Application of High-Throughput Competition Experiments in the Development of Aspartate-Directed Site-Selective Modification of Tyrosine Residues in Peptides

Herein
we report a Cu-catalyzed, site-selective functionalization
of peptides that employs an aspartic acid (Asp) as a native directing
motif, which directs the site of O-arylation at a proximal tyrosine
(Tyr) residue. Through a series of competition studies conducted in
high-throughput reaction arrays, effective conditions were identified
that gave high selectivity for the proximal Tyr in Asp-directed Tyr
modification. Good levels of site-selectivity were achieved in the
O-arylation at a proximal Tyr residue in a number of cases, including
a peptide–small molecule hybrid.