DS0304 -

Artificial Enzymes in the World of Organic Synthesis – ARTENOSYN

Flavoenzymes are very important biocatalysts involved in diverse metabolic pathways with the interesting singularity to perform two very different catalytic activities thanks to the same flavin cofactors but incorporated in different protein scaffolds. In both cases, flavin cofactors gather electrons from NAD(P)H and either activate dioxygen to perform catalytic oxidations such as sulfoxidation, epoxidation and Baeyer-Villiger oxidations, or provide a steady and accurate input of electron towards catalytic partners. We have therefore incorporated a natural flavin cofactor (FMN) into a polymeric matrix (modified polyethyleneimine) mimicking the local microenvironment of enzymes and studied this system for oxidation catalysis under aerobic conditions and radical chemistry under anaerobic conditions. In the first case, the electrons collected by the FMN cofactor from NADH could be used to activate dioxygen and perform oxidation reactions, while in the second one the electrons could be delivered step wisely into the medium and initiate single electron transfers (SET) for radical chemistry catalysis.

In term of oxidation catalysis, the best results were obtained for the Baeyer-Villiger reaction with good yields (up to 70%) and high selectivity versus the epoxidation reaction. This was the first artificial flavo-enzyme performing such reaction using O2 from the air in aqueous medium. (Angew. Chem. Int. Ed. 2018) The replacement of the natural electron source (Nicotinamide Adenine Dinucleotide; NADH) by ascorbate, which is a source cheaper of electrons, led to similar catalytic activity but also allowed the formation and stabilization an interesting radical flavin intermediate which was observed for the first time in aqueous medium outside of a protein scaffold. (Org. Biomol. Chem. 2020)

An opening on photocatalysis was carried out at the end of the project. A photocatalysis reaction by photosensitization of FMN has been carried out successfully on a dienone. In addition, a redox reaction under oxidizing conditions has been proposed with the oxidation of xanthene. This reaction tends to prove that the reaction here is indeed radical in nature.

1) Aerobic Baeyer-Villiger Oxidation Catalyzed by a Flavin-Containing Enzyme Mimic in Water
Y. Chevalier, Y. Lock Toy Ki, D. le Nouen, J.-P. Mahy, J.-P. Goddard, F. Avenier.
Angew. Chem. Int. Ed. 2018, 57, 16412-16415
2) Characterization in Aqueous Medium of an FMN Semiquinone Radical Stabilized by the Enzyme-Like Microenvironment of a Modified Polyethyleneimine.
Y. Chevalier, Y. Lock Toy Ki, C. Herrero, D. le Nouen, J.-P. Mahy, J.-P. Goddard, F. Avenier.
Org. Biomol. Chem. 2020, 18, 4386-4389.

Submission summary

The present ARTENOSYN project aims at developing bioinspired artificial systems capable of catalysing important organic reactions in water, under mild conditions and using harmless reactants such as O2. For this purpose, we are planning to mimic both activities of flavoenzymes, which and capable of catalysing either reduction reactions, by delivering single electrons to a biologic partner, or oxidation reactions, by the reductive activation of O2; and this with the same flavin cofactors, but located in different protein scaffolds. This project is based on recent interesting results obtained by partner 1, demonstrating that the incorporation of flavin cofactors (FMN) into the local microenvironment of a water soluble polymer (modified polyethyleneimine), can generate an artificial reductase capable of collecting electron pairs from NADH and then delivering single electrons to a redox partner such as manganese(III) porphyrins. Thus, under anaerobic conditions, this system must also be able to deliver single electrons to organic molecules into a locally hydrophobic microenvironment and initiate radical reaction by single electron transfer (SET). Partner 2 is an expert on these radical reactions and a large scope of reactions will be evaluated. Alternatively, under aerobic conditions, the reduced flavin (FMNH2) will react with dioxygen to form organo-peroxo intermediates, which is known to perform oxidation reactions such as Beyer-Villiger, epoxydation or sulfoxidation reactions. The first task of the proposal will be to synthesize libraries of modified polyethyleneimines in order to better understand how their hydrophobicity may influence the kinetic and thermodynamic parameters of the electrons transfer. Then, both radical and oxidation reactions will be thoroughly studied and eventually combined into a tandem system. Finally, chiral polyethyleneimines will also be synthesized by simple derivatization with chiral substituents, in order to perform catalytic asymmetric radical reactions and/or catalytic asymmetric oxidation reactions.

Project coordination

Frédéric Avenier (Institut de Chimie Moléculaire et des Matériaux d'Orsay UNIV PARIS11I)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

LCBM UHA Laboratoire de Chimie Biologique et Moléculaire
ICMMO - UNIV PARIS 11 Institut de Chimie Moléculaire et des Matériaux d'Orsay UNIV PARIS11I

Help of the ANR 394,160 euros
Beginning and duration of the scientific project: September 2016 - 42 Months

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