新型脱碳木脂素类化合物合成方法与肿瘤抑制活性研究
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摘要
木脂素是一种具有抗病毒、抗肿瘤、延缓衰老、调节免疫等生物活性的天然产物，在植物的根、茎、叶和果实中都有发现，其基本骨架结构为苯丙素单元。研究发现，带有此类结构单元的化合物可能具有与木脂素相似的生物活性，因此对此类化合物的合成方法也成为了化学家的研究热点之一。
本论文研究了一系列带有脱碳木脂素（两分子苯丙素单元在生物合成的过程中可能通过脱去羰基失去一个碳原子而生成）基本骨架结构的1，3-二芳基丁烯类化合物的合成方法及其生物活性的检测。多年来，此类化合物的合成已经有相当多的文献报道，主要通过布氏酸或者过渡金属Pd、Ni、Co、Ru等催化芳基烯烃进行二聚反应合成。但是以布氏酸为催化剂的二聚反应，二聚产物收率较低，且其空间构型不具备选择性，同时生成二氢化茚类等多种副产物，因此该催化方法并不值得推广。而应用过渡金属催化的方法，虽然能够控制产物的空间选择性，但过渡金属价格昂贵、反应条件苛刻、对环境污染较大，难以满足进一步工业化生产的要求。
基于以上原因，本论文旨在开发芳基烯烃二聚反应的新型催化体系，为合成脱碳木脂素类化合物提供更多的研究方法。首先，在查阅大量参考文献和结合本实验室研究工作的基础上，以带有苯丙素单元的化合物-细辛脑为原料，探索了二聚反应的新型催化体系（Mn(II)/Co(II)/PhP(O)HOR/O2）用于合成脱碳木脂素类化合物，考察了反应的影响因素，优化了反应条件，同时在该催化体系作用下，本反应能够实现产物的空间选择性且反应产物为反式结构。另外，在此基础上借鉴了布氏酸催化二聚反应的机理，进一步开发了新的催化体系（H+/PhP(O)HOR），该体系不但能够实现反应产物的空间选择性，同时也大大提高了反应的收率，所研究的催化体系易于制备，实验方法简便、可行，为进一步开展工业化生产奠定基础。本论文应用1H NMR,13C NMR, HPLC-MS以及元素分析等方法对合成的脱碳木脂素类化合物进行表征，同时考察了它们对人肝癌细胞Bel-7402、人乳腺癌细胞MCF-7、人肺癌细胞A549和人宫颈癌细胞Hela的体外抗癌效果。主要研究内容如下：
1．Mn(II)/Co(II)/PhP(O)HOR/O2催化芳基烯烃类化合物的二聚反应研究
在新催化体系确立的基础上，本论文通过逐一考察单个组分对反应的影响，探索发生该反应的必要条件。结果表明，Mn(II)、Co(II)、O2在反应中都缺一不可，同时PhP(O)HOR也作为催化剂与Mn(II)/Co(II)/O2共同作用，促进反应的发生。接着，作者进一步优化反应条件，经实验证明最佳反应条件为：以乙酸为溶剂，底物与PhP(O)HOR摩尔比为1：3，Mn(II)/Co(II)为原料摩尔量的5%，在持续通入氧气的条件下90oC反应24h，其中3a最高收率达76%。
基于以上研究结果，本论文考察了反应的适用范围，并对可能的反应机理进行了初步的推导。通过以带有不同取代基的芳基烯烃类化合物为原料进行反应，表明芳基烯烃类化合物带有供电基团更有利于反应的发生。在结合相关文献和实验数据的基础上，作者提出了该反应可能是以自由基的加成-消除反应机理进行的。
总之，本论文开发出了用于合成脱碳木脂素类化合物芳基烯烃二聚反应的新的催化体系，该体系相比较文献报道的方法，过渡金属用量更少，能够降低成本、减少污染，反应条件也更为温和。另外，与经典Mn(II)/Co(II)/O2体系催化合成有机膦化合物反应中PhP(O)HOR作为反应物相比，在该反应中PhP(O)HOR与Mn(II)/Co(II)/O2共同形成催化体系促进反应的完成。2．H+/PhP(O)HOR催化合成脱碳木脂素类化合物（3a-3g、3i、3j）方法研究
在结合文献报道应用布氏酸能够催化芳基烯烃类化合物的二聚反应，以及制备PhP(O)HOR过程中，同时也会产生布氏酸（HCl），因此作者以-细辛脑为原料通过应用未纯化的PhP(O)HOR为催化剂，开展二聚反应合成脱碳木脂素类化合物，经多种表征方法证实为目标产物，同时产物为反式构型，且最高产率达到95%。至此，本论文建立了H+/PhP(O)HOR催化芳基烯烃二聚反应的体系。
根据以上结果，作者通过逐一考察单个组分对反应的影响，探索发生该反应的必要催化条件。结果表明，单一酸催化虽然能够引发反应，但存在反应收率低、目标产物空间构型不具备选择性、副产物多等问题，而PhP(O)HOR的参与能够大大提高反应的收率、抑制副反应的发生、并对产物起到空间控制的作用。接着，作者进一步优化反应条件表明，本反应在室温和无溶剂的条件下同样能够得到高收率产物，经实验探索的最佳反应条件为：未纯化的PhP(O)HOR与α-细辛脑摩尔比为1:2，在室温无溶剂条件下反应2h。
基于以上研究结果，作者考察了反应的适用范围，并对可能的反应机理进行了初步的推导。通过以带有不同取代基的芳基烯烃类化合物为原料进行反应，表明芳基烯烃类化合物带有供电基团更有利于反应的发生。在结合相关文献和实验数据的基础上，作者提出了该反应可能是以酸催化形成碳正离子和PhP(O)HOR促进叔氢质子消去两个过程进行的。
总之，作者提出了H+/PhP(O)HOR的催化体系应用于合成脱碳木脂素类化合物，相比较传统布氏酸催化芳基烯烃二聚反应，该体系克服了单独酸催化条件下存在的问题，具有收率高、无副产物并且产物构型具有空间选择性等优点，同时基于PhP(O)HOR的合成特点，该催化体系易于制备，反应条件温和，实验方法简便、可行，并能避免应用过渡金属带来的毒性问题，为进一步工业化生产奠定了基础。
3.所合成脱碳木脂素类化合物（3a-3g）肿瘤抑制活性测定及作用机制分析
首先，本论文通过MTT法考察了所合成化合物对人肺癌细胞A549、人肝癌细胞Bel-7402、人宫颈癌细胞Hela和人乳腺癌细胞MCF-7的抗癌活性，检测表明，所合成脱碳木脂素类化合物对这些肿瘤细胞都具有一定的抑制作用，其中对人肝癌细胞Bel-7402的抑制效果最好，并且化合物3b的半数抑制浓度（IC50）为18.9g/mL，低于相同条件下的对照组紫杉醇的半数抑制浓度（28.0g/mL），说明针对Bel-7402细胞化合物3b表现出比紫杉醇更好的抑制作用。另外，我们以作用于Bel-7402细胞的IC50值分析了化合物结构与活性的关系，初步分析得出了该类化合物具备更高抗癌活性的基本骨架结构，即3f结构。
其次，作者以Bel-7402细胞为研究对象，应用Hoechst-PI双染色法和流式细胞仪法对化合物的抗癌作用机制进行了分析。化合物3a、3b、3c和3f作用Bel-7402细胞后，通过荧光显微镜可明显观察到凋亡细胞增多，核仁收缩，染色质浓缩呈肾形或新月型，并伴有凋亡小体的出现，而其它三种化合物细胞形态变化并没有上述四种明显，这也与它们对应的IC50值结果相吻合。这些结果从细胞形态学角度表明这些化合物对Bel-7402细胞的抑制可能是通过凋亡机制进行的。利用流式细胞仪对化合物作用后的细胞周期分析发现，这些脱碳木脂素类化合物表现出与紫杉醇相似的抑制作用，即将细胞周期阻断于G2期和M期而导致癌细胞死亡。
总之，本论文从化合物的抗癌活性、化合物作用后的细胞形态、细胞周期等对这些脱碳木脂素类化合物的生物活性和抗癌作用机制进行了初步分析。结果证实，这些脱碳木脂素类化合物对肿瘤细胞均有一定抑制作用，并可能通过凋亡机制杀死癌细胞，表现出与紫杉醇类似的抑制作用。另外，研究表明，3f的结构为该类化合物具备更高抗癌活性的基本骨架。值得注意的是，针对Bel-7402细胞化合物3b表现出比紫杉醇更好的抑制效果，因此3b具有较为广阔的研究应用价值。
Lignans are a class of natural products with potent antiviral, antitumor,antioxidant and antiinflammatory properties, and they are widely distributed in theplant kingdom and found in roots, rhizomes, stems, leaves, seeds and fruits. It has beenreported many compounds with phenylpropane units, the basic molecular backbone oflignans, exhibit the similar biological activity as that of lignans. Therefore,methodology for the synthesis of these compounds has been received widespreadinterest.
In this study, we have developed novel methodologies for dimerization of styrenesto1,3-diaryl-1-butenes, the basic molecular backbone of norlignans, and investigatedtheir biological assay.1,3-diaryl-1-butenes are generally prepared by dimerization ofstyrene derivatives via transition-metal catalysts or Br nsted acid catalysts. ButBr nsted acid catalytic dimerization of styrenes affords the mixtures of E, Z-isomersand subsequent byproducts in moderate yield such as indan derivatives or higheroligomers through carbocation process. Although many potent and selectivetransition-metal catalysts have been developed, the limited availability of these metalsas well as their high price and significant toxicity restricts their large-scaleapplications of this reaction. Therefore, we hope to develop novel and multiple catalystsystems for such type of dimerization.
First, we have developed dimerization of styrenes (-asarone based compunds)proceeded by a novel catalyst system of Mn(II)/Co(II)/O2combined with alkylphenylphosphinate, PhP(O)HOR. We next have investigated the optimizedexperimental conditions and a series of stereoselective E-dimer of styrenes basedcompounds have been synthesized. Second, in connection with our previousinvestigation of dimerization of styrenes catalyzed by PhP(O)HOR/Mn(II)/Co(II)/O2,an interesting acid-catalyzed/PhP(O)HOR-promoted dimerization of styrenes hasbeen discovered which involves giving the exclusive E-isomers of head-to-taildimers in excellent yield. The procedure has offered simplicity in operation withregard to facile catalyst system and solvent-free condition. The structure of dimers hasbeen characterized by1H NMR,13C NMR and HPLC-MS. The biological activity ofproducts has been measured by MTT assay using human hepaioma Bel-7402cells,human breast adenocarcinoma MCF-7cells, human lung carcinoma A549cells andhuman cervical carcinoma HeLa cells. The experimental results are as follows:
1. The dimerization of styrenes catalyzed by Mn(II)/Co(II)/PhP(O)HOR/O2
Due to the discovered experiment, we have aimed to test the effects of individualcatalytic factor on the reaction. This result has demonstrated that the dimerizationrequires a synergistic relationship between styrenes, alkyl phenylphosphinate andMn(II)/Co(II)/O2redox system. The optimized condition is: the molar ratio of styrenesto PhP(O)HOR=1:3, the molar amount of Mn(II)/Co(II) is5%that of substrate, at90°C for24h under oxygen condition.
We have further investigated the influence of styrene-based compounds withdifferent substituents on the scope and limitations of dimerization. It is shown thatsubstrate with electron-donating groups preferred the reaction. And it is found that thepresent dimerization of styrenes would proceed via a radical mechanism involving anaddition–elimination sequence.
Taken together, we have found that dimerization of styrenes proceeded by a novelcatalyst system of Mn(II)/Co(II)/O2combined with alkyl phenylphosphinate,PhP(O)HOR, in which PhP(O)HOR acts as a co-catalyst rather than a substrate forhydrophosphorylation of styrenes. Mechanistic studies suggestes the reaction mostlikely proceeded via addition–elimination.2. The dimerization of styrenes catalyzed by H+/PhP(O)HOR
It was suggested that a simple synthesis for PhP(O)HOR with hydrochloric acidresidues by the addition of phenyldichlorophosphine to alcohol. Drawing inspirationsfrom dimerization via Br nsted acid catalysts, we have conducted the dimerization ofstyrenes using unpurified PhP(O)HOBu as catalyst and the E-isomer of dimer isexclusively obtained in good yield (95%).
