Enzymatic Synthesis of Enantiopure (R)-Citronellal from Geraniol via a Short-Chain Dehydrogenase and Ene Reductase
Claudia Ferrer Carbonell (TU Delft - BT/Biocatalysis)
R. Villa (University of Murcia, TU Delft - BT/Biocatalysis)
Iris Viskaal (Student TU Delft)
Diederik J. Opperman (University of the Free State)
C.E. Paul (TU Delft - BT/Biocatalysis)
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Abstract
The development of synthetic routes to produce enantiopure (R)-citronellal as a key intermediate for the synthesis of (–)-menthol and other valuable terpenoids is highly relevant in the pharmaceutical, flavor, and fragrance industries. Herein, we showcase a cascade with two consecutive biocatalytic steps performed separately using the inherent selectivity of a short-chain alcohol dehydrogenase (SDR) and an ene reductase (ERED) from the Old Yellow Enzyme (OYE) family. The first reaction involves the AaSDR1-catalyzed oxidation of relatively inexpensive geraniol in a biphasic system, providing geranial as an intermediate. The organic phase containing geranial is then extracted and transferred to the second step, where the ERED variant OYE2_Y83V catalyzes the asymmetric reduction of geranial to produce (R)-citronellal, achieving >90% conversion and >99% enantiomeric excess. The use of n-heptane in a two-liquid phase system not only facilitates substrate and product solubilization but also minimizes geranial isomerization. This biocatalytic cascade therefore enables the synthesis of enantiopure (R)-citronellal.
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