| Part I:Podophyllotoxin,a representative of naturally occurring aryltetralin lignans,besides its use as the lead-compound for the preparation of anticancer drugs,such as etoposide,teniposide and etopophos,has also received much research attention for its interesting insecticidal and antifungal activities.More recently,we have studied podophyllotoxins and found some compounds showed more potent insecticidal activity than toosendanin,a commercial insecticide derived from Melia azedarach.To find new natural products-based insecticidal agents.We herein further designed a series of 4a-acyloxy-2?/?-bromopodophyllotoxins and investigated their insecticidal activity.The key interesting results were found as follows:Firstly,four intermediates of 2?/?-bromopodophyllotoxins were prepared,and then thirteen new 4a-acyloxy-2?/?-bromopodophyllotoxin derivatives were stereoselectively synthesized.Interestingly,4a-acyloxy-2a-bromopicropodophyllotoxins were easily converted to a more rigid compound 14 by an intramolecular Friedele-Crafts alkylation reactiontion the presence of BF3·Et2O when the reaction time was prolonged to 4-18 h.Compounds 5g,6h,6i,and 14 displayed the more promising and pronounced insecticidal activity than toosendanin,a commercial insecticide derived from Melia azedarach,against the pre-third-instar larvae of Mythimna separata Walker.Part II:Fraxinellone,a well-known and significantnaturally occurring degraded limonoid.It has also received much researcher's attention for its interesting activities in the field of medicinal chemistry such as anti-inflammatory activity,antifertility activity,vascular relaxing activity,and treating T-cell-mediated liver disorders.Additionally,it also exhibited the potent insecticidal activity.Although in early 1972s total synthesis of fraxinellone has been reported,to the best of our knowledge,little attention has been paid to structural modifications of fraxinellone as insecticidal agents.Hence,we use natural active substance fraxinellone as the the lead-compound for the semisynthesis of the big four series of 164 fraxinellone derivatives including 158 novel compounds,and then investigate their insecticidal activity,against the pre-third-instar larvae of Mythimna separata Walker.At last,we also have studied its preliminary structure-activity relationships.The mainly interesting results were found as follows:1.Two key intermediates and twenty-tree new fraxinellone-based hydrazone derivatives were smoothly prepared from fraxinellone via regioselectively allylicoxidation in the presence of selenium dioxide or chromium trioxide under microwave irradiation and subsequent condensation with hydrazides or hydrazines.Their insecticidal activity was evaluated against the pre-third-instar larvae of Mythimna separata Walker in vivo.Especially compounds 6d and 7a displayed the most pronounced insecticidal activity compared with toosendanin,a commercial botanical insecticide derived from Melia azedarach.2.Two small series of thirty-seven novel 4a/10-acyloxy-fraxinellone derivatives were synthesized by modification at the C-4 or C-10 position of fraxinellone and evaluated for their insecticidal activity against the pre-third-instar larvae of Mythimna separata Walker in vivo.An efficient method for the stereoselective synthesis of 4a-hydroxyfraxinellone from fraxinellonone was developed,and the steric configuration of 6h was unambiguously confirmed by X-ray crystallography.Among all compounds,some derivatives displayed potent insecticidal activity;especially compounds 6h,6q,6t,and 7q showed more promising insecticidal activity than toosendanin,a commercial botanical insecticide derived from Melia azedarach.This suggested that introduction of the fluorine atom on the phenyl ring could lead to a more potent compound than one possessing chlorine or bromine.Meanwhile,introduction of the heterocyclic fragments at the C-4 or C-10 position of fraxinellone was essential for their insecticidal activity.3.A series of thirty-seven novel fraxinellone derivatives modified at the C-1 or C-8 position in the B ring were prepared as insecticidal agents against the pre-third-instar larvae of oriental armyworm,Mythimna separate Walker at 1 mg/mL.Five key steric configurations of compounds 2,3,and 8f,8g,8j were further determined by single-crystal X-ray diffraction.It was found that the kinds and the amount of the reduction products of fraxinellone were related to the molar ratio between the reduction agent Red-A1 and the substrate fraxinellone.Among all of the derivatives,compounds 2 and 8i,8j,8o displayed more promising insecticidal activity than their precursor's fraxinellone and toosendanin.The preliminary structure-activity relationships revealed that the lactone(B-ring)of fraxinellone contributed to the observed insecticidal activity;the double bond at the C-2 position of fraxinellone was not necessary for the insecticidal activity;conversion of the oxygen atom of carbonyl group on the lactone of fraxinellone to a sulfur one does not improve the insecticidal activity;introduction of electron-withdrawing groups on the phenyl ring of 8f,to the benzoyloxy series,could result in more potent compounds.4.Six small series of sixty-one novel fraxinellone derivatives modified at the C-2' or C-5' position in the fruan ring were prepared as insecticidal agents against the pre-third-instar larvae of oriental armuworm,Mythimna separate Walker.We have investigated electrophilic substitution reaction in the fruan ring of fraxinellone such as Friedele-Crafts acylation reaction for the frist time,and found the C-5' position more easier for electrophilic substitution reaction than the C-2' position which maybe because of steric effects of lactone(B ring).The steric configuration of 2a,2c,4 and 5 were confirmed by X-ray crystallography without controversy,and the hydrogen proton of the C-5' position was frist substituted by acyloxy group.Among all of the derivatives,compounds 2a,2e,4b,4d,5i,5j,6d,6e,7d,7e,7f,7h and 7j showed more promising insecticidal activity than positive control toosendanin.Especially,compound 7j was the best and its final mortality rate was 64.3%more than toosendanin(46.4%).This suggested that structural modification at C-2' or C-5' position in fruan ring could prepare potent insecticidal agents based on fraxinellone.In conclusion,above-mentioned work will pave the way for further design,structural modification,and development of podophyllotoxin or fraxinellone as an insecticidal agent. |
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