Yiran Zhang
Yale University
Peptide Macrocyclization via Stereogenic Photoredox Minisci Reaction with Ribosomal Guidelines
Macrocyclic peptides are valued therapeutic modality that invites the development of new construction approaches. Novel strategies to incorporate non-canonical residues into peptide macrocycles, both chemically and ribosomally, have been highly sought after. We report here the application of stereogenic photoredox Minisci reaction in peptide macrocyclization, reacting C-terminal N-(acyloxy)phthalimide ester precursors and N-terminal alkyl quinolines to generate diastereomeric cyclic peptides with up to >20:1 diastereoselectivity. Both reaction solvent and acid catalyst are found to significantly influence the diastereoselectivity. We also demonstrate that linear peptides bearing N-terminal alkyl quinoline units can be synthesized ribosomally, and post-translational macrocyclization via photoredox Minisci reaction can be achieved. Overall, this work further expands the accessible chemical space of N-heteroarene grafted peptide macrocycles. The introduction of a new set of quinoline-based building blocks to the genetic code reprogramming campaign offers promise for extensive exploration of such structural features in future peptide therapeutics discovery.
Macrocyclic peptides are valued therapeutic modality that invites the development of new construction approaches. Novel strategies to incorporate non-canonical residues into peptide macrocycles, both chemically and ribosomally, have been highly sought after. We report here the application of stereogenic photoredox Minisci reaction in peptide macrocyclization, reacting C-terminal N-(acyloxy)phthalimide ester precursors and N-terminal alkyl quinolines to generate diastereomeric cyclic peptides with up to >20:1 diastereoselectivity. Both reaction solvent and acid catalyst are found to significantly influence the diastereoselectivity. We also demonstrate that linear peptides bearing N-terminal alkyl quinoline units can be synthesized ribosomally, and post-translational macrocyclization via photoredox Minisci reaction can be achieved. Overall, this work further expands the accessible chemical space of N-heteroarene grafted peptide macrocycles. The introduction of a new set of quinoline-based building blocks to the genetic code reprogramming campaign offers promise for extensive exploration of such structural features in future peptide therapeutics discovery.
