Thiols Act as Methyl Traps in the Biocatalytic Demethylation of Guaiacol Derivatives

Demethylating methyl phenyl ethers is challenging, especially when the products are catechol derivatives prone to follow-up reactions. For biocatalytic demethylation, monooxygenases have previously been described requiring molecular oxygen which may cause oxidative side reactions. Here we show that such compounds can be demethylated anaerobically by using cobalamin-dependent methyltransferases exploiting thiols like ethyl 3-mercaptopropionate as a methyl trap. Using just two equivalents of this reagent, a broad spectrum of substituted guaiacol derivatives were demethylated, with conversions mostly above 90%. This strategy was used to prepare the highly valuable antioxidant hydroxytyrosol on a one-gram scale in 97% isolated yield.

Automated summary

This study demonstrates that demethylating methyl phenyl ethers can be achieved anaerobically using cobalamin-dependent methyltransferases exploiting thiols as a methyl trap. This strategy allows for efficient and high-yielding synthesis of the antioxidant hydroxytyrosol.