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MenD-Catalysed Synthesis of 6-Cyano-4-Oxohexanoic Acid

Nature is an endless source of biocatalysts – enzymes with great properties that can be exploited in industrial biotechnology. Apart from finding new routes to synthesize the needed chemicals, enzymes also reveal new pathways. With the use of enzymes, it is possible to carry out reactions with non-physiological substrates of enzymes and by doing so to gain access to new molecules that have not be found in nature.1 One of the enzymes that can be used for this purpose is 2-succinyl-5-enolpyruvyl-6-hydroxy-3- cyclohexene-1-carboxylate synthase or MenD.2 This enzyme provides biocatalytic access to new types of products which are not related to the products currently accessible by thiamine diphosphate (ThDP) dependent enzyme catalysis.3 MenD catalyses the formation of substituted 1, 4- diketones and 4-oxo acids via enzymatic Stetter reaction. The Stetter reaction is well known for cyanide-catalyzed transformations of mostly aromatic aldehydes. Enzymatic Stetter reactions, however, have been largely unexplored, especially with respect to preparative transformations.4 We have established a MenD- catalyzed 1, 4-addition of -ketoglutaric acid to acrylonitrile in order to synthesize 6-cyano-4- oxohexanoic acid3b on gram-scale.5 The relevance of this reaction is in the potential application of 6-cyano-4-oxohexanoic acid as a building block since this molecule contains a keto group, an acid function, and a nitrile group which can be used to synthesize other functional groups in a straightforward manner.6 The reaction for the synthesis of 6-cyano-4- oxohexanoic acid c (Scheme 1) is a conjugate addition (Stetter reaction) of -ketoglutaric acid A with decarboxylation to acrylonitrile B. The reaction was catalyzed by ThDP-dependent enzyme MenD (EC 2.2.1.9) from Escherichia coli with the addition of cofactor Mg2+ to the reaction mixture. 6-Cyano-4-oxohexanoic acid C was produced on preparative scale in 60 % isolated yield.

MenD, 6-Cyano-4-Oxohexanoic Acid, procedure, synthesis

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