Chemoselective Peptide Backbone Diversification and Bioorthogonal Ligation by Ruthenium‐Catalyzed C−H Activation/Annulation
Liangliang Song, Gerardo M. Ojeda‐Carralero, Divyaakshar Parmar, David A. González‐Martínez, Luc Van Meervelt, Johan Van der Eycken, Jan Goeman, Daniel G. Rivera, Erik V. Van der Eycken
Abstract
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. magnified image