Chemoselective Peptide Backbone Diversification and Bioorthogonal Ligation by Ruthenium‐Catalyzed C−H Activation/Annulation

Abstract

The field of peptide derivatization by metal‐catalyzed C−H activation has been mostly directed to modify the side chains, but poor attention has been given to the peptide backbone. Here we report a ruthenium‐catalyzed C−H activation/annulation process that can chemoselectively modify the peptide backbone producing functionalized isoquinolone scaffolds with high regioselectivity in a rapid and step‐economical manner. This strategy is characterized by racemization‐free conditions and the production of fluorescent peptides, and peptide conjugates to drugs, natural products and other peptide fragments, providing a chemical approach for the construction of novel peptide‐pharmacophore conjugates. Mechanistic studies suggest that amide bonds of peptide backbone act as the bidentate directing group to promote the C−H activation/annulation process. This report provides an unprecedented example of peptide backbone diversification and bioorthogonal ligation exploiting the power of ruthenium‐catalyzed C−H activation.

An asymmetric metal-templated route to amino acids with an isoquinolone coreviaa Rh(iii)-catalyzed coupling of aryl hydroxamates with chiral propargylglycine Ni(ii) complexes

“…8 Recently, in order to construct novel peptide–pharmacophore conjugates, Van der Eycken and co-workers chemoselectively diversified a peptide backbone by introducing an isoquinolone framework via ruthenium-catalyzed C–H activation/annulation; although the reactions were conducted under harsh conditions (copper( ii ) acetate was used as an oxidant at 120 °C under basic conditions), no racemization was observed at the chiral α-AA center. 9 On the other hand, to the best of our knowledge, only one paper about the synthesis of AA derivatives comprising an isoquinolone core has been reported to date, however in a racemic version (Fig. 1B).…”

1H-isochromene-1-ones and isoquinoline-1(2H)-ones with carbonyl group in position 3: Features of synthetic approaches and transformation

“…Thus, Ruthenium-catalyzed coupling with C-H activation made it possible to complete the isoquinolin-1(2H)-one cycle to the benzoylated N-terminal of oligopeptide 107 (Scheme 37). 62 Most of the isoquinolin-1(2H)ones obtained in this work contained phenyl substituents in position 3, and only a few contained functional groups such as Ac, COOMe, and CH2CH2OH in this position.…”

Peptide Diversification through Addition Reaction of Free Carboxylic Acids to Ynamides

“…Based on this, ynamides have been successfully used in the preparation of novel N-containing molecules and versatile N-heterocycles [29,30]. Within our program on the efficient peptide modification [5,7,[31][32][33], we herein disclose a direct peptide modification protocol in an aqueous solution at room temperature through the addition reaction of free carboxylic acids to ynamides (Figure 1d).…”

“…Post-translational modification of peptides has emerged as a vital issue in modulating activity under physiological conditions [3,4]. Considering unnatural peptides showing improved pharmacokinetics and bioactivity, the chemoselective modification of peptides has emerged as an important task because of its ability to fine-tune structural characteristics in helping regulate physicochemical and biological properties [5][6][7]. Furthermore, chemoselectively modified peptides could improve metabolic stability and membrane permeability and/or tune bioactive conformation [8,9].…”