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 (BPs). BPs with different rings bearing various thioether linkages were prepared through a one-pot reaction; 15 BPs with satisfactory yields were achieved. Cross-linkers including xylylene dibromide (xylyl), 2,6-bis(bromomethyl)pyridine (BBP), 4,4'-bis(bromomethyl)biphenyl (BBMP), 1,3-dichloroacetone (DCA), and dichloro-s-tetrazine (DCTZ) 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 m-xylyl with glucose, mannose, and galactose by the click reaction. Consequently, seven bicyclic glycopeptide conjugates (BGPs) 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 (TGP) 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.