One-pot chemoenzymatic cascade synthesis of chiral amines from alcohols

Details

Supervisors

Debecker, Damien P. ; Doutry, Aurélien

Faculty

Faculté des bioingénieurs

Degree label

Master [120] : bioingénieur en chimie et bioindustries, à finalité spécialisée

Abstract

enChiral amines are key compounds in pharmaceuticals, agrochemicals, and chiral synthesis. Among the available synthetic approaches, amine transaminases (ATAs) catalyse the transfer of an amino group from an amine donor to a carbonyl acceptor. ATAs are attractive biocatalysts because of their high regio- and enantioselectivity as well as their mild operating conditions. However, their industrial implementation remains limited by substrate inhibition phenomena, notably caused by their carbonyl substrates. To address this issue, previous work associated with this project developed a chemoenzymatic cascade system in which the ketone substrate is continuously generated in situ from the corresponding alcohol over a heterogeneous catalyst prior to transamination. The resulting cascade reaction relied on Au/SiO2 for alcohol oxidation and on ATA-117-Rd6 immobilized on polymethacrylate resin for transamination. The method allowed reaching higher chiral amine productivities. This master’s thesis aimed to further investigate this strategy through two main objectives: extending the substrate scope of the cascade system and developing a hybrid chemoenzymatic heterogeneous catalyst (HCEHC) combining both catalytic functions within a single material. The substrate screening demonstrated that the scope of the cascade system could be extended beyond the reference substrate (1-phenylethanol) to compounds differing in molecular size, alcohol position, halogen substitution, and aromatic character. In parallel, Au nanoparticles were successfully deposited onto the commercial enzyme immobilization resin through a deposition–precipitation method, yielding an active oxidation catalyst (Au/Resin). Subsequent immobilization of ATA-117-Rd6 produced a hybrid catalyst, “E-Au/Resin”, capable of catalysing the overall cascade reaction. The material remained structurally stable under the investigated conditions, demonstrating the feasibility of integrating both catalytic functions within a single heterogeneous material. However, no clear evidence of enhanced substrate channelling could be established. Overall, this work demonstrates the potential of hybrid chemoenzymatic catalysis for the synthesis of chiral amines and highlights the importance of catalyst design, nanoparticle organization, and process optimization for improving cascade efficiency and developing greener synthetic routes.