Cobalamin-Dependent Apparent Intramolecular Methyl Transfer for Biocatalytic Constitutional Isomerization of Catechol Monomethyl Ethers

Abstract

Isomerization is a fundamental reaction in chemistry. However, isomerization of phenyl methyl ethers has not been described yet. Using a cobalamin-dependent methyl transferase, a reversible shuttle concept was investigated for isomerization of catechol monomethyl ethers. The methyl ether of substituted catechol derivatives was successfully transferred onto the adjacent hydroxy moiety. For instance, the cobalamin-dependent biocatalyst transformed isovanillin to its regioisomer vanillin with significant regioisomeric excess (68% vanillin). To the best of our knowledge, isomerization by methyl transfer employing a methyl transferase has not been reported before.

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

“…To our delight, it turned out that the methyl transferase dhaf ‐MT is not limited to catechols as acceptors, as previously reported, [14, 15] but also accepts thiol compounds. Using two equivalents of 3‐mercaptopropionic acid 3 a resulted in 57 % conversion.…”

“…However, that reaction was limited by its equilibrium (Scheme 1 A); [14] By omitting a methyl acceptor, isomerization, and thus intramolecular methyl transfer, was observed (Scheme 1 B). [15] This isomerization was also a prominent side reaction in the case of the intermolecular methyl transfer due to equilibria. Furthermore, in the intermolecular methyl transfer, the structural similarity between donor and acceptor led to a mixture of products, which was difficult to separate, resulting in poorer yields.…”

Oxygen-Free Regioselective Biocatalytic Demethylation of Methyl-phenyl Ethers via Methyltransfer Employing Veratrol-O-demethylase

“…This type of substrate was not accepted by the previously described MTase from D. hafniense . 31 , 34 − 36 However, when MT-vdmB was used in combination with the carrier protein vdmA from the same organism as described in literature, only very low conversion for demethylation of veratrol 1a (10 mM substrate concentration) was observed (3%) when using a 5-fold molar excess of 3,4-dihydroxybenzaldehyde 4c as a methyl acceptor ( Scheme 1 ). The acceptor was converted to the regioisomers vanillin 2c and isovanillin 3c in a 3:1 ratio.…”

“… 32 , 33 A specific methyltransferase dhaf4610 from Desulfitobacterium hafniense ( D. hafniense ) has been recently employed for the methylation of catechols and demethylation of guaiacol derivatives. 34 − 36 Unlike the well-investigated S -adenosyl methionine (SAM)-dependent methyltransferases, 37 − 39 which are restricted toward methylation only, this MTase 29 , 40 has been shown to enable both methylation and demethylation in a reversible manner. 34 , 35 Thereby, the MTase transfers the methyl group from the cofactor methylcobalamin (Me-Cob III ) 41 − 44 to the substrate giving cobalt in the oxidation state I (Cob I ).…”

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

“…To our delight, it turned out that the methyl transferase dhaf-MT is not limited to catechols as acceptors, as previously reported, [14,15] but also accepts thiol compounds. Using two equivalents of 3-mercaptopropionic acid 3 a resulted in 57 % conversion.…”