Synthesis Of Chiral Molecules Based On Acylcyclopropane And Ribavirin And Study Of Their Biological Activitie

Chiral pesticides have become the focus of research and development of new pesticides due to their advantages of high efficacy,small dosage,safer crops and environmental ecology,and market competitiveness.Asymmetric synthesis is the leading innovation of chiral technology in modern chemistry.N-heterocyclic carbene(NHC)catalysis is a unique direction in organic asymmetric catalysis.After nearly 20 years of rapid development,it has achieved the activation mode for carbonyl compounds(such as aldehydes,acids,esters,anhydride,etc.),imines and olefins.It can control many known reactions with stereoselectivity,and synthesize new skeleton compounds that cannot be synthesized by traditional preparation technology through its unique catalytic activation mode.Acylcyclopropane is a kind of structural unit with biological activity,and its derivatives have agricultural biological activities such as antifungal,bacterial,and insecticidal.Ribavirin is a broad-spectrum plant antiviral agent,which can effectively inhibit the proliferation of a variety of plant viruses.In this dissertation,a series of novel chiral acylcyclopropane derivatives and ribavirin derivatives have been constructed by structural modification or molecular splicing of the basic framework of acylcyclopropane and ribavirin by asymmetric catalysis of NHC.The biological activity of new chiral compounds was tested to screen leed compounds with high activities,which can provide specific theoretical guidance for the research and development of new chiral green pesticides.The main research contents of this dissertation are as follows:(1)N-heterocyclic carbene(NHC)-catalyzed carbonyl nucleophilic substitution reaction between 1-cyclopropylcarbaldehydes and N-sulfonyl imines for access to linear aminoenone products.The aminoenones containing cyclopropyl fragments can be afforded in moderate to excellent yields under mild conditions.At the same time,ketene compounds containing cyclopropane can also be converted into new multifunctional molecular compounds with cyclopropane skeleton.We then tested the in vitro antibacterial activity of the aminoenones against Xanthomonas oryzae pv.Oryzae(Xoo).The results showed that the compound I-3u(47.07%)showed similar antibacterial activity to the commercial drug Thiodiazole-copper(47.59%)at 50μg/m L.Subsequently,we also tested the antifungal activity of the series of compounds.The results showed that most of the compounds had good antifungal activities against Colletotrichum capsica(C.c.),and the compounds I-3s(56.36%)and I-3t(56.23%)showed similar antifungal activity to the commercial drug Azoxystrobin(62.01%)at 50 μg/m L.(2)The remote α-carbon of the cyclopropylcarbaldehydes is activated by NHCs to react with cyclic N-sulfonyl α-iminoesters through asymmetric Mannich reactions.Chiral multicyclic δ-lactam products can be afforded in moderate to good yields and diastereoselectivities with generally excellent enantioselectivities.Three chiral centers are involved in the processes,with one isomer selectively afforded as the main product from the eight possible enantio-and diastereomers.We then tested the in vitro antibacterial activity of chiral multicyclic δ-lactam products,and studied the effect of compounds with different configurations on biological activity.The results showed that some compounds had good antibacterial activities,compounds(R)-Ⅱ-3b(66.05%),and(Rac)-Ⅱ-4f(65.49%)have better antibacterial activities against Xanthomonas axonopodis pv.Citri(Xac)than the control drug Bismerthiazol(65.22%)at 100 μg/m L.And compounds(R)-Ⅱ-3b(41.13%),(R)-Ⅱ-4e(39.09%),and(Rac)-Ⅱ-4f(42.38%)showed similar antibacterial activities against Xac to the control drug Bismerthiazol(46.51%)at 50 μg/m L.Lactam compounds with different configurations also had certain effects on antibacterial activity.For example,the antibacterial activities of the R configuration of compounds II-3b and II-4e are better than that of the S configuration,and the antibacterial activities of the Rac configuration of compounds II-4f and II-4j are better than that of the S and R configurations.Therefore,compounds(R)-Ⅱ-4e and(Rac)-Ⅱ-4f have excellent antibacterial activities against Xac,and can be used as potential anti-bacterial agents.(3)We have developed a new strategy for concise chemical synthesis of nucleoside esters via catalytic regio-selective acylation of the pentose unit of nucleosides.Through the influence of NHC catalysts(and in the presence of boronic acids in certain cases),the 5’-or 3’-OH group of nucleosides can be selectively acylated.No protection and de-protection steps are required during all the operations.Our method allows for concise access to many nucleoside ester prodrugs(Molnupiravir and ATV006)with profound impact on global health issues such as Covid-19 pandemic.We tested the antiviral activity against Tobacco Mosaic Virus(TMV)and Potato Virus Y(PVY)of mono-esterified nucleoside derivatives.The results showed that most of the mono-esterified nucleoside compounds have better anti-TMV activities than ribavirin,compounds III-9(60.51%,64.61%),III-27(61.09%,68.72%),III-28(59.12%,65.56%),III-29(60.56%,66.27%)and III-46(62.11%,66.81%)showed better anti-TMV curative and protective activities than the control drug Ningnanmycin(56.56%,64.39%).Some of these compounds have better anti-PVY activity than ribavirin,compounds III-9(60.79%,58.79%),III-29(60.33%,56.12%),III-36(59.17%,54.57%),III-42(61.12%,58.02%),and III-49(60.06%,58.87%)showed similar curative and protective activities against PVY as the control drug Ningnanmycin(60.90%,57.02%).By analyzing the structure-activity relationship of highly active compounds,we found that aromatic aldehydes with electron withdrawing groups can enhance the anti-TMV and anti-PVY activities of nucleoside derivatives.Replacing base groups with adenosine substituents also increases the anti-TMV and anti-PVY activity of nucleoside derivatives.By comparing the antiviral activity of 5’-O-acylation products and 3’-O-acylation products,it was found that most of the 5’-O-acylation products had better antiviral activity than 3’-O-acylation products.Therefore,compounds III-9 and III-29 have excellent anti-TMV and PVY activities,and can be used as potential anti-plant virus drugs.