artificial enzyme: an heteregeneous catalyst – CrystalBall

Catalytic processes are at the cutting-edge of the development of green chemistry. The project «crystalball» represents a major asset for the design of a sustainable chemistry, with an original combination of biocatalysis and chemical metal based catalysis. Our original strategy relies on the conception of a heterogeneous crystal/solution version of the already demonstrated artificial enzymes technology coupled to an infinite declension of catalyzed reactions. Such an approach consists of the reproduction of the fine control at the metal-containing active site in a combination of an inorganic catalyst and a protein scaffold. This control is allowed through constraints imposed by the protein environment both on the sequence of the chemical steps and the orientation of substrates along the catalytic cycle.
The project will be based on the setting up of oxidation reactions catalyzed «in cristallo», thanks to the gain in mechanical and chemical stability of protein crystals by Cross Linking methods (CLEC). This mature methodology comprises the introduction of chemical connections between the protein molecules into the lattice of the protein crystal to gain in rigidity. Up to now, the CLEC technology has been benchmarked for the biocatalysis implicating reductases but the field of oxidation remains to be explored. We will increase the stability of our hybrid family based on NikA, a Ni transport protein in E. coli, in order to scan more reactions conditions (solvent, temperature, pH), that will permit infinite oxidation reactions.
The project will focus on two catalytic oxidation reactions (i) the controlled hydroxylation of polycyclic aromatic hydrocarbons, pollutant compounds, (ii) the transformation of sulfide into sulfoxides, ultimate enantioselective step for the synthesis of sulfoxide based drugs in the pharmaceutical industry. The selection of these reactions results of the oxidative capacity of our already demonstrated NikA hybrids, in which the inorganic complex drives the nature of the reaction. The catalytic specificities of theses hybrids represent also a great challenge for sustainable chemistry. First, the need for selective route to sulfoxides is crucial in the drug synthesis. Their use in medicine is extensive in particular with the marketing of chiral sulfinyl compounds, like esomeprazole (for the treatment of anti-ulcer agents). The synthesis of these molecules involves an oxidation step of a sulfide to yield a chiral sulfoxide as a majority, which is a challenging step for chemists. Second, the safe development of selective catalytic systems for aromatic oxidation is not fulfilled so far under mild conditions. Consequently, the successful use of dioxygen as the oxidant should be a major breakthrough while avoiding deleterious side reactions. The strategy here relies on the mimic of the unique capabilities of protein architecture through the control of spatial and/or temporal distribution of substrates and oxidant. The targeted oxygenated products of aromatic hydrocarbons have also a great potential as building blocks for organic syntheses and could also be an asset for the remediation of polyaromatic hydrocarbons, some of which being components of the lignin polymers.
The approach will consist of (i) to better understand the CLEC technology on our NikA protein hybrids for oxidation processes, (ii) to get new scope of chiral sulfoxide production, (iii) to oxidize aromatic substrates for remediation and high value products synthesis, (iv) to get new insights in the control of the reaction steps of oxidation reactions. For all these purposes we will combine X-Ray crystallographic and spectroscopic studies.
The impact of this project will be expected (i) to foster the field of heterogeneous Biocatalysis, (ii) to control the dioxygen activation for selective reactions, (iii) to provide new strategies for enantioselective sulfoxidations, (iv) to open the field of oxidation for CLEC technology.