Novel C-C Coupling Reactions under Nickelaphotoredox Catalysis
Final Report Abstract
During my stay at Princeton University, I was working on the ligand-directed, photoredox-mediated decarboxylative functionalization of native proteins with various Michael acceptors. This project was a continuation of a photoredox-mediated bioconjugation reaction that was previously developed in the group of Prof. MacMillan. The idea was to tether an organic photocatalyst to a known protein-binding ligand, which would then direct the photocatalyst to its respective binding site on the protein surface. Upon irradiation with blue light, the photocatalyst should induce the functionalization of carboxylic acid-bearing side chains of the naturally occurring amino acids aspartate and glutamate in the proximity of the binding site. More specifically, the carboxylic acid should undergo CO2 extrusion and the resulting transient radical should subsequently be intercepted by a Michael acceptor to form a new carbon-carbon bond. The described reaction was attempted with two well-studied protein substrates: human carbonic anhydrase I and the serine protease NS3 from the hepatitis C virus. The protein-binding ligands, an aromatic sulfonamide and the experimental drug candidate asunarpevir (Bristol-Myers Squibb), were attached to an organic photocatalyst to attempt the functionalization of human carbonic anhydrase I and the serine protease NS3, respectively. In addition, two novel Michael acceptors, which feature bioorthogonal handles (terminal alkyne or azide) for subsequent diversification, were prepared. Unfortunately, the outlined ligand-directed functionalization of proteins could not be realized. The proteins proved to be unreactive under the chosen reaction conditions, which is most likely caused by quenching interactions between the excited photocatalyst and some of the protein side chains (e.g. tyrosine, tryptophan, and histidine). However, the novel Michael acceptors have been successfully used for the C-terminal functionalization of human insulin instead. Those results have recently been accepted for publication in the prestigious journal Nature Chemistry.
Publications
- Nat. Chem. 2017: Decarboxylative alkylation for site-selective bioconjugation of native proteins via oxidation potentials
S. Bloom, C. Liu, D. K. Kölmel, J. X. Qiao, Y. Zhang, M. A. Poss, W. R. Ewing, D. W. C. MacMillan
(See online at https://doi.org/10.1038/NCHEM.2888)
