Fluorinated S‐Adenosylmethionine as a Reagent for Enzyme‐Catalyzed Fluoromethylation. Issue 52 (10th November 2021)

• Record Type: Journal Article
• Authors: Peng, Jiaming; Liao, Cangsong; Bauer, Carsten; Seebeck, Florian P.
• Is Part Of: Angewandte Chemie international edition. Volume 60:Issue 52(2021)
• Page Start: 27178
• Page End: 27183
• Publication Date: 2021-11-10
• Subjects: biocatalysis -- enzymes -- fluorine -- methyltransferase -- monofluoromethylation; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.202108802
• Languages: English
• ISSNs: 1433-7851

Abstract

Abstract: 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. Abstract : In a biocatalytic approach to the production of fluorinated compounds, halide methyltransferases (HMTs) were found to form fluorinated S ‐adenosylmethionine (SAM) from S ‐adenosylhomocysteine and fluoromethyliodide. Although too unstable for isolation, fluorinated SAM was accepted as a substrate by C‐, N‐ and O‐specific SAM‐dependent methyltransferases (MTs) to enable the fluoromethylation of small molecules (see scheme).