Diversity of enzymatic SAM-dependent C-methylation of aromatic compounds

Covering: up to May 2025C-Methylation is a widespread transformation that occurs in all domains of life. It plays a central role in numerous biological processes and drives the diversification of natural products. These S_N2-type methylation reactions are often catalyzed by S-adenosyl-L-methionine (SAM)-dependent methyltransferases (MTs). The frequent occurrence and structural diversity of C-methylated natural products is remarkable, especially considering that carbon is the least electronegative atom that typically serve as a methyl acceptor. Compared to polarizable heteroatoms, C-methylation requires an activation of the carbon atom by an adjacent functional group to form a nucleophilic carbanion and allow nucleophilic attack on the methyl donor SAM. This reactivity can be observed, for example, in activated aromatic compounds. In organic synthesis, direct aromatic methylation remains a challenge as it usually requires stringent conditions that often lead to overalkylation and poor regioselectivity. Nature has developed strategies to facilitate this electrophilic aromatic substitution reaction with remarkable regio- and chemoselectivity, ranging from selective C-monomethylation of ubiquitous molecules such as L-tyrosine to geminal dimethylation of complex polyketides resulting in dearomatization. This comprehensive review highlights the diversity of aromatic SAM-dependent MTs, their versatile substrates, and the resulting natural products.