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Title Ενζυμική ασύμμετρη σύνθεση χειρόμορφων ενδιαμέσων και φυσικών φερορμονών με απομονωμένες κετορεδουκτάσες
Alternative Title Enzymatic asymmetric synthesis of chiral intermediates and natural pheromones with isolated ketoreductases
Author Καλαϊτζάκης, Δημήτρης
Thesis advisor Σμόνου, Ιουλία
Abstract In the present dissertation the stereoselective enzymatic reductions by using NAD(P)H-dependent isolated ketoreducases were studied for the synthesis of valuable chiral intermediates such us optically active α-substituted-β-hydroxy ketones and α-substituted-1,3-diols. The chemoenzymatic synthesis of the pheromones Sitophilure, Sitophilate, Stegobinone and Stegobiol was accomplished succesfully. The relative and absolute configuration for all the products of the enzymatic reductions were determined by NMR methods. The reduction of thirteen α-substituted-1,3-diketones with 32 isolated ketoreductases is presented in the first chapter. In every case at least one optically pure hydroxy ketone was produced, while in many cases three out of the four possible stereoisomers were formed with excellent optical purity. All these results show that the ketoreductases are very active, stereoselective and regioselective towards these substrates. For the unsymmetrical diketones the enzymatic reduction was accomplished via Dynamic Kinetic Resolution. The second chapter describes the chemoenzymatic synthesis of the pheromone Sitophilure of rice weevil and maize weevil. This synthesis started from the commercially available 3,5-heptanedione and was accomplished in only three steps with overall yield 81%. In the third chapter the chemoenzymatic synthesis of the pheromone of granary weevil, Sitophilate is presented. The synthesis was accomplished via enzymatic reduction of an α-methyl-β-keto ester. It was completed in four steps with overall yield 62%. The effect of substrate modification as well as reaction conditions (temperature and pH) in the stereoselectivity of ketoreductases used in this particular chemoenzymatic synthesis was also studied here. In chapter four the chemoenzymatic synthesis of the substances of drugstore beetles pheromone via enzymatic reduction of a β-keto ester and a 1,3-diketone is presented. The synthesis was achieved with high stereoselectivity producing the pheromone Stegobinone in pure crystalline form. In chapter five the determination of the relative stereochemistry for all the products of all the enzymatic reductions was achieved. For the monosubstituted hydroxy ketones the assignment was accomplished by calculating the coupling constant between the two asymmetric hydrogens. It was found that this constant was smaller for the syn isomers than the coupling constant for the corresponding anti. For the disubstituted hydroxy ketones the Heathcocks rule was applied. The chemical shifts of three specific carbons were measured with 13C NMR spectroscopy. A new empirical rule for the assignment of the relative configuration of α-monosubstituted-β-hydroxy ketones by 1H NMR spectroscopy is presented. This method is based on the downfield chemical shift of the carbinol proton of syn isomer compared to the corresponding anti. In the sixth chapter the absolute stereochemistry of the optically active secondary alcohols was determened. The assignment was accomplished utilizing the chiral derivatizing agent a-methoxy phenylacetic acid (MPA). This method relied on the calculation of ΔδR-S differentiation between the corresponding R-MPA and S-MPA esters of the products from the enzymatic reductions that were studied. In the seventh chapter the enzymatic synthesis of α-substituted-1,3-diols utilizing the isolated ketoreductases is presented. This synthesis was achieved by enzymatic reduction of the initially formed α-substituted-β-hydroxy ketones in optically pure form by the same reductive enzymes. The enzymatic reduction was performed, in many cases, with high activity and diastereoselectivity producing optically active 1,3-diols.
Language Greek
Issue date 2006-10-26
Collection   Faculty/Department--Faculty of Sciences and Engineering--Department of Chemistry--Doctoral theses
  Type of Work--Doctoral theses
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