Due to the discovered experiment, we have systematically examined individualcatalytic factors. It is shown lack of acid catalysis or acid catalysis in the absence ofPhP(O)HOBu resulted in no or slow reaction, demonstrating acid catalysis makessignificant contribution to this kind of reaction, and PhP(O)HOBu further promotesthe formation of styrene dimer. Meanwhile, in the presence of PhP(O)HOBu, thebyproduct can be completely suppressed under independent acid condition andstereoselective E-dimers have been obtained. The studied dimerization efficientlyoccurs the molar ratio of ratio of styrenes to unpurified PhP(O)HOR=1:3,solvent-free condition and room temperature.
We have further investigated the influence of styrene-based compounds withdifferent substituents on the scope and limitations of dimerization. It is shown thatsubstrate with electron-donating groups preferred the reaction. Mechanism study indicates the combined H+/PhP(O)HOR catalyst system plays pivotal dual roles, theformation of carbonium ion intermediate catalyzed by acid and PhP(O)HOR-promotedtertiary hydrogen elimination.
In conclusion, we have developed a novel and efficient acid-catalyzed/PhP(O)HOR-promoted styrene dimerization, in which a series of stereoselective E-dimer of substituted styrenes can be synthesized with good yield under mild and
solvent-free condition. Based on the synthesis of PhP(O)HOR with hydrochloric
acid residues, H+/PhP(O)HOR is a readily available catalyst system requiringno further purification facilitating to simply reaction procedure.3. Biological activity assay of products and investigation of their anticancermechanism
Cytotoxicity has been studied by using an MTT assay to identify Bel-7402cells,MCF-7cells, A549cells and HeLa cells still active in respiration. It is shown thatproducts exhibit cytotoxicity to cells; especially,3b treated with Bel-7402cells showslower cytotoxicity (IC50:18.9g/mL) than free paclitaxel (28.0g/mL). In addition,we have analyzed the relationship between structure and activity based on the result ofIC50. It was indicated that a basic backbone with anticancer activity is3f.
We have preliminarily investigated anticancer mechanism of products usingBel-7402cells by Hoechst-PI dual staining and flow cytometry method. Fromfluorescent image, it is observed the decreased amount of apoptotic cells, nuclearshrinkage, chromatic condensation, and apoptotic body formation when cells treatedwith3a,3b,3c and3f. In contrast, cell morphology treated with other threecompounds changed little, which is consistent with the result of IC50. From cellmorphology initial analysis, apoptosis mechanism of synthesized products may inducecell death. From result of cell cycle as measured by flow cytometry assay, thesynthesized products exhibit the same cytotoxic activity as paclitaxel, which can causecell cycle arrest in the G2/M phase and finally cell death through apoptosismechanism.
In summary, we have analyzed biological activity and anticancer mechanism bycytotoxicity, cell morphology and cell cycle. It is indicated that products exhibitcytotoxicity to cancer cells, especially Bel-7402cells. The synthesized products causecell death by apoptosis mechanism. It is worth noting that3b can be a promisinganticancer agent for application of cancer chemotherapeutic drugs.
本论文研究了一系列带有脱碳木脂素（两分子苯丙素单元在生物合成的过程中可能通过脱去羰基失去一个碳原子而生成）基本骨架结构的1，3-二芳基丁烯类化合物的合成方法及其生物活性的检测。多年来，此类化合物的合成已经有相当多的文献报道，主要通过布氏酸或者过渡金属Pd、Ni、Co、Ru等催化芳基烯烃进行二聚反应合成。但是以布氏酸为催化剂的二聚反应，二聚产物收率较低，且其空间构型不具备选择性，同时生成二氢化茚类等多种副产物，因此该催化方法并不值得推广。而应用过渡金属催化的方法，虽然能够控制产物的空间选择性，但过渡金属价格昂贵、反应条件苛刻、对环境污染较大，难以满足进一步工业化生产的要求。
基于以上原因，本论文旨在开发芳基烯烃二聚反应的新型催化体系，为合成脱碳木脂素类化合物提供更多的研究方法。首先，在查阅大量参考文献和结合本实验室研究工作的基础上，以带有苯丙素单元的化合物-细辛脑为原料，探索了二聚反应的新型催化体系（Mn(II)/Co(II)/PhP(O)HOR/O2）用于合成脱碳木脂素类化合物，考察了反应的影响因素，优化了反应条件，同时在该催化体系作用下，本反应能够实现产物的空间选择性且反应产物为反式结构。另外，在此基础上借鉴了布氏酸催化二聚反应的机理，进一步开发了新的催化体系（H+/PhP(O)HOR），该体系不但能够实现反应产物的空间选择性，同时也大大提高了反应的收率，所研究的催化体系易于制备，实验方法简便、可行，为进一步开展工业化生产奠定基础。本论文应用1H NMR,13C NMR, HPLC-MS以及元素分析等方法对合成的脱碳木脂素类化合物进行表征，同时考察了它们对人肝癌细胞Bel-7402、人乳腺癌细胞MCF-7、人肺癌细胞A549和人宫颈癌细胞Hela的体外抗癌效果。主要研究内容如下：
1．Mn(II)/Co(II)/PhP(O)HOR/O2催化芳基烯烃类化合物的二聚反应研究
在新催化体系确立的基础上，本论文通过逐一考察单个组分对反应的影响，探索发生该反应的必要条件。结果表明，Mn(II)、Co(II)、O2在反应中都缺一不可，同时PhP(O)HOR也作为催化剂与Mn(II)/Co(II)/O2共同作用，促进反应的发生。接着，作者进一步优化反应条件，经实验证明最佳反应条件为：以乙酸为溶剂，底物与PhP(O)HOR摩尔比为1：3，Mn(II)/Co(II)为原料摩尔量的5%，在持续通入氧气的条件下90oC反应24h，其中3a最高收率达76%。
基于以上研究结果，本论文考察了反应的适用范围，并对可能的反应机理进行了初步的推导。通过以带有不同取代基的芳基烯烃类化合物为原料进行反应，表明芳基烯烃类化合物带有供电基团更有利于反应的发生。在结合相关文献和实验数据的基础上，作者提出了该反应可能是以自由基的加成-消除反应机理进行的。
总之，本论文开发出了用于合成脱碳木脂素类化合物芳基烯烃二聚反应的新的催化体系，该体系相比较文献报道的方法，过渡金属用量更少，能够降低成本、减少污染，反应条件也更为温和。另外，与经典Mn(II)/Co(II)/O2体系催化合成有机膦化合物反应中PhP(O)HOR作为反应物相比，在该反应中PhP(O)HOR与Mn(II)/Co(II)/O2共同形成催化体系促进反应的完成。2．H+/PhP(O)HOR催化合成脱碳木脂素类化合物（3a-3g、3i、3j）方法研究
在结合文献报道应用布氏酸能够催化芳基烯烃类化合物的二聚反应，以及制备PhP(O)HOR过程中，同时也会产生布氏酸（HCl），因此作者以-细辛脑为原料通过应用未纯化的PhP(O)HOR为催化剂，开展二聚反应合成脱碳木脂素类化合物，经多种表征方法证实为目标产物，同时产物为反式构型，且最高产率达到95%。至此，本论文建立了H+/PhP(O)HOR催化芳基烯烃二聚反应的体系。
根据以上结果，作者通过逐一考察单个组分对反应的影响，探索发生该反应的必要催化条件。结果表明，单一酸催化虽然能够引发反应，但存在反应收率低、目标产物空间构型不具备选择性、副产物多等问题，而PhP(O)HOR的参与能够大大提高反应的收率、抑制副反应的发生、并对产物起到空间控制的作用。接着，作者进一步优化反应条件表明，本反应在室温和无溶剂的条件下同样能够得到高收率产物，经实验探索的最佳反应条件为：未纯化的PhP(O)HOR与α-细辛脑摩尔比为1:2，在室温无溶剂条件下反应2h。
基于以上研究结果，作者考察了反应的适用范围，并对可能的反应机理进行了初步的推导。通过以带有不同取代基的芳基烯烃类化合物为原料进行反应，表明芳基烯烃类化合物带有供电基团更有利于反应的发生。在结合相关文献和实验数据的基础上，作者提出了该反应可能是以酸催化形成碳正离子和PhP(O)HOR促进叔氢质子消去两个过程进行的。
总之，作者提出了H+/PhP(O)HOR的催化体系应用于合成脱碳木脂素类化合物，相比较传统布氏酸催化芳基烯烃二聚反应，该体系克服了单独酸催化条件下存在的问题，具有收率高、无副产物并且产物构型具有空间选择性等优点，同时基于PhP(O)HOR的合成特点，该催化体系易于制备，反应条件温和，实验方法简便、可行，并能避免应用过渡金属带来的毒性问题，为进一步工业化生产奠定了基础。
3.所合成脱碳木脂素类化合物（3a-3g）肿瘤抑制活性测定及作用机制分析
首先，本论文通过MTT法考察了所合成化合物对人肺癌细胞A549、人肝癌细胞Bel-7402、人宫颈癌细胞Hela和人乳腺癌细胞MCF-7的抗癌活性，检测表明，所合成脱碳木脂素类化合物对这些肿瘤细胞都具有一定的抑制作用，其中对人肝癌细胞Bel-7402的抑制效果最好，并且化合物3b的半数抑制浓度（IC50）为18.9g/mL，低于相同条件下的对照组紫杉醇的半数抑制浓度（28.0g/mL），说明针对Bel-7402细胞化合物3b表现出比紫杉醇更好的抑制作用。另外，我们以作用于Bel-7402细胞的IC50值分析了化合物结构与活性的关系，初步分析得出了该类化合物具备更高抗癌活性的基本骨架结构，即3f结构。
其次，作者以Bel-7402细胞为研究对象，应用Hoechst-PI双染色法和流式细胞仪法对化合物的抗癌作用机制进行了分析。化合物3a、3b、3c和3f作用Bel-7402细胞后，通过荧光显微镜可明显观察到凋亡细胞增多，核仁收缩，染色质浓缩呈肾形或新月型，并伴有凋亡小体的出现，而其它三种化合物细胞形态变化并没有上述四种明显，这也与它们对应的IC50值结果相吻合。这些结果从细胞形态学角度表明这些化合物对Bel-7402细胞的抑制可能是通过凋亡机制进行的。利用流式细胞仪对化合物作用后的细胞周期分析发现，这些脱碳木脂素类化合物表现出与紫杉醇相似的抑制作用，即将细胞周期阻断于G2期和M期而导致癌细胞死亡。
总之，本论文从化合物的抗癌活性、化合物作用后的细胞形态、细胞周期等对这些脱碳木脂素类化合物的生物活性和抗癌作用机制进行了初步分析。结果证实，这些脱碳木脂素类化合物对肿瘤细胞均有一定抑制作用，并可能通过凋亡机制杀死癌细胞，表现出与紫杉醇类似的抑制作用。另外，研究表明，3f的结构为该类化合物具备更高抗癌活性的基本骨架。值得注意的是，针对Bel-7402细胞化合物3b表现出比紫杉醇更好的抑制效果，因此3b具有较为广阔的研究应用价值。
Lignans are a class of natural products with potent antiviral, antitumor,antioxidant and antiinflammatory properties, and they are widely distributed in theplant kingdom and found in roots, rhizomes, stems, leaves, seeds and fruits. It has beenreported many compounds with phenylpropane units, the basic molecular backbone oflignans, exhibit the similar biological activity as that of lignans. Therefore,methodology for the synthesis of these compounds has been received widespreadinterest.
In this study, we have developed novel methodologies for dimerization of styrenesto1,3-diaryl-1-butenes, the basic molecular backbone of norlignans, and investigatedtheir biological assay.1,3-diaryl-1-butenes are generally prepared by dimerization ofstyrene derivatives via transition-metal catalysts or Br nsted acid catalysts. ButBr nsted acid catalytic dimerization of styrenes affords the mixtures of E, Z-isomersand subsequent byproducts in moderate yield such as indan derivatives or higheroligomers through carbocation process. Although many potent and selectivetransition-metal catalysts have been developed, the limited availability of these metalsas well as their high price and significant toxicity restricts their large-scaleapplications of this reaction. Therefore, we hope to develop novel and multiple catalystsystems for such type of dimerization.
