Revisiting NO₂ as Protecting Group of Arginine in Solid-Phase Peptide Synthesis

The protection of side-chain arginine in solid-phase peptide synthesis requires attention since current protecting groups have several drawbacks. Herein, the NO₂ group, which is scarcely used, has been revisited. This work shows that it prevents the formation of δ-lactam, the most severe side-reaction during the incorporation of Arg. Moreover, it is stable in solution for long periods and can be removed in an easy-to-understand manner. Thus, this protecting group can be removed while the protected peptide is still anchored to the resin, with SnCl₂ as reducing agent in mild acid conditions using 2-MeTHF as solvent at 55 °C. Furthermore, we demonstrate that sonochemistry can facilitate the removal of NO₂ from multiple Arg-containing peptides.