【作者】 王超；

【导师】 胡艾希； 叶姣；

【作者基本信息】 湖南大学 ， 应用化学， 2009， 硕士

【摘要】 天然产物的结构多样性为农药研究者们提供了一个数量巨大的先导化合物库,对先导化合物用有机合成的方法进行结构优化改造,是创制新农药的重要途径。鱼藤酮是早期人们从鱼藤属等植物根部中提取分离出来的一种具有杀虫活性的化合物,是三大传统植物性杀虫剂之一,但其光稳定性差和害虫防治效率低等缺陷,很难标准化和商品化,使得它的应用和推广受到极大的限制。由于鱼藤酮的杀虫谱广、残留期短、不易产生抗药性、对人畜安全和有利于促进生态平衡等优点使得鱼藤酮作为绿色农药极具开发潜力。针对鱼藤酮作为农药来使用存在的这些缺陷,以鱼藤酮为先导化合物,进行化学结构改造和修饰,合成鱼藤酮类衍生物,在提高其杀虫杀菌活性和稳定性是目前亟待解决的研究课题。在掌握了鱼藤酮类衍生物的结构与稳定性、生物活性关系基础之上,以鱼藤酮为底物,在保持其基本构型不变的情况下进行化学结构改造和修饰,首先将鱼藤酮12位的酮羰基通过肟化反应,用C=N来替代具有强吸电性的C=O降低12a-H的活性,抑制12a位置的氧化降解来提高整个分子结构的稳定性。鱼藤酮肟在碱性的条件下和卤代物烷基化剂反应制备了21种鱼藤酮肟醚类衍生物(3 ~ 23);鱼藤酮肟与酰氯经酯化反应制备了6种鱼藤酮肟酯类衍生物(24 ~ 29);鱼藤酮肟与异氰酸酯反应制备了4种鱼藤酮氨基肟酯类衍生物(30 ~ 33),并对所合成的衍生物进行结构表征。考察了碱强度、溶剂、微波辐射等对鱼藤酮肟烷基化反应的影响。用溶剂挥发法培养得到鱼藤酮肟乙基醚(4)和N-(1-辛基)-氨基甲酸鱼藤酮肟酯(33)的晶体,单晶X-射线衍射分析进一步确定了鱼藤酮肟醚类和氨基甲酸鱼藤酮肟酯类衍生物的典型结构。鱼藤酮肟醚和氨基甲酸鱼藤酮肟酯类衍生物基本保留了鱼藤酮的母体结构,这两类衍生物结构中的环A所在平面和环D所在平面所构成的V字形结构二面角角度与鱼藤酮以及鱼藤酮肟的V字形二面角角度稍有变化,它们角度的大小顺序是:鱼藤酮(105.30°) > N-(1-辛基)-氨基甲酸鱼藤酮肟酯(103.16°) >鱼藤酮肟(101.30°) >鱼藤酮肟乙基醚(99.35°);另外,12位取代基的变化会导致A环上甲氧基偏离A环所在的平面。化合物4分子之间无明显的氢键,化合物33分子中NH键的质子与相邻分子中C=O键的氧形成了分子间氢键,同时,普遍存在的范德华力进一步稳定了晶体结构。采用Potter喷雾法和浸渍法测试鱼藤酮肟类衍生物分别对粘虫、稻黑尾叶蝉、蚕豆蚜、棉红蜘蛛毒杀活性。用含毒培养基法测试了鱼藤酮肟类衍生物对小麦赤霉病菌,辣椒疫霉病菌,稻瘟病菌,黄瓜灰霉病菌,稻纹枯病菌,油菜菌核病菌以及用盆栽法测试对小麦白粉病菌的生长抑制活性,筛选出既对粘虫有一定的毒杀作用又对稻纹枯病菌有较强抑制作用的二鱼藤酮肟苄基醚。选出部分具有活性的衍生物,采用玻片涂布法让合成的鱼藤酮类衍生物在室外接受一定强度的自然光照射后,定时取样,利用高效液相色谱外标法对鱼藤酮衍生物的降解残留做定量分析,研究鱼藤酮类衍生物的光降解过程,得出:鱼藤酮肟醚类衍生物的降解趋势与鱼藤酮相似;二鱼藤酮肟苄基醚(23)其半数降解时间均超过鱼藤酮(16 h)。与鱼藤酮肟醚类衍生物相比较,鱼藤酮肟酯类衍生物的降解过程较为复杂。最后,采用反相高效液相色谱法测定了鱼藤酮类衍生物的脂水分配系数,克服了传统摇瓶法的操作费时、对所得样品纯度要求高和结果重现性差等缺点。更多还原

