The Synthesis Of Isolongifolenone And Its Oxime Derivatives And Their Biological Activity Research

In recent years,based on natural product to synthesize novel compounds has been of an interest as result of its biological and pharmacological properties.Lately,1,2,3,4,5,6-hexahydro-1,1,5,5-tetramethyl-7H-2,4a–methanonaphthalen-7–one（isolongifolenone）has been found to exert potent against tyrosinase and breast cancer.Besides,isolongifolenone was superior to Deet in repelling ticks and deterring feeding mosquitoes.As known to us,oxime ether derivatives have been the hot topic for research workers due to their widely bioactivitives such as anti-bacterial,antifungal,larvicidal,antineoplastic activities and etc.Therefore,this thesis was designed and synthesized a series of isolongifolenone oxime ethers（ester）derivatives based on the background above.Furthermore,their activities such as antibacterial and insecticidal activity were also investigated.Firstly,we adopted isolongifolene as the starting material to synthesize bioactive isolongifolenone by allylic oxidation,and optimal industial synthesis condition of isolongifolenone was also comprehensively studied.Secondly,isolongifolenone oxime,oxime–eher（ester）and lactam derivatives were designed and synthesized.Finally,the bioassays of antibacterial,antifungal and insecticidal activity were carried out.The work is briefly summarized as follows in three parts:1.Optimization for the synthesis of isolongifolenoneIsolongifolenone was prepared using isolongifolene as initial material through allylic oxidation.Mn-Cu Ox,Mn-Co Ox,Mn-Al Ox,Cu-Co Ox,Cu-Fe Ox and Cu-Al Ox of 6 kinds of mixed metal oxides were selected as heterogeneous catalysts,all of which can lead to 90%or more yield of isolongifolenone and the conversion of isolongifolene was100%,when respectively in combination with appropriate tert-butyl hydroperoxide（TBHP）and oxygen as oxidant under ambient conditions.We have found Mn-Cu Ox has a higer catalytic active of all mixed oxides,which can lead to 95.2%yield of isolongifolenone.Therefore,we has chosen Mn-Cu Ox as heterogeneous catalyst,TBHP and oxygen as the oxidant under ambient condition to seek for an optimum industrial condition for the synthesis of isolongifolenone adopting a method of orthogonal experiment and Do E,a statistical approach.Besides,the single test of temperature,solvent,time and other factors on the reaction were also investigated.Mn-Cu Ox or other mixed oxides were characterized by XRD,SEM,IR,ICP and BET.Furthermore,a variety of cyclic olefins oxidation experiments were carried out with the aim to study the scope of the reaction in a system of Mn-Cu Ox/TBHP,and it also affords a new methodology for the allylic oxidation.2.The synthesis of isolongifolenone oxime and its oxime derivativesThe amount of isolongifolenone was synthesized based on the above optimized conditions.Isolongifolenone oxime was synthesized through the reaction of isolongifolenone and hydroxylamine hydrochloride.Isolongifonone oxime derivatives were synthesized by the reaction of alkylation for oxime-ethers,acylation for oxime-esters or Beckmann rearrangement reaction for lactam compounds.The structures of the target compounds including intermediate compounds were identified by X-ray crystal diffraction,¹H NMR,¹³C NMR,IR,MS,elemental analysis and etc.3.Biological study for isolongifolenone and its oxime derivativesThe in vitro bioassays of antibacterial,antifungal and insecticidal activity were carried out.The antibacterial activity against five test organisms,one Gram positive strains Staphylococcus aureus（S.aureus）and four Gram negative bacterial,Escherichia coli（E.coli）,Pneumobacillus,Pseudomonas aeruginosa（P.aeruginosa）,Proteus vulgaris and antifungal activity against aspergillus niger,colletotrichum musae,corn sheath blight,exserohilum turcicum and alternaria musae organisms was evaluated by the disk diffusion method and the minimum inhibitory concentration（MIC）of compounds was determined by microdilution method,while insecticidal activity was tested adopting armyworm,prodenia litura,ostrinia nubilalis,soybean aphid and rice planthopper as control object.Initially,at the concentration of 200ug/ml and screened out the compounds with insecticidal activity,then diluted into a variety of different concentrations to find out the lowest concentration of insecticidal activity,each group of experimental repeated three times or more.The results of bioactive test above show that compound 8a has been found to be more active in resisting all the tested bacterial and fungus when in comparison to the standard drug amoxicillin.It is worthy to note that compound 16 which was synthesized by Beckmann rearrangement reaction of isolongifone oxime,exerted potent insecticidal activity against soybean aphids.Furthermore,compound 15a exhibited more effective in killing armyworms than the standard drug flucycloxuron.This paper provides a useful reference and deep use in the search for novel isolongifolenone derivatives.