【作者】 董宏波；

【导师】 王明安；

【作者基本信息】 中国农业大学 ， 农药学， 2014， 博士

【摘要】 以天然产物为先导化合物开发新农药具有容易降解、选择性高、对环境友好等优点,因此渐渐成为新型绿色农药研发的主要途径之一。(6R)-3,7-二甲基-7-羟基-2-辛烯-1,6-内酯是从蜜蜂寄生菌Ascosphaera apis的代谢产物以及西藏荜澄茄(Litsea cubeba)果实提取物中分离得到的具有广谱杀菌活性的天然产物,Muricatacin和6-乙酰氧基十六碳烷酸-5-内酯是从番荔枝科植物刺果番荔枝(Annona Muricata)以及传播疟疾和西尼罗河病毒的淡色库蚊Culex pipiens fatigans的卵块表面的分泌物中分离出的具有昆虫拒食和产卵引诱信息素功能的天然产物。本论文围绕它们的合成及生物活性开展了以下三部分工作。第一部分研究了两条以甲基庚烯酮和橙花醇为原料经4-6步反应全合成消旋和光活性3,7-二甲基-7-羟基-2-辛烯-1,6-内酯的路线,总收率在6.3%-32.9%之间。与此同时首次完成了天然产物3,7-二甲基-2,6-辛二烯内酯(a-09)与(E)-6,7-二羟基-3,7-二甲基-2-辛烯酸(a-05)的全合成。在此基础上,发展了先将烯烃环氧化、而后在樟脑磺酸的催化下羧酸与环氧基团发生分子内的SN2反应关环合成七元环内酯的新策略,得到含有α-羟基侧链的七元环内酯化合物共28个,其中首次通过Sharpless不对称双羟基化为关键步骤还合成了三对光活性异构体,它们的e.e.值在88.8%-95.4%,并通过Mosher酯和X-射线衍射方法确定了它们绝对构型。第二部分首次以商品化的炔酸和炔醇为原料,利用Shi不对称环氧化反应和Sharpless不对称双羟基化为关键步骤同时引入两个手性中心,通过6-11步反应分别以总收率16.5%-26.9%完成了天然产物Muricatacin和6-乙酰氧基十六碳烷酸-5-内酯的四个光学纯异构体的全合成,并通过X-射线衍射方法确定了(-)-epi-Muricatacin的绝对构型。第三部分对合成的目标化合物进行了离体杀菌活性测定,结果表明部分化合物具有比天然产物更好的杀菌活性。如化合物d-06对棉花立枯菌、水稻纹枯菌、油菜菌核菌与黄瓜灰霉菌的ECso分别为10.684,3.693,5.094,0.455mg/L,化合物e-07对棉花立枯菌、水稻纹枯菌、小麦赤霉菌与辣椒疫霉菌的ECso分别为2.831,4.605,10.731,5.065mg/L。初步探讨了它们的结构-活性关系,发现当天然产物的烯丙位甲基被芳环取代后,化合物的杀菌活性得到显著的提高；Muricatacin的四个立体异构体中,(5R,6R)-Muricatacin,(5S,6S)-Muricatacin,(5R,6S)-Muricatacin,(5S,6R)-Muricatacin对水稻纹枯的抑制率分别为72.34%,65.23%,91.08%,84.78%,进一步精密毒力测定结果显示Muricatacin的四个异构体对水稻纹枯的EC50分别为8.818,16.665,4.602,5.253mg/L。更多还原

【Abstract】 Pesticides based on natural products are degradable, selective and environmental friendly. Therefore, development of pesticides using natural products as lead compounds gradually becomes one of the main utilizing methods.(6R)-3,7-dimethyl-7-hydroxy-2-octen-6-olide was first isolated from the honey bee fungal entomopathogen Ascosphaera apis, as well as the fruit of plant Litsea cubeba in Tibet, and exhibited good antifungal activities. Muricatacin was first isolated from the seeds of Annona muricata which showed antifeeding activity, and6-acetoxy-5-hexadecanolide as a kind of oviposition attractant pheromones was first isolated from the apical droplets formed on the egg of the mosquito Culex pipens fatigans, which has the ability to transmit the West Nile virus. This paper can be divided into three parts based on the synthesis and bioactivity of these natural products. R-a-06a-05a-09Muricatacin6-acetoxy-5-hexadecanolideIn the first part, racemic and chiral3,7-dimethyl-7-hydroxy-2-octen-6-olide were totally synthesized by4-6steps with overall yields of6.3%-32.9%using methyl-5-hepten-2-one and nerol as raw materials in two routes, respectively. Natural products3,7-dimethyl-2,6-octadien-1,6-olide (a-09) and (E)-6,7-dihydroxy-3,7-dimethyloct-2-enoic acid (a-05) were also synthesized for the first time. A new strategy were developed including olefin epoxidation and intramolecular SN2replacement with catalyst camphorsulfonic acid,28seven-membered lactones with hydroxyl group at side chain were prepared by this protocol. Three pairs of optical isomers have been synthesized with e.e. values of88.8%-95.4%. Their absolute configurations were determined by Mosher ester and X-ray diffraction.In the second part, asymmetric total synthesis of Muricatacin and6-acetoxy-5-hexadecanolide have been accomplished from the commercial4-pentynoic acid and alkynol via Shi’s AE and Sharpless AD reactions as the key steps in6-11steps with an overall yields of16.5%-26.9%. The absolute configuration of (-)-epi-Muricatacin was confirmed by X-ray diffraction.The in vitro antifungal activities of these compounds were evaluated in the third part of this paper. The results showed that some of these derivatives exhibit good fungicidal activity, such as the EC50f compound d-06against R. solani, R. solani Kuhn, S. sclerotiorum and B. cinerea were10.684,3.693,5.094,0.455mg/L, and the EC50of compound e-07against R. solani, R. solani Kuhn, F. graminearum and P. capsici were2.831,4.605,10.731,5.065mg/L, respectively. The structure-activity relationships showed that the antifungal activity were increased significantly when the allylic methyl was replaced by aromatic groups; inhibition rates of (5R,6R)-Muricatacin,(5S,6S)-Muricatacin,(5R,6S)-Muricatacin,(5S,6R)-Muricatacin against R. solani were72.34%,65.23%,91.08%,84.78%with the EC50valus were8.818,16.665,4.602,5.253mg/L, respectively.更多还原