Multigram Scale Enzymatic Synthesis of (R)‐1‐(4′‐Hydroxyphenyl)ethanol Using Vanillyl Alcohol Oxidase

• Published in: Advanced synthesis & catalysis Vol. 360; no. 12; pp. 2370 - 2376
• Main Authors: Ewing, Tom A., Kühn, Jasmin, Segarra, Silvia, Tortajada, Marta, Zuhse, Ralf, van Berkel, Willem J. H.
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 15.06.2018; Wiley Subscription Services, Inc
• Subjects: Alcohol; Alcohol oxidase; Alcohols; Alkylphenols; Chemistry; Chemistry, Applied; Chemistry, Organic; Enantiomers; Enantioselectivity; Enzymes; Ethanol; Flavoprotein; Hydroxylation; Oxidoreductases; Physical Sciences; Science & Technology; Substrates; Synthesis; OXYGEN ACTIVATION; BIOTECHNOLOGY; Enantioselectivity; Hydroxylation; MECHANISM; 4-ALKYLPHENOLS; Flavoprotein; Alcohols; REDUCTION; Alkylphenols; VILLIGER OXIDATION PROCESS; OXYFUNCTIONALIZATION; Oxidoreductases; DERIVATIVES; PENICILLIUM-SIMPLICISSIMUM
• ISSN: 1615-4150; 1615-4169
• DOI: 10.1002/adsc.201800197

The enantioselective oxyfunctionalisation of C−H bonds is a highly interesting reaction, as it provides access to chiral alcohols that are important pharmaceutical building blocks. However, it is hard to achieve using traditional methods. One way in which it can be achieved is through the action of oxidative enzymes. Although many reports of the oxyfunctionalisation capabilities of enzymes at an analytical scale have been published, reports on the use of enzymes to achieve oxyfunctionalisation on a synthetically relevant scale are fewer. Here, we describe the scale‐up of the conversion of 4‐ethylphenol to (R)‐1‐(4′‐hydroxyphenyl)ethanol using the flavin‐dependent enzyme vanillyl alcohol oxidase. The process was optimised by testing different reaction media and substrate and enzyme concentrations and by performing it under an oxygen atmosphere. Under optimised reaction conditions, 4.10 g (R)‐1‐(4′‐hydroxyphenyl)ethanol at 97% ee was obtained from 10 g 4‐ethylphenol (isolated yield 36%). These results highlight some of the challenges that can be encountered during scale‐up of an enzymatic oxyfunctionalisation process to a synthetically relevant scale and will be of use for the development of enzymatic processes for the synthesis of industrially relevant compounds.