Mut6 exhibited the highest activity and achieved 22% conversion after 24h. In summary, the phenolic acids 1a-d are generally poorly accepted by VvROMT and its mutants. For each of the phenolic acids, there are variants available with selectivity for the methylation of 2a-d without undesired conversion of 1a-d. Yet, even the methylation of small amounts of 1a-d will prevent enzymatic decarboxylation, leading to the accumulation of the intermediate 1e-f. Therefore, a sequential mode of decarboxylation and methylation was chosen as a practical approach mode for the envisioned reaction sequence. narrow active site cavity. Interestingly, VvROMT and all investigated variants showed strict selectivity for the O-methylation of the meta-hydroxy group (Scheme 3). This striking regioselectivity resembles the selectivity of VvROMT for the meta-hydroxy groups of resveratrol and pinostilbene, respectively, whereas the para-hydroxy groups of both were not converted. O-methyl transferases are often regioselective towards catecholic substrates. For instance, isoeugenol O-methyltransferase from Clarkia breweri was highly regioselective for the methylation of the 3'-OH group of the flavonoids eriodictyol, luteolin, and quercetin. O-methylation of 2b forms vinyl guaiacol 2c, which is itself a substrate of the enzyme. This allows direct conversion of caffeic acid via coupled decarboxylation and the two O-methylation steps directly into para-, meta-dimethoxystyrene 2g.