The transformation of (abundant) oxygenated biomass-derived building blocks via chemo-enzymatic methods is a valuable concept for accessing useful compounds, as it combines the high selectivity of enzymes and the versatility of chemical catalysts. In this work, we demonstrate a straightforward combination of a phenolic acid decarboxylase (PAD) and palladium on charcoal (Pd/C) that affords the flavor compound 4-ethylguaiacol from ferulic acid. The use of a two-phase system proved to be advantageous in terms of enzyme activity, stability, and volumetric productivity and allows us to carry out the hydrogenation step directly in the organic layer containing exclusively the intermediate, vinylguaiacol. The enzymatic decarboxylation step in the biphasic system afforded 89% conversion of 100 mM (19 g L-1) ferulic acid with an isolated yield of 75%. By extracting 4- vinylguaiacol continuously into the organic phase, conversion was enhanced to 92% using 170 mM (33 g L-1) ferulic acid, which was only possible in the continuous extraction and distillation setup developed. The reaction cascade (PAD-Pd/C) is demonstrated at gram scale, affording the target product 4-ethylguaiacol (1.1 g) in 70% isolated yield in a two-step two-pot process. The enzymatic step was characterized in detail to overcome major constraints, and the process favorably compares in terms of the environmental impact with traditional approaches.
