Enzymatic Synthesis of Enantiopure (R)‐Citronellal from Geraniol via a Short‐Chain Dehydrogenase and Ene Reductase

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 Aa SDR1‐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.