Studies On Synthesis And Antifungal Activity Of Multi-substituted Oxygen/phosphorus-containing 5-membered Heterocycles

For a long time,the researches on natural products have been hoped that it can benefit human health and improve the quality of life.One of the important applications is to develop new drugs.Natural products often contain biologically active substances with novel structures and unique biological effects.However,the complex composition of natural products and the shortage of natural active contents make it far from meeting humans’ needs.Therefore,it is important and meaningful to synthesize useful derivatives similar to the core skeleton of biological active natural products by organic synthesis to increase their biological activities.It is also one of the methods of discovering lead compounds in new drugs development.Heterocyclic compounds are widely found in natural products.Due to their novel structures and unique biological effects,they have been widely used in medicine,pesticides and other fields,rendering it a research focus in organic chemistry.As a kind of heterocyclic compound,the five-membered heterocyclic skeleton is widely used in the fields of pesticides,medical materials,etc.,such as the commercially available fungicides thiabendazole,ethaboxam,and sterilized phosphorus.In the past few decades,organophosphorus compounds have played an important role in the regulation of life,pesticides,medicines,materials and catalysis,especially in pesticides.However,the extensive use of pesticides has led to the development of resistance to various pathogens.Therefore,the development of new pesticides is still an important research topic.The application of heterocyclic compounds in pesticides has become a trend in the development of new pesticides.The development of new pesticides requires four stages:First,the research phase of lead compounds,including the discovery,optimization and biometric research of lead compounds.Second,in-depth screening of highly active compounds.Third,the research and development stage of the candidate creation product.Fourth,the industrialization development stage of the creation of the product variety.The discovery and optimization of lead compounds is the basis for the creation of new pesticides and the only way to create new pesticides.For the modification of the molecule,more functional groups are introduced into the original molecular core skeleton,and then the biological activity is studied.It is well known that the chemical properties of the main group elements are similar.Imagine if the heteroatoms in the core skeleton are replaced with their main group elements,is there a better biological activity?Therefore,we hope to replace the nitrogen with phosphorus in isoxazole drugs and derivatives containing with indole.The antibacterial activity of such compounds is worthy of study.Based on the good biological activity of organophosphorus compounds and heterocyclic compounds,combined with the application in organic synthesis and through a review of a large number of literatures,a series of 2,5-dihydrofuran,2,5-dihydro-1,2-oxaphosphole 2-oxide and 3-alkenyl benzo[b]phosphole oxides derivatives are developed in this work with antifungal activity test.Rigorous experiments and mechanical study were performed.The details are summarized as follows:1、I2 mediated synthesis of(4-iodo-2,5-dihydrofuran-3-yl)diphenylphosphine oxide derivativesDihydrofuran derivatives,as a typical five-membered heterocyclic skeleton in nature,play an important role in the fields of natural product chemistry,pesticides and chemical biology.The 2,5-dihydrofuran compounds are one of dihydrofuran derivatives.And widely used in organic synthesis.In this dissertation,the intramolecular cyclization of phosphinoyl-α-allenic alcohols mediated by I2 can synthesize(4-iodo-2,5-dihydrofuran-3-yl)diphenylphosphine oxide derivatives.Through the screening of solvents,iodine sources,etc.,better reaction conditions were obtained,and 14 unreported iodonylphosphino-substituted 2,5-dihydrofuran derivatives were synthesized.The compounds were characterized by nuclear magnetic resonance spectroscopy(1H NMR,13C NMR,31P NMR),mass spectrometry(HRMS),infrared spectroscopy,melting point.The possible mechanism was proposed by literature research.2、A