Regioselective Synthesis of Multiple Thioether-Bridged Peptides via a One-Pot Reaction

In this work, the previously reported SeODR strategy was used successfully for the synthesis of bicyclic peptides (<b>BPs</b>). <b>BPs</b> with different rings bearing various thioether linkages were prepared through a one-pot reaction; 15 <b>BPs</b> with satisfactory yields were achieved. Cross-linkers including xylylene dibromide (<b>xylyl)</b>, 2,6-bis(bromomethyl)pyridine (<b>BBP)</b>, 4,4'-bis(bromomethyl)biphenyl (<b>BBMP</b>), 1,3-dichloroacetone (<b>DCA)</b>, and dichloro-<i>s</i>-tetrazine (<b>DCTZ)</b> are all compatible with the SeODR approach used for deprotection of the S-acetamidomethyl (Acm) group in peptides. Moreover, four novel monosaccharide-based cross-linkers were prepared through the conjugation of <i><b>m</b></i><b>-xylyl</b> with glucose, mannose, and galactose by the click reaction. Consequently, seven bicyclic glycopeptide conjugates (<b>BGPs</b>) were first synthesized by the use of the SeODR strategy in a one-pot manner, and good yields were all achieved. In these syntheses, monosaccharide and triazole groups in the monosaccharide-based cross-linkers were all compatible with the SeODR approach. Finally, a tricycle glycopeptide conjugate (<b>TGP</b>) based on conotoxin mr3e bearing three different monosaccharide cross-linkers was successfully synthesized by a combination of the SeODR strategy with the synthetic strategy of the monosaccharide-based cross-linkers. Therefore, multiple cyclic peptides with a large structural diversity can be synthesized conveniently by the combined strategies, with the multiple cyclic peptides being glycosylated by different monosaccharides.