Asymmetric α-Hydrobenzylation of Enamines to Form Quaternary Carbons: Towards a New Class of MRSA-Targeting Antibiotics

• Applicant: Dr. Nils Lennart Ahlburg
• Subject Area: Organic Molecular Chemistry - Synthesis and Characterisation ; Biological and Biomimetic Chemistry ; Theoretical Chemistry: Electronic Structure, Dynamics, Simulation
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 535701813

sp3-sp3 Coupling is a young, promising field of organic chemistry with the potential to revolutionize synthesis like Pd-catalyzed cross coupling has done before. A recently published method by the Shenvi group allows the sp3-sp3 coupling of tertiary and benzylic radicals, generated from the corresponding olefins (MHAT) and benzyl halogenides. An iron(II)porphyrin catalyst sorts and couples the radicals in a hetero- and diastereoselective SH2-reaction. This enables the convenient synthesis of terpenophenolics. Some terpenophenolics, contained within the plants of the Eugenia genus, show astonishing efficacy and selectivity towards various MRSA strains (Eugenial C, D). The project presented herein aims to create a chiral porphyrin-catalyst capable of coupling tertiary and benzylic radicals in an enantioselective fashion. An optional goal is the synthesis of an alternative, more efficiently designed class of ligands. Therefore, a computational protocol is in development to preselect scaffolds that merit synthesis from the plethora of known ligands. Simultaneously, this helps us better our understanding of the reaction mechanism. The capability to create stereoisomers, especially enantiomeric couples, is of critical importance for the investigation of the mode of action of the terpenophenolics. Their effects are likely rooted in the interaction (imine formation) of the diacylphloroglucinol unit (Eugenial C) with proteinaceous lysines. Benjamin F. Cravatt, pioneer of activity-based protein profiling (ABPP) and collaboration partner, has recently presented a method for the identification of such interactions. When enantiomers show major differences in their activity, this is likely rooted in the stereochemical properties of the binding site, as opposed to solubility, membrane penetration or metabolic effects. As part of this project, we plan to supply our collaboration partner with promising, natural and artificial structures (and their enantiomers). The knowledge obtained from these experiments will then inform the future synthesis of even more effective anti-MRSA agents.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Ryan A. Shenvi, Ph.D.