In summary, we have developed a new cyclization strategy to prepare heterobiaryl-containing peptides using oxadiazole-forming isocyanide reagent Pinc as well as oxazole-forming isocyanide reagent 2. We have shown that two structurally distinct heterobiaryl peptide macrocycles (either oxadiazole-or oxazole-containing) can be prepared from a single linear peptide sequence. Through careful structural analysis, we have determined that structural modulation can be achieved through alteration of the f-dihedral angle of the heterobiaryl linkage. We have demonstrated that oxazoleheterobiaryl linkages produced from reagent 2 prefer a non-planar orientation that lead to downstream structural effects unlike those observed in oxadiazole-heterobiaryl peptides produced from reagent 1. We have also found that the lipophilicity of heterobiaryl-containing peptides can be altered depending on the nature of the linage where the oxazole heterobiaryl-containing peptides is noticeably more non-polar to the analogous oxadiazole heterobiaryl-containing peptide. In addition, in 4-aminobenzoic acid derived peptides, we have shown that incorporation of an oxadiazole-heterobiaryl linkage results in an unprecedented disruption of the reduced amide IMHB in products 16a and 16b, respectively. As far as we can tell this is the only example in which an otherwise rigid reduced amide IMHB has been entirely perturbed as a result of peptide backbone contortion. Our work serves as a framework for the rapid synthesis of heterobiaryl-containing peptide libraries with distinct and tunable secondary structures which has potential significance in the development of bioactive peptide macrocycles.