First, we have developed dimerization of styrenes (-asarone based compunds)proceeded by a novel catalyst system of Mn(II)/Co(II)/O2combined with alkylphenylphosphinate, PhP(O)HOR. We next have investigated the optimizedexperimental conditions and a series of stereoselective E-dimer of styrenes basedcompounds have been synthesized. Second, in connection with our previousinvestigation of dimerization of styrenes catalyzed by PhP(O)HOR/Mn(II)/Co(II)/O2,an interesting acid-catalyzed/PhP(O)HOR-promoted dimerization of styrenes hasbeen discovered which involves giving the exclusive E-isomers of head-to-taildimers in excellent yield. The procedure has offered simplicity in operation withregard to facile catalyst system and solvent-free condition. The structure of dimers hasbeen characterized by1H NMR,13C NMR and HPLC-MS. The biological activity ofproducts has been measured by MTT assay using human hepaioma Bel-7402cells,human breast adenocarcinoma MCF-7cells, human lung carcinoma A549cells andhuman cervical carcinoma HeLa cells. The experimental results are as follows:
1. The dimerization of styrenes catalyzed by Mn(II)/Co(II)/PhP(O)HOR/O2
Due to the discovered experiment, we have aimed to test the effects of individualcatalytic factor on the reaction. This result has demonstrated that the dimerizationrequires a synergistic relationship between styrenes, alkyl phenylphosphinate andMn(II)/Co(II)/O2redox system. The optimized condition is: the molar ratio of styrenesto PhP(O)HOR=1:3, the molar amount of Mn(II)/Co(II) is5%that of substrate, at90°C for24h under oxygen condition.
We have further investigated the influence of styrene-based compounds withdifferent substituents on the scope and limitations of dimerization. It is shown thatsubstrate with electron-donating groups preferred the reaction. And it is found that thepresent dimerization of styrenes would proceed via a radical mechanism involving anaddition–elimination sequence.
Taken together, we have found that dimerization of styrenes proceeded by a novelcatalyst system of Mn(II)/Co(II)/O2combined with alkyl phenylphosphinate,PhP(O)HOR, in which PhP(O)HOR acts as a co-catalyst rather than a substrate forhydrophosphorylation of styrenes. Mechanistic studies suggestes the reaction mostlikely proceeded via addition–elimination.2. The dimerization of styrenes catalyzed by H+/PhP(O)HOR
It was suggested that a simple synthesis for PhP(O)HOR with hydrochloric acidresidues by the addition of phenyldichlorophosphine to alcohol. Drawing inspirationsfrom dimerization via Br nsted acid catalysts, we have conducted the dimerization ofstyrenes using unpurified PhP(O)HOBu as catalyst and the E-isomer of dimer isexclusively obtained in good yield (95%).
Due to the discovered experiment, we have systematically examined individualcatalytic factors. It is shown lack of acid catalysis or acid catalysis in the absence ofPhP(O)HOBu resulted in no or slow reaction, demonstrating acid catalysis makessignificant contribution to this kind of reaction, and PhP(O)HOBu further promotesthe formation of styrene dimer. Meanwhile, in the presence of PhP(O)HOBu, thebyproduct can be completely suppressed under independent acid condition andstereoselective E-dimers have been obtained. The studied dimerization efficientlyoccurs the molar ratio of ratio of styrenes to unpurified PhP(O)HOR=1:3,solvent-free condition and room temperature.
We have further investigated the influence of styrene-based compounds withdifferent substituents on the scope and limitations of dimerization. It is shown thatsubstrate with electron-donating groups preferred the reaction. Mechanism study indicates the combined H+/PhP(O)HOR catalyst system plays pivotal dual roles, theformation of carbonium ion intermediate catalyzed by acid and PhP(O)HOR-promotedtertiary hydrogen elimination.
In conclusion, we have developed a novel and efficient acid-catalyzed/PhP(O)HOR-promoted styrene dimerization, in which a series of stereoselective E-dimer of substituted styrenes can be synthesized with good yield under mild and
solvent-free condition. Based on the synthesis of PhP(O)HOR with hydrochloric
acid residues, H+/PhP(O)HOR is a readily available catalyst system requiringno further purification facilitating to simply reaction procedure.3. Biological activity assay of products and investigation of their anticancermechanism
Cytotoxicity has been studied by using an MTT assay to identify Bel-7402cells,MCF-7cells, A549cells and HeLa cells still active in respiration. It is shown thatproducts exhibit cytotoxicity to cells; especially,3b treated with Bel-7402cells showslower cytotoxicity (IC50:18.9g/mL) than free paclitaxel (28.0g/mL). In addition,we have analyzed the relationship between structure and activity based on the result ofIC50. It was indicated that a basic backbone with anticancer activity is3f.
We have preliminarily investigated anticancer mechanism of products usingBel-7402cells by Hoechst-PI dual staining and flow cytometry method. Fromfluorescent image, it is observed the decreased amount of apoptotic cells, nuclearshrinkage, chromatic condensation, and apoptotic body formation when cells treatedwith3a,3b,3c and3f. In contrast, cell morphology treated with other threecompounds changed little, which is consistent with the result of IC50. From cellmorphology initial analysis, apoptosis mechanism of synthesized products may inducecell death. From result of cell cycle as measured by flow cytometry assay, thesynthesized products exhibit the same cytotoxic activity as paclitaxel, which can causecell cycle arrest in the G2/M phase and finally cell death through apoptosismechanism.
In summary, we have analyzed biological activity and anticancer mechanism bycytotoxicity, cell morphology and cell cycle. It is indicated that products exhibitcytotoxicity to cancer cells, especially Bel-7402cells. The synthesized products causecell death by apoptosis mechanism. It is worth noting that3b can be a promisinganticancer agent for application of cancer chemotherapeutic drugs.
引文
[1] Stahelin H. Activity of a new glycosidic ligand derivative (VP-16-213) relatedto podophyllotoxin in experimental tumors. European Journal of Cancer,1973,9:215-221.
[2] Harvey A L. Medicines from Nature: are natural products still relevant to drugdiscovery? Trends in Pharmacological Sciences,1999,20:196-198.
[3] Noble R L. The discovery of the vinca alkaloids-chemotherapeutic agentsagainst cancer. Biochemistry and Cell Biology,1990,68:1344-1351.
[4] Devita V T J, Serpick A A, Carbone P O. Combination chemotherapy in thetreatment of advanced Hodgkin’s disease. Annals of Internal Medicine,1970,73:881-895.
[5] Ma Mei-fagn, Yu T, Dai Shao-jun, et al. Determination of contents of10-Hydroxycamptothecin in camptotheca acuminate by high-performanceliquid chromatogram. Journal of Forestry Research,2002,13:144-146.
[6] Wang A X, Li S. Hydroxycamptothecin-loaded nanoparticles enhance targetdrug delivery and anticancer effect. BMC Biotechnology,2008,8:46-48.
[7] Hearon W M, Macgregor W S. The naturally occurring lignans. ChemicalReviews,1995,55:957-1068.
[8]马辰,罗淑荣.鬼臼植物中木脂素类化合物的研究进展.中草药,2000,31:229-231.
[9]冯瑞红.沙地柏中木脂素化合物的分离及杀虫活性研究[D].陕西杨凌:西北农林科技大学无公害农药研究服务中心，2007.
[10]王彬,贾正平,蔡文清等.瑞香狼毒总木脂素的体外抗肿瘤活性.兰州大学学报(自然科学版),2008，44:63-65.
[11]杨华,蔡于深,庞冀燕等.苯并呋喃类木脂素衍生物通过抑制细胞周期蛋白质活性诱导MCF-7细胞G2/M期阻滞及凋亡.广西医科大学药学学报,2008,43:138-144.
[12] Power K A, Saarinen N M, Chen J M, et al. Mammalian lignans enterolactoneand enterodiol, alone and incombination with the isofiavone genistein, do notpromote the growth of MCF-7xenografts in ovariectomized athymic nude mice.Int J Cancer,2006,118:1316-1320.
[13] Prasad K. Antioxidant activity of secoisolariciresinol diglucosidederivedmetabolites, secoisolariciresinol, enterodiol, and enteorlactone. Int J Angiol,2000,9:220-222.
[14]李欣,袁建平,刘昕等.木脂素---一类重要的天然植物雌激素.中国中药杂志,2006,31:2021-2025.
[15] Westcot N D, Muir A D. Flax seed lignan in disease prevention and healthpromotion. Phytochemistry Rev,2003,5:401-403.
[16] Niemeyer H B, Metzler M. Differences in the antioxidant activity of plant andmammalian lignans. J Food Eng,2003,56:255-260.
[17] Pool-Zobel B L, Adlercerutz H, Glei M, et al. Isoflavonoids and lugnans havedifferent potentials to modulate oxidative genetic damage in human colon cells.Carcinogenesis,2000,21:1247-1250.
[18] Moss G P. Nomenclature of lignans and neolignans. Pure and AppliedChemistry,2000,72:1493-1523.
[19] Hyun S B, Sanghyun L, Yong P K, et al. Inhibition of prostaglandin E2production by taiwanin C isolated from the root of acanthopanax chiisanensisand the mechanism of action. Biochemical Pharmacology,2002,64:1345-1354.
[20] Ahmed R, Lehrer M, Stevenson R. Synthesis of thomasic acid. Tetrahedron,1973,29:3753-3759.
[21] Klyne W, Stevenson R, Swan R J. Optical rotatory dispersion. Part XXVIII.The absolute configuration of otobain and derivatives. Journal of the ChemicalSociety C: Organic,1966,0:893-896.
[22] Li L, Meng F H, Guo J F, et al. Simultaneous quantification of tracheloside andtrachelogenin in rat plasma using liquid chromatography/tandem massspectrometry. Journal of Chromatography B Analytical Technologies in theBiomedical and Life Sciences.2007,879:1033-1037.
[23] Nishibe S, Tsuha T, Takasaki M, et al. Transformation to epitrachelogeninmethyl ether from teachelogenin methyl ether. Nature Medicine,2002,56:13-16.
[24] KhamLach K, Dhal R, Brown E. Total syntheses of (-)-trachelogenin,(-)-nortrachelogenin and (+)-wikstromol.1989,30:2221-2224.
[25] Tang X, Zhang J J, Chen J, et al. Arctigenin efficiently enhanced sedentarymice treadmill endurance. Plos One,2011,6:242-244.
[26] Huang S L, Yu R T, Gong J, et al. Arctigenin, a natural compound, activatesAMP-activated protein kinase via inhibition of mitochondria complex I andameliorates metabolic disorders in ob/ob mice. Diabetoloqia,2012,55:1469-1481.
[27]陈宁,吴安心,田元等.芳基不同型双并四氢呋喃木脂素的新合成方法.高等学校化学学报.1997,18:416-417.
[28] Mcrae W D, Towers G H N. Biological activities of lignans. Phytochemistry,1984,23:1207-1220.
[29] Liu J S, Huang M F, Gao Y L, et al. The structure of chicanine, a new lignanfrom a chisandra. Canadian Journal of Chemistry,1981,59:1680-1684.
[30] Rimando A M, Rezzuto J M, Ramsworth N R, et al. New lignans fromanogeissus acuminate with HIV-1reverse transcriptase inhibitory activity.Journal of Natural products,1994,57:896-904.
[31] Luo M M, Matsui A, Esumi T. et al. Concise synthesis of anolignan A.Tetrahedron Letters,2000,41:4401-4402.
[32]刘嘉森,黄梅芬.华中五味子的研究——IV.安五酸和dl-安五脂素的结构及d-表加巴辛的绝对构型.化学学报,1984,42:264-270.
[33] Ho Pai-Jiun, Chou Chen-Kung, Kuo Yueh-Hsiung, et al. Taiwanin A inducedcell cycle arrest and p53-dependent apoptosis in human hepatocellularcarcinoma HepG2cells. Life Sciences,2007,80:493-503.
[34] Shyur L F, Lee S H, Chang S T, ea al. Taiwanin A inhibits MCF-7Cancer cellactivity through induction of oxidative stress, upregulation of DNA damagecheckpoint kinases, and activation of p53and Fasl/Fas signaling pathways.Phytomedicine,2010,15:16-24.
[35] Hu W, Li L, Wagn Q, et al. Dibenzocyclooctadiene lignans from kadsuracoccinea. Journal of Asian Natural Products Research,2012,14:364-369.
[36]刘嘉森,马玉廷.神农架地区五味子科植物成分的研究III：五味子酯G, H和I的分离与结构研究.化学学报,1988,46:465-471.
