Regioisomer Formation with Agmatine Guanidino Group, Its Implications for Agmatine Peptide Cyclization, and Application of Bis-Boc-Agmatine

Agmatine peptides play a significant role in the therapeutic design. Imparting an agmatine moiety to a peptide molecule through amine amidination with electrophilic guanylating agents could be challenging given the lability of the various nucleophilic groups on peptides and the harsh reaction conditions. Agmatine sulfate could function as an agmatine synthon, but its sparse solubility in common organic solvents limits its application for peptide syntheses. Neutralization of agmatine sulfate could effectively enhance its solubility in organic solvents. Nevertheless, the deprotonated guanidino group poses a competition reaction against the agmatine 4-amino group in the envisioned amidation reaction. The formed regioisomeric impurity bears an unpaired amino group that could be undesirably entangled in the following reaction steps, further complicating and jeopardizing the agmatine peptide synthesis. Bis-Boc-agmatine, a guanidino-protected species, could be readily fused to peptide molecules exclusively through its amino group without forming regioisomeric impurities. A successful synthesis of an agmatine-bearing cyclic peptide FE 201836 has been accomplished using bis-Boc-agmatine as the building block in this study. Moreover, the strategy of managing the detected isomeric impurity in the synthetic process has been advocated through isolating the isomeric intermediate, tracing its further transformation in the following synthetic steps, and detecting the presence of the ultimate isomeric impurity in the final product.