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.