[37] Micard V, Grabber J H, Ralph J. Dehydrodiferulic acids from sugar-beet pulp.Phytochemistry,1997,44:1365-1368.
[38] Zhen Y, Po M H. Naturally occurring benzofuran: isolation, structureelucidation and total synthesis of5-(3-hydroxypropy-7-methoxy-2-(3-methoxy-4’-hydroxyphenyl)-3-benzobfurancarbaldehyde, a novel adenosineA1receptor ligand isolated from salvia miltiorrhiza bunge(danshen).Tetrahedron Letters,1991,32:2061-2064.
[39] Fukuyama Y, Nakahara M, Minami H, et al. Two new benzofuran-Type lignansfrom the wood of viburnum awabuki. Chemical＆Pharmaceutical Bulletin,1996,44:1418-1420.
[40] Fernandes J B, Ribeiro M N, Gottlieb O R, et al. Eusiderins and1,3-diarylpropanes from virola species. Phytochemistry,1980,19:1523.
[41] Motter M F M, Kato M J, Massayoshi Y. Butanolides and a neolignan from thefruits of iryanthera paraensis huber. Phytochemistrry,1996,43:669-671.
[42] Ramasamy K, Agarwal R. Multitargeted therapy of cancer by silymarin. CancerLetters,2008,269:352-362.
[43] Lee W S, Baek Y I, Kim J R, et al. Antioxidant activities of a new lignan andaneolignan from saururus chinensis. Bioorganic＆Medicinal ChemistryLetters,2004,14:5623-5628.
[44] Barata L E S, Baker P M, Gottlieb O R, et al. Neolignans of Virolasurinamensis.Phytochemistry,1978,17:783-786.
[45] Diaz Pedro S P, Massayoshi Y, Otto R G. Neolignans from Aniba lancifolia.Phytochemistry,1980,19:285-288.
[46] Thomas M W, Sheila I, Mccrae. The effect of acetyl groups on the hydrolysis ofryegrass cell walls by xylanase and cellulose from trichoderma koningii.Phytochemistry,1985,24:1051-1055.
[47] G Kotani A, Kojima S, Hakamata H, et.al. Determination of honokiol andmagnolol by micro HPLC with electrochemical detection and its application tothe distribution analysis in branches and leaves of magnolia obovata. Chem.Pharm. Bull.2005,53:319-322.
[48] Fukuyama Y, Otoshi Y, Miyoshi K, et al. Neurotrophicsesquiterpene-neolignans from magnoliaobovata: structure and neurotrophicactivity. Tetrahedron1992,48:377-392.
[49] Cheng H I, Duh C Y, Lee K H. New Cytotoxic Butanolides from Litseaacutivena. Journal of natural Products,2001,64:1502-1505.
[50] Enzell C R, Thomas B R. The wood resin of agathis australis. Acta ChemicalScandinavica,1965,19:913-919.
[51] Suzuki S, Umezawa T, Shimada M. Stereochemical diversity in lignanbiosynthesis and establishment of norlignan biosynthetic patheay. Bioscience,Biotechnology, and Biochemistry.2002,66:1262-1269.
[52] Yamamura M, Suzuki S, Hattori T, et al. Subunit composition of hinokiresinolsynthase controls enantiomeric selectivity in hinokiresinol formation. Orgnic＆Biomolecular Chemistry,2010,8:1106-1110.
[53] Emiko M, Motohiko T, Sachiko T, et al. Stereochemistry of cis-andtrans-Hinokiresinol and their estrogen-like activity. Chemical＆Pharmaceutical Bulletin,2000,48:389-392.
[54] Su B N, Zhu Q X, Jia Z J. A new nor-neolignan from Cremanthodium ellisii.Chinese Chemical Letters,1999,10:129-130.
[55]刘长军,侯嵩生.抗癌活性物质鬼臼木脂素的研究进展.天然产物研究与开发,1997,19:81-83.
[56]崔银姬.木脂素对MCF-7乳腺癌细胞抗增殖作用及其机制的研究[D].吉林延吉:延边大学基础医学院病理学研究部,2010.
[57] Tsai L L, Lee F P, Wu C C, et al. New cytoxic cyclobutanoid amides, a newfuranoid lignans and anti-platelet aggregation constituents from piperarborescens. Planta Medica,2005,71:535-542.
[58]杨毅,张成路,潘鑫复.木脂素抗艾滋病病毒研究.化学进展,2003,15:327-331.
[59] Gnabre J N, Ito Y, Ma Y, et al. Isolation of anti-HIV-1lignans from larreatridentate by counter-current chromatography. Journal of chromatography A,1996,719:353-364.
[60] Zhang T M, Wang B E, Liu G T. Effect of schisandrin B on lipoperoxidativedamage to plasma membrane of rat liver in vitro. Acta Phamacol Sin,1992,13,255-260.
[61]刘华英,北五味子木脂素提取工艺及提取物抑菌作用的研究[D].长春:吉林农业大学资源与环境学院,2006.2006.
[62]天津医学院寄生虫教研室.40种中草药体外杀猪蛔虫作用的初步实验观察.新医药学杂志,1994,2:31-33.
[63]王岳.70种药用植物抗菌效能的试验.植物学报,1994,3:121-135.
[64]韩桂秋,马迎,李长龄.胡椒属植物中木脂素类血小板活化因子拮抗活性成分及构效关系的研究,北京医科大学学报,1992,24:347-350.
[65] Benveniste J, Henson P M, Cochrane C G. Leukocyte-dependent histaminerelease from rabbit platelets. The role of lgE, basophils, and aplatelet-activating factor. The Journal of Experimental medicine,1972,136:1356-1377.
[66]林琎.脱氧鬼臼毒素杀虫作用机理初步研究[D].陕西杨凌:西北农林科技大学无公害农药研究服务中心,2004,25-26.
[67] Kao Chai-Lin, Chern Ji-Wagn. A novel strategy for the synthesis of benzofuranskeleton neolignans: application to ailanthoidol, XH-14, and obovaten. TheJournal of Organic Chemistry,2002,67:6772-6787.
[68] L ü tjens H, Scammells P J. Synthesis of natural products possessing abenzo[b]furan skeleton. Tetrahedron Letters,1998,36:6581-6584.
[69]庞冀燕,汪波,许遵乐.2-取代芳基苯并[b]呋喃类化合物的合成.有机化学，2005,25:176-181.
[70]汪秋安,张红,王力.新型苯并呋喃新木脂素类化合物的合成研究.湘潭大学自然科学学报,2007,29,71-74.
[71] Lemière G, Gao M, Groot A D.3’,4-Di-O-methylcedrusin: synthesis, resolutionand absolute configuration. Journal of the Chemical Society, PerkinTransactions1,1995:1775-1779.
[72] Yang Z, Liu H B, Lee, C M. Compounds from danshen. Part7. regioselectiveintroduction of carbon-3substituents to5-alkyl-7-methoxy-2-phenylbenzo[b]furans: synthesis of a novel adenosine A1receptor ligand and its derivatives. The Journal of Organic Chemistry,1992,57:7248-7257.
[73] Patricia M P, Angela R A, Maria C M Y. nor-lignans from the leaves of styraxferrugineus (styracaceae) with antibacterial and antifungal activity.Phytochemistry,2000,55:597-601.
[74] Yurdanur Y A, Huseyin A. benzofurans and another constituent from seeds ofstyrax officinalis. Phytochemistry,2003,63:939-943.
[75] Nikaido T, Ohmoto T, Noguehi H, et al. Inhibitors of cyclic AMPphosphodiesterase in medicinal plants. Planta Medica,1981,43:18-23.
[76] Bemcierta A P, Whiting D A. Stereoselective total syntheses of the di-O-methylethers of agataresinol, sesquirin-A, and hinokiresinol, and oftri-O-methylsequirin-E, characteristic norlignans of coniferae. Journal of theChemical Society Perkin Transactions,1978,1:1257-1263.
[77] Muraoka O, Zheng B Z, Fujiwara N, et al. Enantioselective total synthesis ofthe di-O-methyl ethers of (-)-agatharesinol,(+)-hinokiresinol and(-)-sugiresinol, characteristic nodignans of coniferae. Journal of the ChemicalSociety Perkin Transactions,1996,5:405-411.
[78] Brown E, Dujardin G, maudet M. Asymmetric Endoselective [4+2]Heterocycloadditions of styrenedienophiles with chiral benzylidenepyruvicesters. Total synthesis of (-)-O-dimethylsugiresinol. Tetrahedron,1997,53:9679-9694.
[79] Matsuo K, Sugimura W, Shimizu Y, et al. Synthesis of (-)-sugiresinol dimethylether utilizing(-)-quinic acid. Heterocyeles,2000,53:1505-1513.
[80] Barros M T, Maycock C D, Ventura M R. Enantioselective total synthesis of(+)-eutypoxide B. The Journal of Organic Chemistry.1997,62:3984-3988.
[81] Evans P A, Leahy D K. Regioselective and enantiospecific Rhodium-catalyzedallylic alkylation reactions using copper(1) enolates: synthesis of(-)-sugiresinol dimethyl ether. Journal of the American Chemical Society.2003,125:8974-8975.
[82]权伟国.(-)-Heliconol A、Kawain类、二氢异香豆素类及脱碳木脂素类化合物的全合成研究[D].兰州:兰州大学化学化工学院2007.
[83] Tsuji J. Palladium reagents and catalysts: new perspectives for the21st century.John Wiley＆Sons, Chichester.2004.
[84] Grenoulllet P, Nelbecker D, Tkatchenko I. Catlonlc allylmetal complexes.9.1dimerization acrylates catalyzed by allylpalladlum complexes. Role of theligand and indirect evidence for the occurrence of hydridopalladium species.Organometallics.1984,3:1130-1132.
[85] Sen A, Lai Ta-Wang, Thomas R R. Reactions of electrophilic transition metalcations with olefins and small ring compounds. Rearrangements andpolymerizations. Journal of Organometallic Chemistry.1988,358:567-588.
[86] Kiyotomi K, Tadao K, Tadasshi H. Preparation of divalent Pd(II) species onsepiolite and its catalysis of olefin dimerizations. Journal of MolecularCatalysis,1988,48:343-347.
[87] Jiang Z Z, Sen A. Tailored cationic Palladium(II) compounds as catalysts forhighly selective linear dimerization of styrene and linear polymerization ofp-divinylbenzene. Journal of the American Chemical Society.1990,112:9655-9657.
[88] Jiang Z Z, Sen A. Tailored cationic palladium(II) compounds as catalysts forhighly selective dimerization and polymerization of vinylic monomers:synthetic and mechanistic aspects. Organometallics,1993,12:1406-1415.
[89] Tsuchimoto T, Kamiyama S, Negoro R. Palladium-catalysed dimerization ofvinylarenes using indium triflate as an effective co-catalyst. ChemicalCommunication,2003,7:852-853.
[90] Bedfor R B, Betham M, Blake M E. Asymmetric styrene dimerisation usingmixed palladium-indium catalysts. Tetrahedron,2005,61:9799-9807.
[91] Nishiwaki N, kamimura R, hosokawa T, et al. Efficient double bond migrationof allylbenzenes catalyzed by Pd(OAc)2-HFIP system with unique substituenteffect. Tetrahedron letters,2010,51:3590-3592.
[92] Fanfoni L, Meduri A, Zangrando E, et al. New chiral P-N ligands for theregion-and stereoselective Pd-catalyzed dimerization of styrene. Molecules,2011,16:1804-1824.
[93] Yamada S, Obora Y, Sakaguchi S, et al. A new type of carbonylation of styrenescatalyzed by Pd(OAc)2combined with molybdovanadophosphate. Bulletin ofthe Chemical Society of Japan,2007,80:1194-1198.
[94] Bruce P, Giang Vo-Thanh, Didier G, et al. First application of chiral ionicliquids in asymmetric baylis-hillman reaction. Tetrahedron Letters,2004,45:6425-6428.
[95] Baudoux J, Judeinstein P, Cahard D, et al. Design and synthesis of novel ionicliquid/liquid crystals (IL2Cs) with axial chirality. Tetrahedron Letters,2005,46:1137-1140.
[96] Ishida Y, Sasaki D, Miyauchi H, et al. Design and synthesis of novelimidzaolium-based ionic liquids with a pseudo crown-ether moiety:diastereomeric interaction of a racemic ionic liquid with enantiopure europiumcomplexes. Tetrahedron Letters,2004,45:9455-9459.
