New catalytic reaction development by laboratory evolution of protein-based catalysts

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Generating molecules of interest by developing new catalytic reactions is a defining feature in current organic chemistry. Despite tremendous advances using classical approaches, such as small molecule and heterogenous catalysis, many very important reactions do not have a catalytic solution. Classical catalyst types often fail due to limited catalyst control.Proteins are superior catalysts as their macromolecular structure offers precise molecular recognition. The multitude of active site amino acid interactions provide unique control over substrate conformations, transition states and reactivities of intermediates. Capitalizing on this multitude of interactions in protein active sites, we should be able to overcome energy barriers that are unattainable by classical methods. New catalytic reactions can be envisioned that are enabled by proteins macromolecular structure and that have so far not been conquered, neither in biology nor synthetic chemistry.The proposed Emmy Noether group aims for an highly interdisciplinary approach by exploiting proteins to develop catalysts for desired C-C and C-X bond forming reactions. This will be achieved by taking advantage of reactivity patterns known from synthetic organic chemistry, exploring catalytic promiscuity of the myriad of enzyme classes and applying state of the art laboratory evolution experiments. In our proof of concept studies, we envision to generate catalysts for various sought-after reactions including 1) the enantioselective anti-Markovnikov alkene oxidation, 2) asymmetric hydrofunctionalization of unactivated alkenes, 3) regiocontrol in arene alkylation or 4) carbonyl olefination using simple alkenes as olefination reagent. The latter two will be enabled by establishing a platform for enzymatic Lewis acid catalysis that will open the door to a huge variety of very important C-C bond forming reactions. The target reactions harness different enzyme classes and use different mechanisms such as metal-dependent oxidation chemistry, metal-dependent non-redox reactions as well as cofactor-free, cooperative acid/base catalysis. Catalytic access to these reactions has disruptive potential as multi-step reaction sequences using stoichiometric reagents will be replaced with sustainable catalytic transformations that form desired bonds selectively in one synthetic operation. The evolved enzyme variants will serve as basis for mechanistic studies to gain understanding in the molecular interactions that enable these transformations and to study scope and limitations in synthesis. Further, whole new synthetic metabolic pathways will be accessible by combining these “new-to-nature” enzyme function with established biocatalysts to access even more complex overall reactions. In short, the proposed Emmy Noether group exploits protein engineering to enable and understand new chemical transformations and aims to develop a new class of protein-based catalysts for synthetic chemistry.