Study On The Synthesis And Antifungal Activity Of Nitrogen Heterocyclic Molecules Enabled By Anionic Stereogenic-at-Cobalt(Ⅲ) Complexes

As a class of important agricultural production materials,pesticides have been widely used to control insects and weeds.With the rapid development of agriculture,the usage of pesticides is also increasing quickly,causing serious damage to the ecological environment.Therefore,the development of high-efficiency and green pesticides is an important but difficult research domain.Recently,it has been found that several enantiomers of racemic pesticides show significant differences in biological activities,ecotoxicities,and environmental behaviors.Thus,the use of chiral pesticides can reduce dosage and enhance efficacy.In agriculture,developing efficient and green chiral pesticides has significant researchful and practical values.Five-membered N-heterocyclic skeleton compounds are widely found in pesticides,such as isoxazoline herbicides（Metiozolin）,pyrazole carbamates,pyrazole phosphate insecticides,and acaricides.The azaspiro polycyclic skeleton compounds are also one class of N-heterocyclic compounds with unique biological activities,which are widely found in alkaloids,such as Aspidophytine,which is an effective insecticidal substance.In this thesis,a novel strategy for the asymmetric synthesis of N-heterocyclic skeletons is investigated.Based on the anionic stereogenic-at-cobalt（Ⅲ）complexes catalytic system,a series of chiral pyrazolines,isoxazolines,and alkaloid-like N-heterocyclic compounds are efficiently synthesized,and the antifungal activity of the synthesized chiral nitrogen heterocyclic compounds is preliminarily studied.Specific contents are as follows:（1）Asymmetric bromo（iodo）amine cyclization ofβ,γ-unsaturated hydrazone（oxime）is achieved by using Br（?）nsted acids of anionic stereogenic-at-cobalt（Ⅲ）complexes,leading to a series of chiral pyrazoline and isoxazoline compounds（48 examples,up to 99%yield,97:3e.r.）.In gram-scale experiments,both yield and enantioselectivity do not decrease significantly even if reducing the amount of catalysts and bromination reagents.In synthetic applications,the halogen atom of chiral pyrazoline and isoxazoline products can be easily transferred to the azide group and after a click reaction,chiral triazole compounds are obtained without any erosion of enantioselectivities.Finally,the antifungal activity of some pyrazoline and isoxazoline products is tested against Fusarium graminearum,Botrytis cinerea,and Sclerotinia sclerotiorum.The preliminary study showed that isoxazoline compounds have more significant antifungal activity than pyrazoline derivatives.The inhibition rate of（±）-W2 to the Botrytis cinerea is 86.37%,The inhibition rate of（±）-W4against three plant pathogenic fungi is above 60%,and the inhibition rate of Fusarium graminearum is 75.82%.（±）-W6 shows good antifungal activity against three plant pathogenic fungi,which were 71.41%,76.69%,and 56.93%,respectively.These results indicate that the synthesized isoxazoline compounds have potential pesticide application value.（2）Through an asymmetric Ugi reaction/post-Ugi transformation strategy,we have efficiently constructed a series of complex aza polycyclic compounds with multiple consecutive stereocenters and excellent stereoselectivities.A series of chiralα-amidopropargylamides are obtained via sodium salts of anionic stereogenic-at-cobalt（Ⅲ）complexes-catalyzed asymmetric Ugi four-component reactions of aromatic aldehydes,amines,isocyanates,and propargyl carboxylic acids（32 examples,up to 96.5:3.5 e.r.）.Subsequently,α-amidopropargylamides can easily transfer to azaspiro polycyclic scaffolds compounds via"one-pot multi-step"post-Ugi reactions,including a Br（?）nsted acid-promoted deprotection,a gold-catalyzed ipso-cyclization,and a switchable aza-Michael addition reaction（3 various skeletons,48 examples,up to 99:1 e.r.,>95:5 d.r.）Control experiments and crystal structure analysis reveals the mechanism of the post-Ugi processes and elucidates the origin of stereocontrol in both ipso-cyclization and aza-Michael addition reactions.In the subsequent bioactivity study,the antifungal activities of some compounds are tested against Fusarium graminearum,Trichoderma viride,and Botrytis cinerea.Preliminary results show that the selected compounds X1-X6 and X8 show low inhibitory rates against Fusarium graminearum and Botrytis cinerea at the concentration of 100（μg/m L）,the compound X7 exhibits good antifungal activity against Fusarium graminearum（41.98%）.Compounds X1,X2,and X5 reveal good inhibitory effects on Trichoderma viride of 47.09%,55.79%,and 58.99%,respectively.Based on the test results,the structure-activity relationship of the compounds is preliminarily discussed,and the EC₅₀ activity of the compounds with good activity is determined.The EC₅₀ values of（R）-X2,（1R,5R）-X5 against Trichoderma viride are 101.76μg/m L,66.22μg/m L,respectively.These results indicate that the synthesized aza polycyclic compounds have potential pesticide application value.