[97] Gadenne B, Hesemann P, Moreau J J E. lonic liquids incorporatingcamphorsulfonamide units for the Ti-promoted asymmetric diethylzinc additionto benzaldehyde. Tetrahedron Letters,2004,44:8157-8160.
[98] Kim E J, Ko S Y, Dziadulewicz E K. Mitsunobu alkylation of imidazole: aconvenient route to chiral ionic liquids. Tetrahedron Letters,2005,46:631-633.
[99] Ishida Y, Miyauchi H, Saigo K. Design and synthesis of a novelimidazolium-based ionic liquid with planar chirality. Chemical communication,2002,19:2240-2241.
[100] Levillain J, Dubant G, Abrunhosa I, et al. Synthesis and properties of thiazolinebased ionic liquids derived from the chiral pool. Chemical Communication,2003,23:2914-2915.
[101] Anthony M L, Stephanie C W, Mary E W, et al. An lonic liquid form of DNA:redox-active molten salts of nucleic acids. Journal of the American Society,2001,123:218-222.
[102] Bao W L, Wang Z M, Li Y. Synthesis of chiral lonic liquids from natural aminoacids. The journal of Organic Chemistry,2003,68:591-593.
[103] Ding J, Desikan V, Han X X. et al. Use of chiral lonic liquids as solvents for theenantioselective photoisomerization of dibenzobicyclo[2,2,2]octatrienes.Organic Letters,2005,7:335-337.
[104] Schrōder U, Wadhawan J D, Compton R G. et al. Water-induced accelerated iondiffusion: voltammetric studies in1-methyl-3-[2,6-(S)-dimethylocten-2-yl]imidazolium tetrafluoroborate,1-butyl-3-methylimidazolium tetrafluoroborateand hexafluorophosphate ionic liquids. New Journal of Chemistry,2000,24:1009-1016.
[105] Wadhawan J D, Schroder U, Neudeck A, et al. Lonic liquid modified electrodes.Unusual partitioning and diffusion effects of Fe(CN)64-/3-in droplet and thinlayer deposits of1-methyl-3-(2,6-(S)-dimethylocten-2-yl)-imidazoliumtetrafluoroborate. Journal of Electroanalytical Chemistry,2000,493:75-83.
[106] Kabalka G W, Dong G, Venkataiah B. investigation of the behavior ofarenediazonium salts with olefins in BMimPF6. Tetrahedron Letters,2004,45:2775-2777.
[107] Peng J J, Li J Y, Lai G Q, et al. Dimerization of styrene to1,3-diphenyl-1-butene catalyzed by Pdlladium-Lewis acid in ionic liquid.Journal of Molecular Catalysis A: Chemical,2006,255:16-18.
[108] Sivulka D J, Seikop S K. Reconstruction of historical exposures in the usNickel alloy industry and the implications for carcinogenic hazard and riskassessments. Regulatory Toxicology and Pharmacology,2009,53:174-185.
[109] Prosper M’Bemba-Meka, Nicole L, Saroj K C. Nickel compound-induced DNAsingle-strand breaks in chromosomal and nuclear chromatin in human bloodlymphocytes in vitro: role of oxidative stress and intracellular calcium.Mutation Research/Genetic Toxicology and Environmental mutagenesis,2005,586:124-137.
[110] Sivulka D J, Conard B R, Hall G W, et al. Species-specific inhalable exposuresin the Nickel industry: A new approach for deriving inhalation occupationalexposure limits. Regulatory Toxicology and Pharmacology,2007,48:19-34.
[111] Patierno S R, Dirscherl L A, Xu J. Transformation of rat tracheal epithelialcells to immortal growth variants by particulate and soluble Nickel compounds.Mutation Research/Genetic Toxicology,1993,300:179-193.
[112] Agatzini-Leonardou S, Tsakiridis P E, Oustadakis P, et al. Hydrometallurgicalprocess for the separation and recovery of nickel from sulphate heap leachliquor of nickeliferrous laterite ores. Minerals Engineering,2009,22:1181-1192.
[113] Das G K, Lange J A B D. Reductive atmospheric acid leaching of westAustralian smectitic nickel laterite in the presence of sulphur dioxide andcopper(II). Hydrometallurgy,2011,105:264-269.
[114] Dawans F. Dimerisation stereospecifique du styrene en presence deBis(trifluoroacetate de Nickel-allyle). Tetrahedron Letters,1971,22:1943-1946.
[115] Ascenso J, Dias A R, Gomes P T, et al. Cationic3-allylmetal complexes,12.Oligomerization of styrene with cationic allylnickel compounds: catalysts,products and the influence of phosphines. Macromolecular Chemistry andphysics,1989,190:2773-2787.
[116] Ascenso J, Carrondo M A A F De C T, Dias A R, et al. Cationic benzyl nickelcomplexes as homogeneous catalysts for styrene oligomerization. X-ray crystalstructure of [Ni(3-CH2C6H5)(PPh3)2]PF6·CH2Cl2. Polyhedron,1989,8:2449-2457.
[117] Yi C Y, Hua R M, Zeng H X. Efficient and selective nickel(II)-catalyzed tail-tohead dimerization of styrenes affording1,3-diaryl-1-butenes. CatalysisCommunications,2008,9:85-88.
[118] Higashimura M, Imamura K, Yokogawa Y, et al. Novel dimerization,alkoxylation, and sulfidation of olefins catalyzed by RuCl3·nH2O. ChemistryLetters,2004,33:728-729.
[119] Lee D W, Yi C S. Chain-selective and regioselective ethylene and styrenedimerization reactions catalyzed by a well-defined cationic ruthenium hydridecomplex: new insights on the styrene dimerization mechanism.Organometallics,2010,29:3413-3417.
[120] Fontaine M, Hubert A J, Noels A F, et al. Cobalt-catalysed dimerizaion ofstyrenes under syngas. Journal of Organometallic Chemistry,1991,417:C28-C31.
[121] Wang C C, Lin P S, Cheng C H. Cobalt-catalysed dimerization of alkenes.Tetrahedron Letters,2004,45:6203-6206.
[122] Jeganmohan M, Cheng C H. Cobalt-and nickel-catalyzed region andstereoselective reductive coupling of alkynes, allenes, and alkenes with alkenes.Chemistry-A European Journal,2008,14:10876-10886.
[123] Jose R, Corma A. Iron-catalyzed region and stereoselective head-to-taildimerisation of styrenes. Advanced Synthesis＆Catalysis,2010,352:1571-1576.
[124] Humphrey M B, Lamanna W M, Husk G R, et al. Crystal and molecularstructure of (eta.5-pentamethylcyclopentadienyl)(trifluoromethanesulfonato)Iron(II) dicarbonyl: a strong electrostatic iron-triflate interaction. InorgnicChemistry,1983,22:3355-3358.
[125] Williams D B, Stoll M E, Scott L B, et al. Coordination chemistry of thebis-(trifluoromethylsulfonyl)imide anion: molecular interactions in roomtemperature ionic liquids. Chemical Communications,2005,11:1438-1440.
[126] Yamamoto Y, Itonaga K. Versatile friedel-crafits-type alkylation of benzenederivatives using a molybdenum complex/ortho-chloranil catalytic system.Chemistry-A European Journal,2008,14:10705-10715.
[127] Vicente F, Hermenegildo G, Vicente M, et al. Carbenium ions generated uponadsorption of4-methoxystyrenes onto acid zeolites. A kinetic study.Tetrahedron,1998,54:3827-3832.
[128] Matsubara C, Kojima M. Effect of Co-adsorbed water on photodimerizationand photooxygenation of4-methoxystyrene included in NaY. TetrahedronLetters,1999,40:3439-3442.
[129] Sinha A K, Joshi B P, Acharya R. DDQ mediated one step dimerisation ofbeta-asarone or beta-asarone rich acorus calamus oil in the formation of novelneolignan. US Patent.0187306A1,2003.
[130] Kumar S A, Prasad J B, Acharya R. Formation of neolignan by DDQ mediateddimerisation of dihydroasarone. WO Patent.080551A1,2003.
[131] Iwahama T, Sakaguchi S, Ishii Y. Catalytic radical addition of ketones toalkenes by a metal-dioxygen redox system. Chemical Communication,2000,23:2317-2318.
[132] Kagayama T, Fuke T, Ishii Y, et al. A remarkable effect of bases on the catalyticradical addition of cyanoacetates to alkenes using a Mn(II)/Co(II)/O2redoxsystem. Bulletin of the Chemical society of Japan,2005,78:1673-1676.
[133] Hirase K, Iwahama T, Ishii Y, et al. Catalytic radical addition of carbonylcompounds to alkenes by Mn(II)/Co(II)/O2system. The Journal of OrganicChemistry,2002,67:970-973.
[134] Hirase K, Sakaguchi S, Ishii Y. Addition of carboxyalkyl radicals to alkenesthrough a catalytic process, using a Mn(II)/Co(II)/O2redox system. The Journalof Organic Chemistry,2003,68:5974-5976.
[135] Tayama O, Nakano A, Ishii Y, et al. Hydrophosphorylation of alkenes withdialkyl phosphates catalyzed by Mn(III) under air. The Journal of OrganicChemistry,2004,69:5494-5496.
[136] Kagayama T, Nakano A, Ishii Y, et al. Phosphonation of arenas with dialkylphosphates catalyzed by Mn(II)/Co(II)/O2redox couple. Organic letters,2006,8:407-409.
[137] Yuan C Y, Qi Y M. Studies on organophosphorus compounds. A facile synthesisof-amino-substituted benzylphosphonic and phosphinic acids by use ofthiophosphoramide. Synthesis,1986,10:821-825.
[138] Oleksyszyn J, Tyka R M, Astalerz P. Direct synthesis of1-aminoalkanephosphonic and1-aminoalkanephosphinic acids fromphosphorustrichloride or dichlorophosphines. Synthesis,1978,6:479-480.
[139] Green D, Patel G, Elgendy S, et al. The synthesis of1-aminobenzylphosphonicacids from benzylidiphenylmethylamines for use as structural units inantithrombotic tripentides. Tetrahedron,1994,50:5099-5108.
[140] Lu Shui-Yu, Hamerton I. Recentdevelopments in the chemistry of halogen-freeflameretardant polymers. Progress in Polymer Science,2002,27:1661-1712.
[141] Gao F, Tong L F, Fang Z P. Effect of a novel phosphorouse-nitrogen containingintumescent flame retardant on the fire retardancy and the thermal behaviour ofpoly(butylenes terephthalate). Polymer Degradation and Stability,2006,91:1295-1299.
[142]王彦林,王冬军.膨账型阻燃剂新戊二醇乙撑磷酰胺的合成.塑料助剂,2009,3:29-31.
[143] Nune S K, Tanaka M. Palladium-catalysed regioselective addition reaction ofethyl phenylphosphinate with terminal acetylenes: ligand and solventdependent regioselectivity. Chemical Communication,2007,27:2858–2860.
[144] Deprèle S, Montchamp J. Palladium-Catalyzed Hydrophosphinylation ofAlkenes and Alkynes. Journal of the American Chemical Society,2002,124:9386-9387.
[145] Xu Q, Zhao C Q, Han L B. Stereospecific Nucleophilic Substitution ofOptically Pure H-Phosphinates: A General Way for the Preparation of ChiralP-Stereogenic Phosphine Oxides. Journal of the American Chemical Society,2008,130:12648-12655.
[146] Han L B, Choi N, Tanaka M. Oxidative Addition of HP(O)Ph2to Platinum(0)and Palladium(0) Complexes and Palladium-Catalyzed Regio andStereoselective Hydrophosphinylation of Alkynes. Organometallics,1996,15:3259-3261.
[147] Stockland R A, Levine A M, Giovine M T, et al. Reductive Elimination fromMetal Phosphonate Complexes: Circumvention of Competing ProtonolysisReactions. Organometallics,2004,23:647-656.
[148] Han L B, Zhang C, Yazawa H, et al. Efficient and Selective Nickel-CatalyzedAddition of H-P(O) and H-S Bonds. Journal of the American Chemical Society,2004,126:5080-5081.
[149] Zhao C Q, Han L B, Tanaka M, et a1. Rhodium-CatalyzedHydrophosphorylation of Terminal Alkynes Leading to Highly SelectiveFormation of (E)-Alkenylphosphonates: Complete Reversal of Regioselectivityto the Palladium-Catalyzed Counterpart. Angewandte Chemie InternationalEdition,2001,40:1929-1933.
