synthesis of Terlipressin: Influence of the Boc-Protected and Free N-Terminal Amino Group

An industry-ready approach for the synthesis of terlipressin is developed: the entire peptide chain assembly and subsequent disulfide bond closure are carried out on a polymeric carrier with a specific precaution for the protection of the N-terminal α-amino group. The effect of various factors on the purity of crude disulfide was studied, and the solid-phase cyclization process was optimized. The designed approach has high fidelity and reproducibility and is applicable for a large-scale peptide synthesis (we show it up to 15 g of the pure product). Using molecular modeling, we have found that the state of the N-terminal amino group (free or protected) has a significant influence on the ability of two cysteine side chains to reach each other, paving the way to a rational choice of protecting groups in peptide synthesis.