Synthesis And Insecticidal Activities Of Obacunone Derivatives Modified In The B And D Rings

Plant secondary metabolites,which result from the interaction between plants and environment(life and non-life)during the long period of evolution,have special degradation pathways and may lead to less or slower resistance development and lower pollution.It is one of the important ways of developing novel and environmentally-friendly pesticides to directly utilize plant secondary metabolites or to use them as precursors for structural modification.Obacunone,a naturally occurring limonoid,is isolated from the rutaceae or meliaceae plants,has received much attention for its interesting properties such as anti-tumor,antioxidant and insecticidal activities.To our knowledge,few reports have been published to structural modifications of obacunone as insecticidal agents.Hence,obacunone was used as a lead-compound for structural modifications in its B and D rings,and five series(one hundred and two compounds)of obacunone derivatives were prepared.Their insecticidal activity was also investigated.Finally,the preliminary structure-activity relationships(SARs)of obacunone derivatives were discussed.The main results were found as follows:1.Three series(forty-one compounds)of novel oxime ester(I-a~I-x),oxime sulfonate ester(II-a~II-f)and oxime ether(III-a~III-k)derivatives of obacunone were synthesized by modification of obacunone at its C7-position.Their structures were well characterized by mp,optical rotation,IR,~1H NMR and HRMS.Three configurations of compounds I-m,I-r and I-s were determined by single-crystal X-ray diffraction,and their C=N double bonds of oxime were in E configuration.The reaction temperature could regulate the process of obacunone into C7-oximeobacunone.The oxime ether derivatives of obacunone were effectively obtained using microwave-assisted conditions(Cs2CO3 as a base,and acetone as a solvent at 100 oC).The insecticidal activity of these derivatives was evaluated against pre-third-instar larvae of Mythimna separata Walker by the leaf-dipping method at the concentration of 1 mg/mL.Among all derivatives,compounds I-e,I-r,I-s,I-w,III-a and III-b(their final mortality rates were greater than 60%)displayed more promising insecticidal activity than their precursor’s obacunone and toosendanin.The SARs indicated that introduction of oxime ether moiety at the C-7 position of obacunone could result in more potent compounds,and especially introduction of the side chain of oxime ether moiety was the aliphatic chain.2.Two key intermediates and thirty-three new 7α/β-acyloxyobaxunone derivatives(IV-1a,IV-1b and IV-2a~IV-2e’)were smoothly prepared from obaxunone reduced by NaBH4 and subsequent condensation with different carboxylic acids.Their structures were well characterized by mp,optical rotation,IR,~1H NMR and HRMS,and the configurations of 3-1,3-2,and IV-2q were further determined by single-crystal X-ray diffraction.It was found that different reaction solvents can effectively control the yields of the products of obaxunone when obaxunone was reduced by NaBH4.When a solution of NaBH4 in methanol was added dropwise to a solution of obaxunone in methanol,the ratio of 7α-hydroxyobaxunone and 7β-hydroxyobaxunone was 1/3.8.However,when a solution of NaBH4 in methanol was added dropwise to a solution of obaxunone in methanol,the ratio of 7α-hydroxyobaxunone and 7β-hydroxyobaxunone was 1.81/1.7α-Acyloxyobaxunone derivatives were only obtained when 7α-hydroxyobaxunone reacted with the corresponding anhydride in reflux condition.Their insecticidal activity was tested against pre-third-instar larvae of M.separata at 1 mg/m L.Compounds IV-1b,IV-2g and IV-2l exhibited more promising insecticidal activity than obacunone and toosendanin.The SARs indicated that the insecticidal activity of alkylacyloxy derivatives was generally more potent than that of arylacyloxy ones,and the side chain length of alkylacyloxy derivatives was also very important for the insecticidal activity.3.Twenty-eight ester derivatives of 7α/β-acetoxylobacunones(V-1a~V-1m,V-2a~V-2d and V-2g~V-2q)were obtained by reduction of C16-carbonyl group of 7α/β-acetoxylobacunones with 6 equiv of NaBH4 at 0 oC,followed by condensation with different carboxylic acids.Their structures were well characterized by mp,IR,~1H NMR.Their insecticidal activity was tested against pre-third-instar larvae of M.separata at 1 mg/mL.Compounds V-1e,V-1j,V-1l,V-1m,V-2k,V-2m and V-2n displayed more remarkable insecticidal activity than obacunone and toosendanin.This suggested that reduction and esterification at C-16 position of 7α-acetoxylobacunone(IV-1a)could give the potent insecticidal compounds.On the contrary,structural modifications at C-16 position of 7β-acetoxylobaxunone(IV-2a)decreased the insecticidal activity of the corresponding compounds.