Studies On Synthesis Of1,3-diols Through Non-classical Reaction Of Aryl Grignard Reagents With Isopropenyl Acetate And Their Antifungal Activities

1,3-diol compounds exist in some natural products and have some biological activity. They are widely used in preservatives, pharmaceuticals and pesticides. Seeking for economic and easy synthesis method of1,3-diols and their biological activity are the study target of the chemists. The reaction of Grignard reagents with enol ester is often accompanied with the rearrangement of the enol ester. The products, reaction mechanism, reaction activity and stereoselectivity of the issues are to be further in-depth study.A series of anti-/syn-2,4-diaryl-2,4-pentanediols and anti-/syn-1,3-diaryl-1,3-butanediols have been efficiently synthesized from substituted aryl Grignard reagents reaction with isopropenyl/vinyl acetate in a one-step reaction. The reaction reactivity and stereoselectivity of the two enol ester reaction with aryl Grignard reagents were compared. The possible mechanism of phenylmagnesium bromide (PhMgBr) reaction with isopropenyl acetate was analysized by both experimental and theoretical studies. Substituent effect and intermolecular interactions of some crystal structures were analysized. Title1,3-diols as potential antifungal agents were evaluated and their in vitro antifungal activities were measured against several fungal species.In all, this thesis involves five aspects as bellow:(1) Summarized the research progress of synthesis and biological activity of1,3-diols in recent years. The types and examples of the synthesis method and their application in organic synthesis were briefly introduced.(2) A series of anti-/syn-2,4-diaryl-2,4-pentanediols have been efficiently synthesized from substituted aryl Grignard reagents reaction with isopropenyl acetate through nonclassical method and accompanied with several byproducts anti-/syn-4-methyl-2,6-diphenylheptane-2,4,6-triols. Some anti-/syn-1,3-diaryl-1,3-butanediols were obtained by aryl Grignard reagents reaction with vinyl acetate in order to investigate reaction activity and stereoselectivity of the Grignard reagents reaction with enol ester. The stereoselectivity was determined with ratio of anti- syn-isomers. The reactivity and stereoselectivity of aryl Grignard reagents reaction with isopropenyl acetate are higher than that with vinyl acetate.(3) Eighteen single crystals of anti-/syn-2,4-diaryl-2,4-pentanediols, anti-1,3-diaryl-1,3-butanediols and anti-4-methyl-2,6-diphenylheptane-2,4,6-triols were obtained from slow evaporation of petroleum-ethyl acetate solution at room temperature, and crystal structures were determined by X-Ray diffraction analysis. Intramolecular S(6), intramolecular C(6) and dimers R44(8) type O-H…O hydrogen bonds (HBs) were descripted with Graph-set theory. Dimers and the π-π stacking interactions were formed in syn-diols. In anti-diols, one-dimensional (1D) infinite chains structures were formed by the intra-and intermolecular HBs. All of the crystal structures were stabilized by classical intra-and intermolecular HB interactions. In addition to the classical HBs and van der Waals interactions, there are some other different weak interactions such as C-H…O、C-H…π、C-H…F、C-Cl… in3D structural array.(4) We speculated that the reaction mechanism of the Phenyl magnesium bromide reaction with isopropenyl acetate may occurred rearrangement and experienced a six-member ring intermediate. Then as reaction model, both experimental and density functional theory (DFT) and B3LYP method calculations have been carried out to study the mechanism and stereoselectivity of the reaction. We compared the energy demands of different pathways quantitatively and summarized the energetically most favorable one. On the basis of the electronic and structural analysis of the key intermediates and transition states, we further clarified the reaction mechanism and stereoselectivity. All research work show good correlations between the calculation results and the experimental observations.(5) Title compounds were evaluated as potential antifungal agents and their in vitro antifungal activities were measured against several fungal species, including Rhizoctonia solani, Botrytis cinerea, Sclerotonia sclerotiorum, and so on. It was found that some diols showed prospective antifungal activities against Sclerotonia sclerotiorum. When the substituted group is the same anti-2,4-diaryl-2,4-pentanediols have more activities than that of syn-isomers. The results provide a scientific guidance for further optimization of1,3-diols.