Late-stage C(sp3)-H cross-coupling for high-throughput access to bioactive peptides via Pd catalysis

Summary Amide bond formations and Pd-catalyzed C–C cross-couplings are among the most frequently used chemical reactions in drug discovery. By chemically linking amino acids or (hetero)aromatics as diversified building blocks, these reactions generate vast combinatorial libraries of peptides and small molecules, respectively, for high-throughput testing in bioassays. While this strategy has proven highly successful in drug development, the pursuit of future drug candidates calls for convergent C(sp³) cross-coupling catalysis that covers underexplored molecular space. Here, we report on the convergent, late-stage C–C cross-coupling between (hetero)aromatic drug scaffolds and N-terminal glycine residues in bioactive peptides. This enables the diversification of small-molecule scaffolds with short-chain peptides or, inversely, linking bioactive peptides with drug-like (hetero)aromatics. In addition, we show that the potential of this reaction further extends to solid-phase peptide synthesis and high-throughput library synthesis, key synthetic technologies in drug discovery.