Design of heterogeneous biocatalysts for flow chemical processes : towards a greener transamination reaction
(2018)
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- For decades, the drug manufacture has been using polluting reagents that are released in the environment. Nowadays, greener production modes are being targeted. In this direction, biocatalysis probably represents a decisive opportunity. Transaminases (TA) have already been used for the green production of chiral amines (drug precursors). There are however two main limitations to the use of TA in such organic synthesis: (1) the difficulty to recover the free enzymes after a batch reaction, (2) the low yield for chiral amines, owing to unfavourable thermodynamics. To tackle these challenges, the main objectives of this thesis are (i) developing heterogeneous biocatalysts using suitable carriers and efficient immobilization methods; (ii) developing a continuous flow biocatalytic reactor for transamination reactions; (iii) implementing strategies for the displacement of the thermodynamic equilibrium. TA are efficiently immobilized onto APTES-functionalized macrocellular silica monoliths through covalent grafting using glutaraldehyde as a coupling agent. The monoliths can be mounted in a simple flow set-up. In the flow mode, TA are active and stable over long period of time, and enantioselectivity is retained. An optimized APTES functionalization method was developed, that allowed to boost the enzymatic activity. The influence of temperature on enzyme impregnation was also highlighted. Hydrophobic silica monoliths were studied as supports, but, hydrophobicity appeared to have no impact on the enzyme immobilization and activity. Using a three-enzyme system to consume the co-product, the equilibrium could be displaced towards the formation of the chiral amine. In flow mode, such strategy was successful only when the added enzymes were free and in high concentration. Finally, we show that our flow system can be used to immobilize another type of enzyme (tyrosine ammonia-lyase), to design other efficient flow mode biocatalytic processes for amine synthesis.
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van den Biggelaar, ,. L. (2018). Design of heterogeneous biocatalysts for flow chemical processes : towards a greener transamination reaction. https://hdl.handle.net/2078.5/62646