【Abstract】 Structural diversity of natural products provided a library containing considerable lead compounds for pesticide researchers, so it is an important way to develop new pesticides using organic synthesis methods for structural optimization of the leading compounds. Rotenone is the principal active ingredient of Cube Resin used as an insecticide, belonging to the three major traditional botanical insecticides. Because of the photochemical degradation behavior and the low efficiency of pest control, it is difficult to be standardized and commercialized, and thus makes its application and promotion of great limitations. But it makes rotenone as highly potential for the development of green pesticides, for the advantages of the broad insecticide spectrum, not easy to produce drug resistance and helping to promote the ecological balance of environment. So reforming rotenone into the derivatives with high bioactivity and stability are currently in urgent need of solution research topics.In this study, on the base of the structure-activity relationships for the rotenone derivations, we introduced the oxime O-ether group, substituting C=N for C=O at 12 position, in order to reduce the acidity of the 12a-H and improve the stability of the whole molecular. Firstly, taking rotenone as the lead compound, we synthesis rotenone oxime by using the hydroxylamine hydrochloride reacts with 12-carbonyl of rotenone. Twenty-one rotenone oxime O-ether derivatives were synthesized by the etherification reaction using natural rotenone and a series of halids as substrates in alkaline conditions; Ten rotenone oxime esters derivatives were synthesized by the esterification reaction using natural rotenone and a series of chloride as substrates; Four rotenone oxime esters carbamate derivatives were synthesized by the reaction of rotenone oxime and a series of isocyanate. The effects of the solvents, microwaves were studied to the esterification reaction.Crystals of the compounds 4 and 33 suitable for X-ray analysis were obtained by slow evaporating a mixture solvent of ethanol and acetone at room temperature. And the corresponding stereochemistry assigned by X-ray crystallography show that rotenone derivatives retains the rotenone parent structure on the whole except for changing the dihedral angle of the V-shaped structure.The size of the angles follows the order: rotenone(105.30°) > compound 33(103.16°) > rotenone oxime (101.30°) > compound 4(99.35°); Besides, the changes of the substituents on 12 position caused the methoxy deviation from ring A. There are no obvious hydrogen bonds intermolecular of compound 4. But the hydrogen bonds exist between the proton of NH bond in one molecular and the C=O bond in another molecular from compound 33. Prevalence of Vanderwaals force further stabilizes the crystal structure.Potter-spraying method was used to measure the insecticidal activity of test compounds against M. separata. To measure the activities of test compounds against N. cincticeps, A. fabae and T. urticae, leaf-dipping method is introduced. In addition fungicidal activities of the title compounds against Gibberella zeae, Phytophythora capsici, Pyricularia oryzae, Botrytis cinerea, Sclerotonia sclerotiorum, Rhizoctonia solani and Erysiphe graminis were evaluated using the mycelium growth rate test. In particular, the preliminary biological activity tests show that disubstituted oxime ethers (compound 33) not only have general insecticidal and miticidal activity but also have a novel fungicidal activity against Rhizoctonia solani.In this paper, some active rotenone derivatives were selected to study the process of the photodegradation, through quantitative analyzing the residual products, using of high-performance liquid chromatography (HPLC) external standard method. The results show that the series of rotenone oxime ethers derivatives undergo the similar degradation trends to rotenone. And the DT50 for compound 23 was longer than rotenone (16 h). Compared to rotenone oxime O-ethers derivatives, the degradation process for rotenone oxime ester derivatives are more complex. At last, the lipid water partition coefficients for the derivatives were determined, using the method of HPLC, and this way overcomes the disadvantage of time-consuming operation and the poor reproducibility results from the traditional shake-flask method.更多还原