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

Christopher Grimm,Wolfgang Kroutil,Johanna Schichler,Simona Pompei,Mattia Lazzarotto,Nina Richter,Judith E Farnberger,Michael Fuchs

doi:10.1021/acscatal.0c02790

Christopher Grimm, Wolfgang Kroutil + Show 6 more

Open Access

https://doi.org/10.1021/acscatal.0c02790

Copy DOI

Abstract

The cleavage of aryl methyl ethers is a common reaction in chemistry requiring rather harsh conditions; consequently, it is prone to undesired reactions and lacks regioselectivity. Nevertheless, O-demethylation of aryl methyl ethers is a tool to valorize natural and pharmaceutical compounds by deprotecting reactive hydroxyl moieties. Various oxidative enzymes are known to catalyze this reaction at the expense of molecular oxygen, which may lead in the case of phenols/catechols to undesired side reactions (e.g., oxidation, polymerization). Here an oxygen-independent demethylation via methyl transfer is presented employing a cobalamin-dependent veratrol-O-demethylase (vdmB). The biocatalytic demethylation transforms a variety of aryl methyl ethers with two functional methoxy moieties either in 1,2-position or in 1,3-position. Biocatalytic reactions enabled, for instance, the regioselective monodemethylation of substituted 3,4-dimethoxy phenol as well as the monodemethylation of 1,3,5-trimethoxybenzene. The methyltransferase vdmB was also successfully applied for the regioselective demethylation of natural compounds such as papaverine and rac-yatein. The approach presented here represents an alternative to chemical and enzymatic demethylation concepts and allows performing regioselective demethylation in the absence of oxygen under mild conditions, representing a valuable extension of the synthetic repertoire to modify pharmaceuticals and diversify natural products.

Highlights

An alternative option avoiding molecular oxygen involves the use of cobalamin-dependent methyltransferases (MTases)[29−31] or O-demethylases originating from anaerobic bacteria which utilize aryl methyl ethers as carbon source.[32,33]
We chose the methyltransferase veratrol-Odemethylase (MT-vdmB)[32,47−49] and the carrier protein vdmA both originating from the same organism, namely the anaerobic bacterium Acetobacterium dehalogenans.[50,51]
Biocatalytic Demethylation of the Model Substrates 1a and 1b groups are present in 1,2-position

Summary

■ INTRODUCTION

The demethylation of aryl methyl ethers[1] is a common transformation in organic chemistry to demask the phenol functionality.[2−8] Several phenolic compounds represent valuable pharmaceutical and natural products.[3,9] In general, chemical methods for ether cleavage require harsh reagents such as strong acids and bases[3,4] but may be performed with metal catalysts[5,6] and sodium thiolates.[7,8] alternative approaches toward milder and selective demethylation are demanded.[10,11] O-Demethylation of methyl aryl ethers may be achieved using biocatalysts:[11−14] For example, oxidative enzymes[15−18] such as di- and monooxygenases[19−24] and fungal peroxygenases[25−27] catalyze the O-. Demethylation by using molecular oxygen or hydrogen peroxide as reagents These enzymes are known for the detoxification of organic compounds,[25] degradation of lignin,[21] and the biosynthesis of secondary metabolites. The MTase from D. hafniense is limited to guaiacol derivatives as substrates for demethylation (i.e., methyl donor) and catechol derivatives as methyl acceptor. In a typical reaction, the methyl transfer occurred from the substrate guaiacol 2a as methyl donor to 3,4-dihydroxybenzoic acid 4c as methyl acceptor.[31,34,35]. Since many natural and pharmaceutical compounds[45,46] contain more than one protected methoxy group in close proximity and due to the limitation of the substrate pattern of the MTase from D. hafniense, alternative enzymes transforming substrates with fewer restrictions are needed

■ RESULTS AND DISCUSSION

■ CONCLUSIONS

■ ACKNOWLEDGMENTS

■ REFERENCES