Late Stage Diversification of Peptides by Transition Metal Mediated Cross-Couplings

• Applicant: Professor Dr. Norbert Sewald
• Subject Area: Biological and Biomimetic Chemistry
• Term: since 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 418428678

Brominated aromatic amino acids, especially bromotryptophan, have been established by us as a central synthetic platform for late-stage diversification of peptides. Peptides containing a brominated amino acid can be efficiently derivatized using transition metal-catalyzed cross-coupling reactions, e.g. the Suzuki-Miyaura cross-coupling, the Mizoroki-Heck reaction, and the Negishi cross-coupling. In the previous funding period we were able to show that transition metal catalyzed cross-coupling reactions can be employed for amino acid and peptide modification on a late synthetic stage. Based on this experience we will elucidate accelerating effects of adjacent methionine residues on the Suzuki-Miyaura cross-coupling of bromotryptophan containing peptides and study the late stage peptide diversification by Mizoroki-Heck, Negishi, and Hiyama cross-couplings. Moreover, we will explore combinations of photoredox catalysis and metal catalysis for peptide modification. In addition, the synthesis of C-glycosides using cross-coupling reactions will be investigated. As a benchmark model system, the functional group compatibility of the late stage diversification reactions and the effect of the modification on the biological activity of RGD-peptides will be systematically studied.

• DFG Programme: Research Grants