Investigation Of Chiral Ketones Derived From Galactose And Glycyrrhetinic Acid And Hydroxamic Acid Derivatives Containing Isoxazole And Benzimidazole

Two parts are included in this thesis:One part is about the asymmetric epoxidation of olefins catalyzed by chiral ketones derived from D-galactose and Glycyrrhetinic acid(GA).The other is about the new PDF inhibitors of hydroxamic acid derivatives containing isoxazole and benzimidazole.Epoxidation of olefins is a versatile synthetic method in organic synthesis.Chiral epoxides are very important building groups in the preparation of natural compounds and pharmaceutical products through the selective ring opening of epoxides and transformation of functional groups.Catalytic asymmetric epoxidation is an especially useful technique for the synthesis of chiral compounds.Thus,the development of efficient epoxidation methods continues to be the emphasis in organic chemistry.The asymmetric epoxidation of alkenes can carried out in transition metal catalytic systems.However,there has the limitation that each system adapts to some kind of olefins,and many metal compounds are prohibited in the drugs synthesis.Thus the organocatalytic asymmetric epoxidation of olefins without metals receives considerable attention and achieves great success.The oxidation reagent usually is cheap oxone in chiral ketones mediated epoxidations.Dioxiranes are usually generated from oxone and ketones that are highly efficient toward both electron-deficient and electron-rich olefins.Epoxidation mediated by dioxiranes proceed with quick reaction rate and easily to deal with.Two kinds of chiral ketones have been designed and synthesized as catalysts: 3,4-O-isopropylidene-p-D-galactopyranoside-2-uloses derived from D-galactose (â… )and Glycyrrhetinic acid derivatives(â…¡).Chiral ketones(â… )and Glycyrrhetinic acid derivatives(â…¡)were used,for the first time,to catalyze the epoxidation of olefins by us.We have concentrated our research on D-galactose and Glycyrrhetinic acid(GA)because they are commercially available in large quartities.The steric hinderance,electron-drawing substituents(OR)and the large substituents of chiral center are introduced to chiral ketones(â… ).Chiral ketones(â… )were obtained by a six-step formation of selectively protected hydroxyl functionalities on the 1,3,4- and 6-positions,followed by PDC oxidation.I₂/p-toluenesulfonic acid and I₂/camphor sulfonic acid were firstly used as co-catalysts in the preparation of 3,4-oxazolidine.10 chiral ketones have been used in the epoxidation of olefins.The effects of reaction temperature,pH and solvents have been investigated in our work.There was no obvious enhancement of the enantioselectivity by lowing of the reaction temperature.The yield and stereoselectivity of the reaction increased with increasing the amounts of the catalysts and(or)enhancing pH value.Both of the catalytic efficiency and stability of ketones(â… )with O-substituent in anomer carbon were better than that of ketones with S-substituent in anomer carbon.The emergence of multi-drug resistant bacterial has created an urgent demand for new antibacterial agents with novel mechanisms of action and new structures.One of the new targets currently receiving widespread interest is peptide deformylase(PDF). PDF is an essential iron containing metallo-enzyme that catalyzes the removal of N-formyl group from the N-formyl methionine of ribosome synthesized nascent polypeptide.The absence of deformylase activity in mammal cells,coupled with the observation that the gene encoding PDF(def)exists in all sequenced pathogenic bacterial genomes,has made PDF an attractive target for antibacterial chemotherapy. According to the structure-activity relationships of these compounds and the theory that drug binds with acceptor,we use them as leading compounds to synthesize a series of hydroxamic acid derivatives containing isoxazole and benzimidazole.The desired isoxazole was constructed via multi-step synthesis firstly from the derivatives of benzaldehyde.The target compounds were then obtained via oxidation, esterification and hydroxylamination.The hydroxamic acid containing benzimidazole was synthesized from ethyl benzimidazole acetate which was obtained from aniline and ethyl cyanacetate and hydroxylamine in the alkaline solution.20 new target compounds have been synthesized,and about 70 intermediates were synthesized during the experimental process.All the compounds were characterized by ¹H NMR, IR,ESI-MS and elemental analyses,and the results were in agreement with the proposed structures.All the compounds were evaluated by bacterial inhibitory assay and most of the isoxazole-containing compounds showed antibacterial activity.