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题名: 天然产物cochliomycin A和petrosiol E的全合成研究
作者: 王琳琳
学位类别: 博士
答辩日期: 2014-11
授予单位: 中国科学院研究生院
授予地点: 北京
导师: 杜宇国
关键词: Cochliomycin A,β-间二羟基苯甲酸大环内酯,Petrosiol E,全合成,天然产物,Cochliomycin A, Resorcylic acid lactones, Petrosiol E, Total synthesis, Natural products
其他题名: Total synthesis of cochliomycin A and petrosiol E
学位专业: 有机化学
中文摘要:     天然产物是生物体产生的次级代谢物,具有丰富多样的结构和多种多样的生理活性。以天然产物的全合成为基础,对天然产物进行结构改造和优化,是新药发现的重要源头之一。天然产物绝大多数都为手性分子,高效地获得光学纯的化合物是有机合成研究的主要目标。
利用糖类作为手性源来合成天然产物, 具有原料价廉易得、光学纯度高等优点。本论文提供了一种利用糖为手性源开展天然产物全合成的研究思路,并对分子中带有连续手性羟基的天然产物cochliomycin A和petrosiol E进行了全合成研究。
    2011年,从中国南海海域的柳珊瑚Dichotella gemmacea 得到的真菌月状旋孢腔菌Cochliobolus lunatus的液体培养基中分离得到了新的β-间二羟基苯甲酸大环内酯(β-resorcylic acid lactones,RALs)类天然产物cochliomycin A。Cochliomycin A具有包含三个连续手性羟基的14元环的RAL骨架。研究表明,cochliomycin A能够有效抑制纹藤壶Balanus amphitrite幼虫的附着,并且对金黄色葡萄球菌Staphylococcus aureus具有中等强度的抗菌活性。
    本研究采用价廉易得的L-阿拉伯糖作为手性模板,以最长线性步骤14步、总步骤18步、总产率6%完成了天然产物cochliomycin A的全合成,所合成的cochliomycin A的光谱、质谱、以及旋光度数据与天然产物高度一致。关键反应包括烯烃复分解、Stille偶联、和NaH促进的一锅法分子内酯化反应。
    2012年,从冲绳海域的海绵Petrosia strongylata中分离得到了新天然产物petrosiol E,其具有新奇的2,4-二炔-1,6,7,8-四醇的结构。研究表明,petrosiols E能够促进大鼠肾上腺髓质嗜铬瘤分化细胞株PC12细胞的神经元分化,还可能用来预防和治疗诸如血管再狭窄和动脉粥样硬化等心血管疾病。
    本研究采用价廉易得的D-木糖作为手性模板,以最长线性步骤10步、总步骤13步、总产率32%完成了天然产物petrosiol E的首次全合成,合成品的光谱、质谱、以及旋光度数据与天然产物高度一致,确证了天然产物petrosiol E绝对构型的正确性。
    本研究为合成具有相似结构的化合物提供了简捷高效的路线,为将来对这些化合物进行生物活性测试、构效关系研究、结构修饰和优化,开发高效低毒的新药提供了思路。
英文摘要:     Natural products, including secondary metabolites produced by living creatures, are of high structural diversity, as well as their comprehensive pharmacological or biological activities. Based on total synthesis of natural products, designing and synthesizing their structural analogues, is one of the major sources in drug discovery. Most of natural products are chiral molecules, which inspire synthetic organic chemists to embark on their total synthesis.
    Using carbohydrates as chiral pool materials to synthesize natural products, is advantageous because of their low cost, abundance, and high optical purity. Howerver, coverting carbohydrates into the desired target molecules is challenging. This thesis describes total synthesis of cochliomycin A and petrosiol E by employing carbohydrates as the chiral pool materials.
    Cochliomycin A was isolated from the culture broth of Cochliobolus lunatus, a fungus obtained from the gorgonian Dichotella gemmacea collected in the South China Sea in 2011. Cochliomycin A has a 14-membered resorcyclic acid lactone structure with three contiguous oxy-stereocenters. Cochliomycin A was found to show potent antifouling activity against the larval settlement of the barnacle Balanus Amphitrite and moderate antibacterial activity against Staphylococcus aureus.
    Starting from readily available chiral pool L-arabinose, we completed total synthesis of cochliomycin A in a total of 18 steps, with the longest linear sequence of 14 steps and 6% overall yield. All the spectroscopic data and specific rotation data of our synthetic cochliomycin A are in good agreement with those reported values for natural product. The key reactions involved olefin cross-metathesis, Stille cross-coupling and sodium hydride promoted one-pot intramolecular lactonization.
    Petrosiols E was isolated from an Okinawan marine sponge Petrosia strongylata in 2012. Petrosiol E has an unusual diyne tetraol skeleton. Petrosiol E was found to induce nerve growth factor (NGF-like) neuronal differentiation of PC12 cells. Detailed biological analyses demonstrated that petrosiol E may be useful for the prevention and treatment of vascular diseases such as restenosis and atherosclerosis.
    The first total synthesis of petrosiol E starting from the chiral template D-xylose has been achieved in a total of 13 step reactions, with the longest linear sequence of 10 steps and 32% overall yield. Our work also confirmed the absolute stereochemistry of petrosiol E based on physical data agreements from both synthetic and natural samples.
    Because of compactness and efficiency, our strategies are attractive for the facile synthesis of structurally similar natural products. This work will make contributions to extensive studies of structurally similar natural products, in exploring their biological properties and synthesizing variations (analogues) of them to develop them or their analogues to drug candidates.
内容类型: 学位论文
URI标识: http://ir.rcees.ac.cn/handle/311016/34384
Appears in Collections:环境化学与生态毒理学国家重点实验室_学位论文

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Recommended Citation:
王琳琳. 天然产物cochliomycin A和petrosiol E的全合成研究[D]. 北京. 中国科学院研究生院. 2014.
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