[150] Han L B, Zhao C Q, Tanaka M. Rhodium-Catalyzed Regio-and StereoselectiveAddition of Diphenylphosphine Oxide to Alkynes. The Journal of OrganicChemistry,2001,66:5929-5932.
[151] Reichwein J F, Patel M C, Pagenkopf B L. Rhodium-Catalyzed RegioselectiveOlefin Hydrophosphorylation. Organic Letters,2001,3(26):4303-4306.
[152] Han L B, Tanaka M. Palladium-Catalyzed Hydrophosphorylation of Alkynesvia Oxidative Addition of HP(O)(OR)2. Journal of the American ChemicalSociety,1996,118:1571-1572.
[153] Han L B, Zhao C Q, Onozawa S Y. Retention of configuration on the oxidativeaddition of P-H bond to platinum(0) complexes: The first straightforwardsynthesis of enantiomerically pure P-chiral alkenylphosphinates viapalladium-catalyzed stereospecific hydrophosphinylation of alkynes. Journal ofthe American Chemical Society,2002,124:3842-3843.
[154] Han L B, Zhao C Q. Stereospecific addition of P-H bond to alkenes: Asimplemethod for the preparation of (Rp)-phenylphinates. The Journal of OrganicChemistry,2005,70:10121-10123.
[155] Han L B, Mirzaei F, Zhao C Q, et al. High reactivity of a five-membered cyclichydrogen phosphonate leading to development of facile palladium-catalyzedhydrophosphorylation of alkenes. Journal of the American Chemical Society,2000,122:5407-5408.
[156] Han L B, Ono Y, Shimada S. Palladium-catalyzed dehydrogenative cis doublephosphorylation of alkynes with H-Phosphonate leading to(Z)-bisphosphoryl-1-alkenes. Journal of the American Chemical Society,2008,130:2752-2753.
[157] Xu Q, Han L B. Palladium-catalyzed asymmetric hydrophosphorylation ofnorbornenes. Organic letters,2006,8:2099-2101.
[158] Zhao C Q, Han L B, Tanaka M. Palladium-catalyzed hydrophosphorylation ofallenes leading to region-and stereoselective formation of allylphosphonates.Organometallics,2000,19:4196-4198.
[159] Mirzaei F, Han L B, Tanaka M. Palladium-catalyzed hydrophosphorylation of1,3-dienes leading to allylphosphonates. Tetrahedron Letters,2001,42:297-299.
[160] Asanuma T, Gotoh T, Tsuchida A, et al. Photosensitized dimerization ofstyrene derivatives by a cation radical transfer mechanism. Journal of theChemical Society, Chemical Communications,1977,14:485-486.
[161] Leung P S W, Teng Y, Toy P H. Chromatography-free wittig reactions using abifunctional polymeric reagent. Organic letters,2010,12:4996-4999.
[162]喻爱和,冯勋波,陈超越,等.合成-细辛脑的脱水剂选择.合成化学,2006,14:500-502.
[163] Wieczorek D J S, Boduszek B, Wielkopolski W A, et al. Herbicidal9-aminofluorene-9-phosphonates. Journal für Parktische Chemie,1987,329:165-170.
[164] Risi J, Gauvin D. Contribution a letude de lapolymerisation: II proprietes,mecanisme de formation et constitution des distyrenes et des polystyrenes.Canadian Journal of Research,1936,7:255-267.
[165] Schoepfle C S, Ryan J D. The polymerization of asymmetricaldiphenylethylene. The preparation of1,1,3-triphenyl-3-methylhydrindene.Journal of the American Chemistry,1930,52:4021-4030.
[166] Rosen M J. Studies on the dimerization of styrene in aqueous sulfuric acid. TheJournal of Organic Chemistry,1953,18:1701-1705.
[167] Corson B B, Dorsky J, Nickels J E, et al. Dimerization of styrene in thepresence and absence of solvent, The Journal of Organic Chemistry,1954,19:17-26.
[168] Benito A, Corma A, García H, et al. Dimerization of styrene catalyzed by acid12-membered ring zeolites. Applied Catalysis A: General,1994,116:127-135.
[169] Alok B, Gopalakrishna T. The Michaelis-Arbuzov rearrangement. ChemicalReviews,1981,81:415-430.
[170]刘增勋,刘舜尧,杨秀凤,等.一种新有机膦除草剂的合成与试验.化学工业与工程,1991,8:14-17.
[171] Ye M C, Li L P, Zhao Y F. Structural effects on the electrophile inducedcyclization of organophosphorus compounds. Phosphorus and Sulfur,1988,39:79-83.
[172]赵玉芬,尹应武,吉改姣,等.亚膦酸酯的特性及其应用.清华大学学报（自然科学版）,1992,32:75-85.
[173]段军飞,刘西洋,向建南,等.-氨基苯基膦酸酯衍生物的合成,合成化学,2006,14:588-590.
[174] Kubota T, Takahara T, Nagata M, et al. Colorimetric chemosensitivity testingusing sulforhodamine B. Journal of Surgical Oncology,1993,52:83-88.
[175] Lei S, Chien P Y, Sheikh S, et al. Enhanced therapeutic efficacy of a novelliposome-based formulation of Sn-38against human tumor models in SCIDmice. Anticancer Drugs,2004,15:773-778.
[176] Bjorkman K M, Karl D M. A novel method for the measurement of dissolvedadenosine and guanosine triphosphate in aquatic habitats: applications tomarine microbial ecology. Journal of Microbiological Methods,2001,47:159-167.
[177] Trudil D, Loomis L, Pdbon R, et al. Rapid ATP method for the screening andidentification of bacteria in food and water samples. Biocatalysis,2000,41:27-29.
[178]赵俊萍,张慧丽. LDH释放法测定NK细胞活性对红细胞的影响.肿瘤研究与临床,1999,12:203-204.
[179]张志斌,付晓光.紫杉醇对人胰腺癌细胞株BxPC-3增殖抑制作用的研究.中华肿瘤防治杂志,2007,4:1694-1697.
[180]林宜先,江曼,刘铭球,等.紫杉醇对Lewis肺癌抑制作用及其机理的研究.中国肺癌杂志,2000,3:205-207.
[181] Xiao Y C, Carmen P, Ying P H, et al. Synthesis and biological evaluation ofdimeric RGD peptide-paclitaxel conjugate as a model for integrin-targeted drugdelivery. Joural of Medicinal Chemistry,2005,48:1098-1106.
[182] Diergarten K, Dreps A. Taxol: A new antieoplastic agent. Onkologie,1993,16:329-337.
[183] Singla A K, Garg A, Aggarwal D. Paclitaxel and its formulations. InternationalJournal of Pharmaceutics,2002,235:179-192.
[2] Harvey A L. Medicines from Nature: are natural products still relevant to drugdiscovery? Trends in Pharmacological Sciences,1999,20:196-198.
[3] Noble R L. The discovery of the vinca alkaloids-chemotherapeutic agentsagainst cancer. Biochemistry and Cell Biology,1990,68:1344-1351.
[4] Devita V T J, Serpick A A, Carbone P O. Combination chemotherapy in thetreatment of advanced Hodgkin’s disease. Annals of Internal Medicine,1970,73:881-895.
[5] Ma Mei-fagn, Yu T, Dai Shao-jun, et al. Determination of contents of10-Hydroxycamptothecin in camptotheca acuminate by high-performanceliquid chromatogram. Journal of Forestry Research,2002,13:144-146.
[6] Wang A X, Li S. Hydroxycamptothecin-loaded nanoparticles enhance targetdrug delivery and anticancer effect. BMC Biotechnology,2008,8:46-48.
[7] Hearon W M, Macgregor W S. The naturally occurring lignans. ChemicalReviews,1995,55:957-1068.
[8]马辰,罗淑荣.鬼臼植物中木脂素类化合物的研究进展.中草药,2000,31:229-231.
[9]冯瑞红.沙地柏中木脂素化合物的分离及杀虫活性研究[D].陕西杨凌:西北农林科技大学无公害农药研究服务中心，2007.
[10]王彬,贾正平,蔡文清等.瑞香狼毒总木脂素的体外抗肿瘤活性.兰州大学学报(自然科学版),2008，44:63-65.
[11]杨华,蔡于深,庞冀燕等.苯并呋喃类木脂素衍生物通过抑制细胞周期蛋白质活性诱导MCF-7细胞G2/M期阻滞及凋亡.广西医科大学药学学报,2008,43:138-144.
[12] Power K A, Saarinen N M, Chen J M, et al. Mammalian lignans enterolactoneand enterodiol, alone and incombination with the isofiavone genistein, do notpromote the growth of MCF-7xenografts in ovariectomized athymic nude mice.Int J Cancer,2006,118:1316-1320.
[13] Prasad K. Antioxidant activity of secoisolariciresinol diglucosidederivedmetabolites, secoisolariciresinol, enterodiol, and enteorlactone. Int J Angiol,2000,9:220-222.
[14]李欣,袁建平,刘昕等.木脂素---一类重要的天然植物雌激素.中国中药杂志,2006,31:2021-2025.
[15] Westcot N D, Muir A D. Flax seed lignan in disease prevention and healthpromotion. Phytochemistry Rev,2003,5:401-403.
[16] Niemeyer H B, Metzler M. Differences in the antioxidant activity of plant andmammalian lignans. J Food Eng,2003,56:255-260.
[17] Pool-Zobel B L, Adlercerutz H, Glei M, et al. Isoflavonoids and lugnans havedifferent potentials to modulate oxidative genetic damage in human colon cells.Carcinogenesis,2000,21:1247-1250.
[18] Moss G P. Nomenclature of lignans and neolignans. Pure and AppliedChemistry,2000,72:1493-1523.
[19] Hyun S B, Sanghyun L, Yong P K, et al. Inhibition of prostaglandin E2production by taiwanin C isolated from the root of acanthopanax chiisanensisand the mechanism of action. Biochemical Pharmacology,2002,64:1345-1354.
[20] Ahmed R, Lehrer M, Stevenson R. Synthesis of thomasic acid. Tetrahedron,1973,29:3753-3759.
[21] Klyne W, Stevenson R, Swan R J. Optical rotatory dispersion. Part XXVIII.The absolute configuration of otobain and derivatives. Journal of the ChemicalSociety C: Organic,1966,0:893-896.
[22] Li L, Meng F H, Guo J F, et al. Simultaneous quantification of tracheloside andtrachelogenin in rat plasma using liquid chromatography/tandem massspectrometry. Journal of Chromatography B Analytical Technologies in theBiomedical and Life Sciences.2007,879:1033-1037.
[23] Nishibe S, Tsuha T, Takasaki M, et al. Transformation to epitrachelogeninmethyl ether from teachelogenin methyl ether. Nature Medicine,2002,56:13-16.
[24] KhamLach K, Dhal R, Brown E. Total syntheses of (-)-trachelogenin,(-)-nortrachelogenin and (+)-wikstromol.1989,30:2221-2224.
[25] Tang X, Zhang J J, Chen J, et al. Arctigenin efficiently enhanced sedentarymice treadmill endurance. Plos One,2011,6:242-244.
[26] Huang S L, Yu R T, Gong J, et al. Arctigenin, a natural compound, activatesAMP-activated protein kinase via inhibition of mitochondria complex I andameliorates metabolic disorders in ob/ob mice. Diabetoloqia,2012,55:1469-1481.
[27]陈宁,吴安心,田元等.芳基不同型双并四氢呋喃木脂素的新合成方法.高等学校化学学报.1997,18:416-417.
[28] Mcrae W D, Towers G H N. Biological activities of lignans. Phytochemistry,1984,23:1207-1220.
[29] Liu J S, Huang M F, Gao Y L, et al. The structure of chicanine, a new lignanfrom a chisandra. Canadian Journal of Chemistry,1981,59:1680-1684.
[30] Rimando A M, Rezzuto J M, Ramsworth N R, et al. New lignans fromanogeissus acuminate with HIV-1reverse transcriptase inhibitory activity.Journal of Natural products,1994,57:896-904.
[31] Luo M M, Matsui A, Esumi T. et al. Concise synthesis of anolignan A.Tetrahedron Letters,2000,41:4401-4402.
[32]刘嘉森,黄梅芬.华中五味子的研究——IV.安五酸和dl-安五脂素的结构及d-表加巴辛的绝对构型.化学学报,1984,42:264-270.
