Design, Synthesis And Bioactivity Of 4-Quinolone Derivatives And Trifluoromethylated All-carbon Quaternary Stereocenters Compounds

In the past few decades, quinolone derivatives have been widely applied as a class of antimicrobial drug in the pharmaceutical. field. Owing to the unique structure of these compounds, in recent years, the application in other area such as pesticides, materials and so on are also rapidly growing. In this thesis, a two-site respiratory chain inhibitor NQNO as the lead compound,17 of 2- or 3-alkyl-substituted quinolones were synthesized. According to the principles of substructure combination,4 compounds with both N-hydroxy quinolone-tethered methoxyacrylate were synthesized. As well, we synthesized 71 of 2- or 3-substituted hydroxyamide quinolone derivatives. The structures of the title compounds were confirmed by 1H NMR,13C NMR or HRMS. Finally, the bioassay of these compounds were investigated. It was found that some of the title compounds displayed good inhibitory activity against the bacteria. Among them, compound B05 exhibit bacteria growth inhibition in three kinds of bioassay, revealing that B05 possesses a broad spectrum of antimicrobial activities. In the structure-activity relation of quinolones hydroxyamide derivatives, the substituent R2 in the side chain has little influence on the biological activity, and substituent R1 in the quinolone skeleton play an important role in biological activity. The results provide experimental basis for the discovery of new agricultural fungicide with a quinolone skeleton.Trifluoromethyl compounds, owing to their unique physical, chemical and biological properties, are present in many pharmaceutical molecules. However the approach to the construction of trifluoromethylated all-carbon quaternary stereocenters has been rarely reported. In this thesis, we explored an efficient asymmetric Michael addition of 2-acetyl azaarenes to various β-CF3-β-disubstituted nitroalkenes using a Ni (Ⅱ)-bisoxazoline complex, affording the corresponding addition adducts bearing a trifluoromethyl all-carbon quarternary chiral center. Through trial and error, we obtained the optimized conditions (10 mol% L1-Ni (acac) 2, iso-propanol as solvent and 0℃), we achieved chiral compounds with an all-carbon quaternary stereocenter bearing CF3 group in good yields with excellent enantioselectivities (up to >99% ee). To demonstrate the synthetic potential of this catalytic approach, two products were subjected to one-pot reaction and provided pyrroline derivatives in good yield without any loss in the enantiopurity. One of them, featuring a pyridine moiety, is a insecticide protected by WO patent. Moreover, the in vitro antifungal activities of some products were also investigated, and all tested compounds possessed fungicidal activities to some extent.This work provided academic and experimental fundament to some extent for the discovery of new fungicide; moreover afforded new and concise synthetic strategy for the innovation of new pesticide bearing a trifluoromethylated all-carbon quaternary chiral center.