In the past decade, a large number of target-specific, biaryl-containing peptide macrocycles have attracted the attention of researchers for the treatment of bacterial and fungal infections. As a result of their target selectivity and strong binding affinity, biaryl cyclic peptides represent promising scaffolds in the development of novel bioactive compounds. Especially noteworthy are the antibiotics vancomycin and the arylomycin analog G0775, each possessing potent antibacterial activity (Figure ). Heterobiaryl peptides have also garnered attention in recent years. The heterobiaryl-containing peptide macrocycle complestatin (also known as chloropeptin II) possesses activity against HIV. Heterobiaryl linkages can be found in aciculitin A-C, TMC-95A as well as a synthetic heterobiaryl analog of arylomycin (Figure ). More recently, a novel PCSK9 inhibitor produced by Merck contains a peptide bridge involving a heterobiaryl linkage between a triazole and aryl rings. Synthetically, heterobiaryl and biaryl linkages in peptide macrocycles are typically constructed from building-blocks and then incorporated into the peptide backbone via a conventional amidation reaction. Alternatively, metal-catalyzed ring-closing macrocyclization reactions are used towards heterobiaryl construction. Metal-catalyzed heterobiaryl formation has been utilized in many synthetic routes; however, it is typically limited to peptide sequences that do not contain metal-coordinating amino acids (cysteine, methionine, histidine) and relies on the use of pre-functionalized boron-or tin-containing starting materials, many of which are sensitive to both strongly basic and strongly acidic conditions. Yet another limitation is that biaryl-bearing compounds assembled using metal-catalyzed cross-coupling reactions can be contaminated with trace amounts of transition-metal impurities, making them insufficiently pure to meet stringent drug safety standards. Currently, no method exists that allows for the assembly of heterobiaryl scaffolds during peptide macrocyclization without the reliance on transition-metal catalysis.