[33] Ho Pai-Jiun, Chou Chen-Kung, Kuo Yueh-Hsiung, et al. Taiwanin A inducedcell cycle arrest and p53-dependent apoptosis in human hepatocellularcarcinoma HepG2cells. Life Sciences,2007,80:493-503.
[34] Shyur L F, Lee S H, Chang S T, ea al. Taiwanin A inhibits MCF-7Cancer cellactivity through induction of oxidative stress, upregulation of DNA damagecheckpoint kinases, and activation of p53and Fasl/Fas signaling pathways.Phytomedicine,2010,15:16-24.
[35] Hu W, Li L, Wagn Q, et al. Dibenzocyclooctadiene lignans from kadsuracoccinea. Journal of Asian Natural Products Research,2012,14:364-369.
[36]刘嘉森,马玉廷.神农架地区五味子科植物成分的研究III：五味子酯G, H和I的分离与结构研究.化学学报,1988,46:465-471.
[37] Micard V, Grabber J H, Ralph J. Dehydrodiferulic acids from sugar-beet pulp.Phytochemistry,1997,44:1365-1368.
[38] Zhen Y, Po M H. Naturally occurring benzofuran: isolation, structureelucidation and total synthesis of5-(3-hydroxypropy-7-methoxy-2-(3-methoxy-4’-hydroxyphenyl)-3-benzobfurancarbaldehyde, a novel adenosineA1receptor ligand isolated from salvia miltiorrhiza bunge(danshen).Tetrahedron Letters,1991,32:2061-2064.
[39] Fukuyama Y, Nakahara M, Minami H, et al. Two new benzofuran-Type lignansfrom the wood of viburnum awabuki. Chemical＆Pharmaceutical Bulletin,1996,44:1418-1420.
[40] Fernandes J B, Ribeiro M N, Gottlieb O R, et al. Eusiderins and1,3-diarylpropanes from virola species. Phytochemistry,1980,19:1523.
[41] Motter M F M, Kato M J, Massayoshi Y. Butanolides and a neolignan from thefruits of iryanthera paraensis huber. Phytochemistrry,1996,43:669-671.
[42] Ramasamy K, Agarwal R. Multitargeted therapy of cancer by silymarin. CancerLetters,2008,269:352-362.
[43] Lee W S, Baek Y I, Kim J R, et al. Antioxidant activities of a new lignan andaneolignan from saururus chinensis. Bioorganic＆Medicinal ChemistryLetters,2004,14:5623-5628.
[44] Barata L E S, Baker P M, Gottlieb O R, et al. Neolignans of Virolasurinamensis.Phytochemistry,1978,17:783-786.
[45] Diaz Pedro S P, Massayoshi Y, Otto R G. Neolignans from Aniba lancifolia.Phytochemistry,1980,19:285-288.
[46] Thomas M W, Sheila I, Mccrae. The effect of acetyl groups on the hydrolysis ofryegrass cell walls by xylanase and cellulose from trichoderma koningii.Phytochemistry,1985,24:1051-1055.
[47] G Kotani A, Kojima S, Hakamata H, et.al. Determination of honokiol andmagnolol by micro HPLC with electrochemical detection and its application tothe distribution analysis in branches and leaves of magnolia obovata. Chem.Pharm. Bull.2005,53:319-322.
[48] Fukuyama Y, Otoshi Y, Miyoshi K, et al. Neurotrophicsesquiterpene-neolignans from magnoliaobovata: structure and neurotrophicactivity. Tetrahedron1992,48:377-392.
[49] Cheng H I, Duh C Y, Lee K H. New Cytotoxic Butanolides from Litseaacutivena. Journal of natural Products,2001,64:1502-1505.
[50] Enzell C R, Thomas B R. The wood resin of agathis australis. Acta ChemicalScandinavica,1965,19:913-919.
[51] Suzuki S, Umezawa T, Shimada M. Stereochemical diversity in lignanbiosynthesis and establishment of norlignan biosynthetic patheay. Bioscience,Biotechnology, and Biochemistry.2002,66:1262-1269.
[52] Yamamura M, Suzuki S, Hattori T, et al. Subunit composition of hinokiresinolsynthase controls enantiomeric selectivity in hinokiresinol formation. Orgnic＆Biomolecular Chemistry,2010,8:1106-1110.
[53] Emiko M, Motohiko T, Sachiko T, et al. Stereochemistry of cis-andtrans-Hinokiresinol and their estrogen-like activity. Chemical＆Pharmaceutical Bulletin,2000,48:389-392.
[54] Su B N, Zhu Q X, Jia Z J. A new nor-neolignan from Cremanthodium ellisii.Chinese Chemical Letters,1999,10:129-130.
[55]刘长军,侯嵩生.抗癌活性物质鬼臼木脂素的研究进展.天然产物研究与开发,1997,19:81-83.
[56]崔银姬.木脂素对MCF-7乳腺癌细胞抗增殖作用及其机制的研究[D].吉林延吉:延边大学基础医学院病理学研究部,2010.
[57] Tsai L L, Lee F P, Wu C C, et al. New cytoxic cyclobutanoid amides, a newfuranoid lignans and anti-platelet aggregation constituents from piperarborescens. Planta Medica,2005,71:535-542.
[58]杨毅,张成路,潘鑫复.木脂素抗艾滋病病毒研究.化学进展,2003,15:327-331.
[59] Gnabre J N, Ito Y, Ma Y, et al. Isolation of anti-HIV-1lignans from larreatridentate by counter-current chromatography. Journal of chromatography A,1996,719:353-364.
[60] Zhang T M, Wang B E, Liu G T. Effect of schisandrin B on lipoperoxidativedamage to plasma membrane of rat liver in vitro. Acta Phamacol Sin,1992,13,255-260.
[61]刘华英,北五味子木脂素提取工艺及提取物抑菌作用的研究[D].长春:吉林农业大学资源与环境学院,2006.2006.
[62]天津医学院寄生虫教研室.40种中草药体外杀猪蛔虫作用的初步实验观察.新医药学杂志,1994,2:31-33.
[63]王岳.70种药用植物抗菌效能的试验.植物学报,1994,3:121-135.
[64]韩桂秋,马迎,李长龄.胡椒属植物中木脂素类血小板活化因子拮抗活性成分及构效关系的研究,北京医科大学学报,1992,24:347-350.
[65] Benveniste J, Henson P M, Cochrane C G. Leukocyte-dependent histaminerelease from rabbit platelets. The role of lgE, basophils, and aplatelet-activating factor. The Journal of Experimental medicine,1972,136:1356-1377.
[66]林琎.脱氧鬼臼毒素杀虫作用机理初步研究[D].陕西杨凌:西北农林科技大学无公害农药研究服务中心,2004,25-26.
[67] Kao Chai-Lin, Chern Ji-Wagn. A novel strategy for the synthesis of benzofuranskeleton neolignans: application to ailanthoidol, XH-14, and obovaten. TheJournal of Organic Chemistry,2002,67:6772-6787.
[68] L ü tjens H, Scammells P J. Synthesis of natural products possessing abenzo[b]furan skeleton. Tetrahedron Letters,1998,36:6581-6584.
[69]庞冀燕,汪波,许遵乐.2-取代芳基苯并[b]呋喃类化合物的合成.有机化学，2005,25:176-181.
[70]汪秋安,张红,王力.新型苯并呋喃新木脂素类化合物的合成研究.湘潭大学自然科学学报,2007,29,71-74.
[71] Lemière G, Gao M, Groot A D.3’,4-Di-O-methylcedrusin: synthesis, resolutionand absolute configuration. Journal of the Chemical Society, PerkinTransactions1,1995:1775-1779.
[72] Yang Z, Liu H B, Lee, C M. Compounds from danshen. Part7. regioselectiveintroduction of carbon-3substituents to5-alkyl-7-methoxy-2-phenylbenzo[b]furans: synthesis of a novel adenosine A1receptor ligand and its derivatives. The Journal of Organic Chemistry,1992,57:7248-7257.
[73] Patricia M P, Angela R A, Maria C M Y. nor-lignans from the leaves of styraxferrugineus (styracaceae) with antibacterial and antifungal activity.Phytochemistry,2000,55:597-601.
[74] Yurdanur Y A, Huseyin A. benzofurans and another constituent from seeds ofstyrax officinalis. Phytochemistry,2003,63:939-943.
[75] Nikaido T, Ohmoto T, Noguehi H, et al. Inhibitors of cyclic AMPphosphodiesterase in medicinal plants. Planta Medica,1981,43:18-23.
[76] Bemcierta A P, Whiting D A. Stereoselective total syntheses of the di-O-methylethers of agataresinol, sesquirin-A, and hinokiresinol, and oftri-O-methylsequirin-E, characteristic norlignans of coniferae. Journal of theChemical Society Perkin Transactions,1978,1:1257-1263.
[77] Muraoka O, Zheng B Z, Fujiwara N, et al. Enantioselective total synthesis ofthe di-O-methyl ethers of (-)-agatharesinol,(+)-hinokiresinol and(-)-sugiresinol, characteristic nodignans of coniferae. Journal of the ChemicalSociety Perkin Transactions,1996,5:405-411.
[78] Brown E, Dujardin G, maudet M. Asymmetric Endoselective [4+2]Heterocycloadditions of styrenedienophiles with chiral benzylidenepyruvicesters. Total synthesis of (-)-O-dimethylsugiresinol. Tetrahedron,1997,53:9679-9694.
[79] Matsuo K, Sugimura W, Shimizu Y, et al. Synthesis of (-)-sugiresinol dimethylether utilizing(-)-quinic acid. Heterocyeles,2000,53:1505-1513.
[80] Barros M T, Maycock C D, Ventura M R. Enantioselective total synthesis of(+)-eutypoxide B. The Journal of Organic Chemistry.1997,62:3984-3988.
[81] Evans P A, Leahy D K. Regioselective and enantiospecific Rhodium-catalyzedallylic alkylation reactions using copper(1) enolates: synthesis of(-)-sugiresinol dimethyl ether. Journal of the American Chemical Society.2003,125:8974-8975.
[82]权伟国.(-)-Heliconol A、Kawain类、二氢异香豆素类及脱碳木脂素类化合物的全合成研究[D].兰州:兰州大学化学化工学院2007.
[83] Tsuji J. Palladium reagents and catalysts: new perspectives for the21st century.John Wiley＆Sons, Chichester.2004.
[84] Grenoulllet P, Nelbecker D, Tkatchenko I. Catlonlc allylmetal complexes.9.1dimerization acrylates catalyzed by allylpalladlum complexes. Role of theligand and indirect evidence for the occurrence of hydridopalladium species.Organometallics.1984,3:1130-1132.
[85] Sen A, Lai Ta-Wang, Thomas R R. Reactions of electrophilic transition metalcations with olefins and small ring compounds. Rearrangements andpolymerizations. Journal of Organometallic Chemistry.1988,358:567-588.
[86] Kiyotomi K, Tadao K, Tadasshi H. Preparation of divalent Pd(II) species onsepiolite and its catalysis of olefin dimerizations. Journal of MolecularCatalysis,1988,48:343-347.
[87] Jiang Z Z, Sen A. Tailored cationic Palladium(II) compounds as catalysts forhighly selective linear dimerization of styrene and linear polymerization ofp-divinylbenzene. Journal of the American Chemical Society.1990,112:9655-9657.
[88] Jiang Z Z, Sen A. Tailored cationic palladium(II) compounds as catalysts forhighly selective dimerization and polymerization of vinylic monomers:synthetic and mechanistic aspects. Organometallics,1993,12:1406-1415.
[89] Tsuchimoto T, Kamiyama S, Negoro R. Palladium-catalysed dimerization ofvinylarenes using indium triflate as an effective co-catalyst. ChemicalCommunication,2003,7:852-853.
[90] Bedfor R B, Betham M, Blake M E. Asymmetric styrene dimerisation usingmixed palladium-indium catalysts. Tetrahedron,2005,61:9799-9807.
[91] Nishiwaki N, kamimura R, hosokawa T, et al. Efficient double bond migrationof allylbenzenes catalyzed by Pd(OAc)2-HFIP system with unique substituenteffect. Tetrahedron letters,2010,51:3590-3592.
[92] Fanfoni L, Meduri A, Zangrando E, et al. New chiral P-N ligands for theregion-and stereoselective Pd-catalyzed dimerization of styrene. Molecules,2011,16:1804-1824.