highly regioselective C(sp2)-P(O)cleavage of phosphinyl allenes to synthesize 4-iodo-2-phenyl-5H-1,2-oxaphosphole 2-oxide and α-iodoenone derivativesPhosphate ester compounds and α,β-unsaturated ketones are important organic compounds and are widely used in pesticides(insecticides,herbicides,fungicides),medicines,etc.,and also an important organic synthesis intermediates.A highly regioselective C(sp2)-P(O)cleavage of phosphinyl allenes mediated by the metal-free condition of I2/TBHP is achieved for the first time.When the substituent R is hydrogen,C(aryl)-P bond were selectively cleaved to form 4-iodo-2-phenyl-5H-1,2-oxaphosphole 2-oxides;once the substrate was changed to a tetra-substituted one,(allene)C-P(O)bond cleavage turned to be the major pathway,leading to the formation of α-iodoenones.This method is easily operated and metal-free with good yields.Based on control experiments and isotope labeling experiments,a possible reaction mechanism was proposed.33 compounds were synthesized,of which 30 were unreported compounds.The compounds were characterized by nuclear magnetic resonance spectroscopy,mass spectrometry,infrared spectroscopy,melting point,single crystal diffraction(X-ray).3、Synthesis of novel 3-alkenyl benzo[b]phosphole oxides by palladium-catalyzed cascade C-O cleavage and direct C-H alkenylationPhosphorus heterocyclic compounds are representative organophosphorus compound,which play an important role in pesticides,materials,asymmetric induction synthesis and other fields.Benzo[b]phosphole oxides as representative phosphonic heterocyclic compounds have received extensive attention in the recent years.In this work,a phosphine oxide-directed intramolecular cyclization of phosphinyl allenes is established for the first time.Through the screening of catalyst,solvents,additives,etc.,better reaction conditions were obtained.Based on control experiments,isotope labeling experiments,and literature research,the intramolecular cyclization was achieved though an unprecedented cascade C-O cleavage and P=O directed C-H alkenylation pathway.27 unreported various 3-alkenyl benzo[b]phosphole oxides were obtained along with broad group tolerance and highly regioselectivity.The compounds were characterized by nuclear magnetic resonance spectroscopy(1H NMR,13C NMR,31P NMR),mass spectrometry(HRMS),infrared spectroscopy,melting point,single crystal diffraction(X-ray).4、Antifungal activity determinationThe fungicidal 74 synthetic compounds against to Alternaria solani,Rhizoctonia solani,Botrytis cinerea,Alternaria mali,Fusarium graminearum and Colletrichum orbiculare were tested by growth rate method.Based on the measurement results,the structure-activity relationship was discussed.Toxicity of compounds with higher activity(η>70%)were determined.The EC50 of the compounds C8、C10、C11、C12、C13、C17、C18、C19 and C20 against Rhizoctonia solani were 23.15 μg/mL、26.19 μg/mL、11.97 μg/mL、3.96 μg/mL、7.25μg/mL、6.41 μg/mL、6.37 μg/mL、12.52 μg/mL、10.88 μg/mL,respectively;the EC50 of the compounds C10、C13、C18 and C19 against Colletrichum orbiculare were 21.89 μg/mL、22.07 μg/mL、38.62 μg/mL、24.00 μg/mL,respectively;the EC50 of the compounds B31、C17 and C19 against Botrytis cinerea were 44.16μg/mL、14.36 μg/mL、16.19 μg/mL,respectively.Through activity studies,2.5-dihydro-1,2-oxaphosphole 2-oxides、2,5-dihydrofurans and 3-alkenyl-substituted benzo[b]phospholene oxides were generally not good at inhibiting the three fungus of Alternaria solani、Alternaria mali and Fusarium graminearum.They had antifungal activity against Rhizoctonia solani、Botrytis cinerea、Colletrichum orbiculare.The antifungal activities of 3-alkenyl-substituted benzo[b]phospholene oxides were generally superior to derivatives of 2,5-dihydro-1,2-oxaphosphole 2-oxides and 2,5-dihydrofurans.The benzo[b]phospholene oxides obtained from the meta-substituted arylphosphine oxide ether show good antifungal activities.In summary,a total of 74 derivatives of 2,5-dihydrofurans,2,5-dihydro-1,2-oxaphosphole 2-oxides and 3-alkenyl benzo[b]phosphole oxides were synthesized in this work,Of which 71 are new compounds that have not been reported.Bactericidal activity studies have shown that some compounds have good inhibitory activity against tested bacteria and provide a reference for the creation of new fungicides.