Chemo-ribosomal synthesis of atropisomeric and macrocyclic peptides with embedded quinolines

Expanding the chemical and structural complexity of genetically encoded peptides remains a challenge in peptide therapeutics discovery. Here we report that linear peptides with a reactive β- or γ-keto amide at their N-termini can be synthesized ribosomally using in vitro translation methods. We show that peptides carrying an N-terminal β-keto amide can be converted into diverse heterocyclic quinoline-peptide hybrids via Friedländer reactions with a variety of 2-aminoarylcarbonyl co-substrates. Reactions with appropriately substituted 2-aminobenzophenones generated quinoline-peptide hybrids with stable biaryl atropisomeric axes. In vitro-translated peptides carrying both an N-terminal β-keto amide and an internal 2-aminoacetophenone motif undergo intramolecular Friedländer macrocyclization reactions that embed a quinoline pharmacophore directly within the macrocyclic backbone. The introduction of N-terminal ketide building blocks into genetically encoded materials and their post-translational derivatization with carbonyl chemistry simultaneously expands the chemical diversity and structural complexity of genetically encoded materials and provides a paradigm for the programmed synthesis of peptide-derived materials that more closely resemble complex natural products.