Poster Presentation International Peptide Symposium 2023

Peptide therapeutics have recently gained increased attention from the pharmaceutical industry due to their high potency and specificity. Compared to natural peptides and proteins, modified peptides or peptidomimetics with non-natural linkages and side chains often exhibit enhanced biological activities, which make them interesting targets as new drug candidates. During the past decades, Pd-catalysed selective C–H functionalisation has attracted considerable attention as a pathway to late-stage peptide modification.^[1]

Despite the considerable progress in directed C–H functionalisation of amino acids, late-stage C(sp³)–H functionalisation of peptides without an exogenous directing group remains to be developed. Moreover, existing methods are limited to the N-terminal primary C(sp³)–H bonds of peptides.^[2] Herein, we present the use of an amidoxime methyl ether, which can be incorporated into peptides at any amide bond, as a directing group for primary and secondary C(sp³)–H arylation of peptides including the unprecedented C(sp³)–H arylation of internal peptide residues. Under the optimised reaction conditions, β-arylated tri- and tetrapeptides were obtained in moderate to good yield (40–71%) and diastereoselectivity (3–20:1). Removal of amidoxime was also achieved to generate the parent amide.