Cascade enzymatic synthesis of a statin side chain precursor - the role of reaction engineering in process optimization.

Autor:	Sudar M; University of Zagreb Faculty of Chemical Engineering and Technology Savska c. 16 HR-10000 Zagreb Croatia msudar@fkit.unizg.hr zfindrik@fkit.unizg.hr +385 1 4597 133 +385 1 4597 157 +385 1 4597 101., Milčić N; University of Zagreb Faculty of Chemical Engineering and Technology Savska c. 16 HR-10000 Zagreb Croatia msudar@fkit.unizg.hr zfindrik@fkit.unizg.hr +385 1 4597 133 +385 1 4597 157 +385 1 4597 101., Česnik Katulić M; University of Zagreb Faculty of Chemical Engineering and Technology Savska c. 16 HR-10000 Zagreb Croatia msudar@fkit.unizg.hr zfindrik@fkit.unizg.hr +385 1 4597 133 +385 1 4597 157 +385 1 4597 101., Szekrenyi A; Technische Universität Darmstadt Peter-Grünberg-Straße 4 64287 Darmstadt Germany., Hernández K; Institute of Advanced Chemistry of Catalonia, Biotransformation and Bioactive Molecules Group, IQAC-CSIC Jordi Girona 18-26 08034 Barcelona Spain., Fekete M; Enzymicals AG Walther-Rathenau-Straße 49b 17489 Greifswald Germany.; piCHEM Forschungs-und Entwicklungs GmbH Parkring 3 8074 Raaba-Grambach Austria., Wardenga R; Enzymicals AG Walther-Rathenau-Straße 49b 17489 Greifswald Germany., Majerić Elenkov M; Ruđer Bošković Institute Bijenička cesta 54 HR-10 000 Zagreb Croatia., Qi Y; Prozomix Ltd Haltwhistle Northumberland NE49 9HA UK., Charnock S; Prozomix Ltd Haltwhistle Northumberland NE49 9HA UK., Vasić-Rački Đ; University of Zagreb Faculty of Chemical Engineering and Technology Savska c. 16 HR-10000 Zagreb Croatia msudar@fkit.unizg.hr zfindrik@fkit.unizg.hr +385 1 4597 133 +385 1 4597 157 +385 1 4597 101., Fessner WD; Technische Universität Darmstadt Peter-Grünberg-Straße 4 64287 Darmstadt Germany., Clapés P; Institute of Advanced Chemistry of Catalonia, Biotransformation and Bioactive Molecules Group, IQAC-CSIC Jordi Girona 18-26 08034 Barcelona Spain., Findrik Blažević Z; University of Zagreb Faculty of Chemical Engineering and Technology Savska c. 16 HR-10000 Zagreb Croatia msudar@fkit.unizg.hr zfindrik@fkit.unizg.hr +385 1 4597 133 +385 1 4597 157 +385 1 4597 101.
Jazyk:	angličtina
Zdroj:	RSC advances [RSC Adv] 2024 Jul 04; Vol. 14 (29), pp. 21158-21173. Date of Electronic Publication: 2024 Jul 04 (Print Publication: 2024).
DOI:	10.1039/d4ra01633e
Abstrakt:	Statins are an important class of drugs used to lower blood cholesterol levels and are often used to combat cardiovascular disease. In view of the importance of safe and reliable supply and production of statins in modern medicine and the global need for sustainable processes, various biocatalytic strategies for their synthesis have been investigated. In this work, a novel biocatalytic route to a statin side chain precursor was investigated in a one-pot cascade reaction starting from the protected alcohol N -(3-hydroxypropyl)-2-phenylacetamide, which is oxidized to the corresponding aldehyde in the first reaction step, and then reacts with two equivalents of acetaldehyde to form the final product N -(2-((2 S ,4 S ,6 S )-4,6-dihydroxytetrahydro-2 H -pyran-2-yl)ethyl)-2-phenylacetamide (phenylacetamide-lactol). To study this complex reaction, an enzyme reaction engineering approach was used, i.e. the kinetics of all reactions occurring in the cascade (including side reactions) were determined. The obtained kinetic model together with the simulations gave an insight into the system and indicated the best reactor mode for the studied reaction, which was fed-batch with acetaldehyde feed to minimize its negative effect on the enzyme activity during the reaction. The mathematical model of the process was developed and used to simulate different scenarios and to find the reaction conditions (enzyme and coenzyme concentration, substrate feed concentration and flow rate) at which the highest yield of phenylacetamide-lactol (75%) can be obtained. In the end, our goal was to show that this novel cascade route is an interesting alternative for the synthesis of the statin side chain precursor and that is why we also calculated an initial estimate of the potential value addition. Competing Interests: There are no conflicts to declare. (This journal is © The Royal Society of Chemistry.)
Databáze:	MEDLINE
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