Thesis presented October 25, 2024

Abstract:
The many properties of enantiopure sulfoxides make them a functional group of choice, both for the pharmaceutical industry and for asymmetric synthesis. Since the twentieth century, several strategies for their synthesis and catalytic methodologies have been described; however, with the aim of sustainable chemistry, few examples in biocatalysis allow us today to obtain enantiopure sulfoxides. We are interested in moving industrial chemical syntheses, particularly oxidation reactions, towards recyclable biocatalysis inspired by living organisms. Our project is based on the development of an enzyme-mediated cascade reaction as an innovative solution for sustainable chemistry, saving time, atoms and energy. The targeted reaction consists in converting an alkene into sulfoxide, via two successive reactions: a hydrothiolation or thiol-ene reaction, often used in chemobiology, followed by sulfoxidation. The challenge of the project lies in the choice of catalysts and the heterogeneous mode of catalysis, namely inorganic catalysis in protein crystals. The aim is to create a heterogeneous catalysis to improve the stability of the complexes, as well as to compartmentalize the two catalysts to prevent them from interfering with each other. The approach then consists of inserting inorganic complexes into protein crystals as an artificial active site in a protein, NikA, a Nickel transport protein, to create a metalloenzyme for both reactions. To set up the tandem reaction, two ArMs were created, one for each reaction, and used concomitantly. Thesis work led to the production of two efficient artificial enzymes operating in cristallo for each reaction, by inserting vanadium complexes for enantioselective sulfoxidation and iron for the hydrothiolation reaction. Several original vanadium complexes have been synthesized and their stability in solution studied, with their localization in the protein also determined. One of the results of this work is the demonstration of the versatility of the protein to stabilize these inorganic systems within it. Another achievement is the efficient catalysis of the two separate reactions. The catalytic properties of the original complexes enabled them to be sorted and the best ones to be involved in the tandem reaction. The latter gave promising preliminary results in their heterogeneous versions, with improved selectivity for sulfoxide. This thesis has therefore validated the choice of protein crystals as a support for heterogeneous catalysis in a tandem reaction, to afford selectivity and recyclability.

Keywords:
Bioinspired chemistry, heterogeneous catalysis, thiol-ene reaction, sulfoxidation, artificial enzymes
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