Residue-selective methods for the modification and cyclization of peptides are useful for the discovery and development of therapeutic peptide leads with metabolically stable structures. To develop new methods, the Roberts laboratory draws inspiration from biologically active cyclic and polycyclic peptide natural products. Examples include the arylomycin and vancomycin families of antimicrobial peptides that scaffold tyrosine- and hydroxyphenylglycine-derived biaryl-linkages.

Accordingly, we have developed methods that leverage the in situ formation of 1,2,4-triazoline-3,5-dione, TAD, moieties, also known as urazoles, on native peptides to achieve tyrosine-selective peptide cyclizations and polycyclizations. Detailed accounts of these methods, and their applications toward biologically active cyclic peptides will be presented.