reported the facile and scalable one-pot synthesis of bio-based O-protected phenolic styrenes via chemical decarboxylation of 1 followed by their direct protection via silylation or acetylation. Recently, Petermeier et al. demonstrated that also enzymatic decarboxylation can be combined with chemical acetylation. Acetylation and silylation of 2 facilitate controlled radical or anionic polymerization. Modification of the functional group can alter the type of the polymerization mechanism and the properties of the final product. Acetylated or silylated monomers are limited to radical polymerization mechanisms. In contrast, methoxy styrenes can undergo cationic photopolymerization to yield polymers with great adhesion properties. For example, 4-methoxystyrene is used in radical and cationic polymerizations to produce polymers used in coatings, adhesives, and optical devices. 3,4-Dimethoxystyrene is also used in polymer chemistry for the preparation of underwater adhesives. Decarboxylation of phenolic acids at elevated temperatures is energy-consuming and prone to lead to undesired side-reactivities. Moreover, methylation by methyl iodine is highly problematic from a green chemistry perspective. In contrast, enzymatic decarboxylation and methylation reactions proceed under very mild reaction conditions. For this, phenolic acid decarboxylase from Bacillus subtilis (BsPAD) has shown high activity and stability. As the decarboxylation of 1a-d proceeds in an aqueous system, enzymatic O-methylation can follow under the same conditions without the requirement of the isolation and purification of the intermediates 2a-d (Scheme 1). Cofactor-free phenolic acid decarboxylase employs an electron-relay mechanism comprised of the delocalizedelectron system and the essential p-hydroxy group on the substrate for the stabilization of the nascent negative charge upon loss of the carboxylate. O-methylation of 1 would disrupt hydrogen bonds between the p-hydroxy group and two catalytic Tyr residues, preventing decarboxylation of p-methoxy phenolic acids 1e-h. Therefore, the order methylation-decarboxylation would not work with bacterial PAD. Decarboxylases accepting methoxy-cinnamic acids have been described but have much lower activity than BsPAD. For PAD, the order decarboxylation-methylation is therefore preferred (Scheme 1b). In view of a possible simultaneous mode of the cascade, we were interested in an O-methyl transferase (OMT) that would accept the hydrophobic phenolic styrenes 2a-d as substrates, but not the hydrophilic acids 1a-d. Plant OMTs are classified into three different types based on the protein sequence and structures. Type I OMTs are cation-independent and active towards hydroxyl moieties of phenylpropanoids. Type II OMTs are cation-dependent and are mainly involved in the biosynthesis of lignin. Finally, type-III OMTs are mainly active towards carboxylic acids. For the methylation of catechol-like compounds type-I OMTs are mainly used such as OMT3 from Sorghum bicolor (SbOMT3), OMT1 from Arabidopsis thaliana (AtOMT1) and OMT from Vitis vinifera (VvROMT). The latter stands out with its good activity towards hydroxylated stilbenes. In previous work, we were able to increase VvROMT mono-and di-methylation activity towards resveratrol by rational design of its active site. We hypothesized that due to the high hydrophobicity of its active site, VvROMT would accept the highly hydrophobic phenolic styrenes 2 while showing less activity towards the polar phenolic acids 1. The selection of VvROMT is further supported by the availability of activesite mutants from Herrara et al. The predicted variants with amino acid substitutions in the hydrophobic active site cavity were based on molecular modeling and a comparative analysis of binding site residues. Investigation of a set of 7 variants revealed significant differences in the O-methylation of resveratrol and pinostilbene, respectively. In lieu of experimentally determined structures and anticipated difficulties in achieving accurate predictions on the effect of amino acid substitutions on the activity towards the small, hydrophobic 1a-d, this set appeared to be a very promising basis for the identification of variants for their conversion.