Unified Access to Biaryl-Bridged Linkages Unlocks Structural Diversification of Noncanonical Cyclic Peptides

Among ribosomally synthesized and post-translationally modified peptides (RiPPs), there exist cyclic peptides featuring rigid and highly linear biaryl linkages. These biaryl cyclic peptides often exhibit unique structural characteristics absent in conventional cyclic peptides, and many display valuable biological activities. Nevertheless, the supply of such biaryl-bridged cyclic peptides and their analogs has been constrained by their intrinsic rigidity. In this study, we report a systematic and comprehensive synthetic strategy for incorporating ten distinct natural and artificial biaryl/triaryl linkages into arbitrary peptide linkers, inspired by RiPP architectures. This unified synthetic platform, which combines electrochemical decarboxylative C-C bond formation with Larock macrocyclization, enables (i) systematic access to RiPP derivatives from readily available building blocks and (ii) facile preparation of fluorine-containing RiPPs, which are of particular importance in medicinal chemistry, as well as biaryl-bridged cyclic peptides spanning diverse ring sizes. In addition, several of the cihunamide analogs synthesized in this study exhibited antibacterial activity.