Biokatalytische C3‐Indol‐Methylierung – ein nützliches Werkzeug für die naturstoffinspirierte stereoselektive Synthese von Pyrroloindolen

Strategic replacement of protons with fluorine atoms or functional groups with fluorine-containing fragments has proven a powerful strategy to optimize the activity of therapeutic compounds. For this reason, the synthetic chemistry of organofluorides has been the subject of intense development and innovation for many years. By comparison, the literature on fluorine biocatalysis still makes for a slim chapter. Herein we introduce S-adenosylmethionine (SAM) dependent methyltransferases as a new tool for the production of fluorinated compounds. We demonstrate the ability of halide methyltransferases to form fluorinated SAM (S-adenosyl-S-(fluoromethyl)-L-homocysteine) from S-adenosylhomocysteine and fluoromethyliodide. Fluorinated SAM (F-SAM) is too unstable for isolation, but is accepted as a substrate by C-, N-and O-specific methyltransferases for enzyme-catalyzed fluoromethylation of small molecules.

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FluorinatedS‐Adenosylmethionine as a Reagent for Enzyme‐Catalyzed Fluoromethylation

Peng

Liao

Bauer

et al. 2021

Angewandte Chemie

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Synthetic Reagents for Enzyme‐Catalyzed Methylation

et al. 2022

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Late-stage methylation is a key technology in the development of pharmaceutical compounds. Methyltransferase biocatalysis may provide powerful options to insert methyl groups into complex molecules with high regio-and chemoselectivity. The challenge of a large-scale application of methyltransferases is their dependence on S-adenosylmethionine (SAM) as a stoichiometric, and thus exceedingly expensive co-substrate. As a solution to this problem, we and others have explored the use of methyl halides as reagents for the in situ regeneration of SAM. However, the need to handle volatile electrophiles, such as methyl iodide (MeI), may also hamper applications at scale. As a more practical solution, we have now developed an enzyme-catalyzed process for the regeneration of SAM with methyl toluene sulfonate. Herein, we describe enzymes from the thiopurine methyltransferase family that accept sulfate-and sulfonate-based methyl donors to convert Sadenosylhomocysteine into SAM with efficiencies that rival MeI-based reactions.

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Selective Biocatalytic N‐Methylation of Unsaturated Heterocycles

et al. 2022

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Methods for regioselective N‐methylation and ‐alkylation of unsaturated heterocycles with “off the shelf” reagents are highly sought‐after. This reaction could drastically simplify synthesis of privileged bioactive molecules. Here we report engineered and natural methyltransferases for challenging N‐(m)ethylation of heterocycles, including benzimidazoles, benzotriazoles, imidazoles and indazoles. The reactions are performed through a cyclic enzyme cascade that consists of two methyltransferases using only iodoalkanes or methyl tosylate as simple reagents. This method enables the selective synthesis of important molecules that are otherwise difficult to access, proceeds with high regioselectivity (r.r. up to >99 %), yield (up to 99 %), on a preparative scale, and with nearly equimolar concentrations of simple starting materials.

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Biokatalytische C3‐Indol‐Methylierung – ein nützliches Werkzeug für die naturstoffinspirierte stereoselektive Synthese von Pyrroloindolen

Cited by 7 publications

References 60 publications

FluorinatedS‐Adenosylmethionine as a Reagent for Enzyme‐Catalyzed Fluoromethylation

FluorinatedS‐Adenosylmethionine as a Reagent for Enzyme‐Catalyzed Fluoromethylation

Synthetic Reagents for Enzyme‐Catalyzed Methylation

Selective Biocatalytic N‐Methylation of Unsaturated Heterocycles

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