[93] Yamada S, Obora Y, Sakaguchi S, et al. A new type of carbonylation of styrenescatalyzed by Pd(OAc)2combined with molybdovanadophosphate. Bulletin ofthe Chemical Society of Japan,2007,80:1194-1198.
[94] Bruce P, Giang Vo-Thanh, Didier G, et al. First application of chiral ionicliquids in asymmetric baylis-hillman reaction. Tetrahedron Letters,2004,45:6425-6428.
[95] Baudoux J, Judeinstein P, Cahard D, et al. Design and synthesis of novel ionicliquid/liquid crystals (IL2Cs) with axial chirality. Tetrahedron Letters,2005,46:1137-1140.
[96] Ishida Y, Sasaki D, Miyauchi H, et al. Design and synthesis of novelimidzaolium-based ionic liquids with a pseudo crown-ether moiety:diastereomeric interaction of a racemic ionic liquid with enantiopure europiumcomplexes. Tetrahedron Letters,2004,45:9455-9459.
[97] Gadenne B, Hesemann P, Moreau J J E. lonic liquids incorporatingcamphorsulfonamide units for the Ti-promoted asymmetric diethylzinc additionto benzaldehyde. Tetrahedron Letters,2004,44:8157-8160.
[98] Kim E J, Ko S Y, Dziadulewicz E K. Mitsunobu alkylation of imidazole: aconvenient route to chiral ionic liquids. Tetrahedron Letters,2005,46:631-633.
[99] Ishida Y, Miyauchi H, Saigo K. Design and synthesis of a novelimidazolium-based ionic liquid with planar chirality. Chemical communication,2002,19:2240-2241.
[100] Levillain J, Dubant G, Abrunhosa I, et al. Synthesis and properties of thiazolinebased ionic liquids derived from the chiral pool. Chemical Communication,2003,23:2914-2915.
[101] Anthony M L, Stephanie C W, Mary E W, et al. An lonic liquid form of DNA:redox-active molten salts of nucleic acids. Journal of the American Society,2001,123:218-222.
[102] Bao W L, Wang Z M, Li Y. Synthesis of chiral lonic liquids from natural aminoacids. The journal of Organic Chemistry,2003,68:591-593.
[103] Ding J, Desikan V, Han X X. et al. Use of chiral lonic liquids as solvents for theenantioselective photoisomerization of dibenzobicyclo[2,2,2]octatrienes.Organic Letters,2005,7:335-337.
[104] Schrōder U, Wadhawan J D, Compton R G. et al. Water-induced accelerated iondiffusion: voltammetric studies in1-methyl-3-[2,6-(S)-dimethylocten-2-yl]imidazolium tetrafluoroborate,1-butyl-3-methylimidazolium tetrafluoroborateand hexafluorophosphate ionic liquids. New Journal of Chemistry,2000,24:1009-1016.
[105] Wadhawan J D, Schroder U, Neudeck A, et al. Lonic liquid modified electrodes.Unusual partitioning and diffusion effects of Fe(CN)64-/3-in droplet and thinlayer deposits of1-methyl-3-(2,6-(S)-dimethylocten-2-yl)-imidazoliumtetrafluoroborate. Journal of Electroanalytical Chemistry,2000,493:75-83.
[106] Kabalka G W, Dong G, Venkataiah B. investigation of the behavior ofarenediazonium salts with olefins in BMimPF6. Tetrahedron Letters,2004,45:2775-2777.
[107] Peng J J, Li J Y, Lai G Q, et al. Dimerization of styrene to1,3-diphenyl-1-butene catalyzed by Pdlladium-Lewis acid in ionic liquid.Journal of Molecular Catalysis A: Chemical,2006,255:16-18.
[108] Sivulka D J, Seikop S K. Reconstruction of historical exposures in the usNickel alloy industry and the implications for carcinogenic hazard and riskassessments. Regulatory Toxicology and Pharmacology,2009,53:174-185.
[109] Prosper M’Bemba-Meka, Nicole L, Saroj K C. Nickel compound-induced DNAsingle-strand breaks in chromosomal and nuclear chromatin in human bloodlymphocytes in vitro: role of oxidative stress and intracellular calcium.Mutation Research/Genetic Toxicology and Environmental mutagenesis,2005,586:124-137.
[110] Sivulka D J, Conard B R, Hall G W, et al. Species-specific inhalable exposuresin the Nickel industry: A new approach for deriving inhalation occupationalexposure limits. Regulatory Toxicology and Pharmacology,2007,48:19-34.
[111] Patierno S R, Dirscherl L A, Xu J. Transformation of rat tracheal epithelialcells to immortal growth variants by particulate and soluble Nickel compounds.Mutation Research/Genetic Toxicology,1993,300:179-193.
[112] Agatzini-Leonardou S, Tsakiridis P E, Oustadakis P, et al. Hydrometallurgicalprocess for the separation and recovery of nickel from sulphate heap leachliquor of nickeliferrous laterite ores. Minerals Engineering,2009,22:1181-1192.
[113] Das G K, Lange J A B D. Reductive atmospheric acid leaching of westAustralian smectitic nickel laterite in the presence of sulphur dioxide andcopper(II). Hydrometallurgy,2011,105:264-269.
[114] Dawans F. Dimerisation stereospecifique du styrene en presence deBis(trifluoroacetate de Nickel-allyle). Tetrahedron Letters,1971,22:1943-1946.
[115] Ascenso J, Dias A R, Gomes P T, et al. Cationic3-allylmetal complexes,12.Oligomerization of styrene with cationic allylnickel compounds: catalysts,products and the influence of phosphines. Macromolecular Chemistry andphysics,1989,190:2773-2787.
[116] Ascenso J, Carrondo M A A F De C T, Dias A R, et al. Cationic benzyl nickelcomplexes as homogeneous catalysts for styrene oligomerization. X-ray crystalstructure of [Ni(3-CH2C6H5)(PPh3)2]PF6·CH2Cl2. Polyhedron,1989,8:2449-2457.
[117] Yi C Y, Hua R M, Zeng H X. Efficient and selective nickel(II)-catalyzed tail-tohead dimerization of styrenes affording1,3-diaryl-1-butenes. CatalysisCommunications,2008,9:85-88.
[118] Higashimura M, Imamura K, Yokogawa Y, et al. Novel dimerization,alkoxylation, and sulfidation of olefins catalyzed by RuCl3·nH2O. ChemistryLetters,2004,33:728-729.
[119] Lee D W, Yi C S. Chain-selective and regioselective ethylene and styrenedimerization reactions catalyzed by a well-defined cationic ruthenium hydridecomplex: new insights on the styrene dimerization mechanism.Organometallics,2010,29:3413-3417.
[120] Fontaine M, Hubert A J, Noels A F, et al. Cobalt-catalysed dimerizaion ofstyrenes under syngas. Journal of Organometallic Chemistry,1991,417:C28-C31.
[121] Wang C C, Lin P S, Cheng C H. Cobalt-catalysed dimerization of alkenes.Tetrahedron Letters,2004,45:6203-6206.
[122] Jeganmohan M, Cheng C H. Cobalt-and nickel-catalyzed region andstereoselective reductive coupling of alkynes, allenes, and alkenes with alkenes.Chemistry-A European Journal,2008,14:10876-10886.
[123] Jose R, Corma A. Iron-catalyzed region and stereoselective head-to-taildimerisation of styrenes. Advanced Synthesis＆Catalysis,2010,352:1571-1576.
[124] Humphrey M B, Lamanna W M, Husk G R, et al. Crystal and molecularstructure of (eta.5-pentamethylcyclopentadienyl)(trifluoromethanesulfonato)Iron(II) dicarbonyl: a strong electrostatic iron-triflate interaction. InorgnicChemistry,1983,22:3355-3358.
[125] Williams D B, Stoll M E, Scott L B, et al. Coordination chemistry of thebis-(trifluoromethylsulfonyl)imide anion: molecular interactions in roomtemperature ionic liquids. Chemical Communications,2005,11:1438-1440.
[126] Yamamoto Y, Itonaga K. Versatile friedel-crafits-type alkylation of benzenederivatives using a molybdenum complex/ortho-chloranil catalytic system.Chemistry-A European Journal,2008,14:10705-10715.
[127] Vicente F, Hermenegildo G, Vicente M, et al. Carbenium ions generated uponadsorption of4-methoxystyrenes onto acid zeolites. A kinetic study.Tetrahedron,1998,54:3827-3832.
[128] Matsubara C, Kojima M. Effect of Co-adsorbed water on photodimerizationand photooxygenation of4-methoxystyrene included in NaY. TetrahedronLetters,1999,40:3439-3442.
[129] Sinha A K, Joshi B P, Acharya R. DDQ mediated one step dimerisation ofbeta-asarone or beta-asarone rich acorus calamus oil in the formation of novelneolignan. US Patent.0187306A1,2003.
[130] Kumar S A, Prasad J B, Acharya R. Formation of neolignan by DDQ mediateddimerisation of dihydroasarone. WO Patent.080551A1,2003.
[131] Iwahama T, Sakaguchi S, Ishii Y. Catalytic radical addition of ketones toalkenes by a metal-dioxygen redox system. Chemical Communication,2000,23:2317-2318.
[132] Kagayama T, Fuke T, Ishii Y, et al. A remarkable effect of bases on the catalyticradical addition of cyanoacetates to alkenes using a Mn(II)/Co(II)/O2redoxsystem. Bulletin of the Chemical society of Japan,2005,78:1673-1676.
[133] Hirase K, Iwahama T, Ishii Y, et al. Catalytic radical addition of carbonylcompounds to alkenes by Mn(II)/Co(II)/O2system. The Journal of OrganicChemistry,2002,67:970-973.
[134] Hirase K, Sakaguchi S, Ishii Y. Addition of carboxyalkyl radicals to alkenesthrough a catalytic process, using a Mn(II)/Co(II)/O2redox system. The Journalof Organic Chemistry,2003,68:5974-5976.
[135] Tayama O, Nakano A, Ishii Y, et al. Hydrophosphorylation of alkenes withdialkyl phosphates catalyzed by Mn(III) under air. The Journal of OrganicChemistry,2004,69:5494-5496.
[136] Kagayama T, Nakano A, Ishii Y, et al. Phosphonation of arenas with dialkylphosphates catalyzed by Mn(II)/Co(II)/O2redox couple. Organic letters,2006,8:407-409.
[137] Yuan C Y, Qi Y M. Studies on organophosphorus compounds. A facile synthesisof-amino-substituted benzylphosphonic and phosphinic acids by use ofthiophosphoramide. Synthesis,1986,10:821-825.
[138] Oleksyszyn J, Tyka R M, Astalerz P. Direct synthesis of1-aminoalkanephosphonic and1-aminoalkanephosphinic acids fromphosphorustrichloride or dichlorophosphines. Synthesis,1978,6:479-480.
[139] Green D, Patel G, Elgendy S, et al. The synthesis of1-aminobenzylphosphonicacids from benzylidiphenylmethylamines for use as structural units inantithrombotic tripentides. Tetrahedron,1994,50:5099-5108.
[140] Lu Shui-Yu, Hamerton I. Recentdevelopments in the chemistry of halogen-freeflameretardant polymers. Progress in Polymer Science,2002,27:1661-1712.
[141] Gao F, Tong L F, Fang Z P. Effect of a novel phosphorouse-nitrogen containingintumescent flame retardant on the fire retardancy and the thermal behaviour ofpoly(butylenes terephthalate). Polymer Degradation and Stability,2006,91:1295-1299.
[142]王彦林,王冬军.膨账型阻燃剂新戊二醇乙撑磷酰胺的合成.塑料助剂,2009,3:29-31.
[143] Nune S K, Tanaka M. Palladium-catalysed regioselective addition reaction ofethyl phenylphosphinate with terminal acetylenes: ligand and solventdependent regioselectivity. Chemical Communication,2007,27:2858–2860.
[144] Deprèle S, Montchamp J. Palladium-Catalyzed Hydrophosphinylation ofAlkenes and Alkynes. Journal of the American Chemical Society,2002,124:9386-9387.
[145] Xu Q, Zhao C Q, Han L B. Stereospecific Nucleophilic Substitution ofOptically Pure H-Phosphinates: A General Way for the Preparation of ChiralP-Stereogenic Phosphine Oxides. Journal of the American Chemical Society,2008,130:12648-12655.
[146] Han L B, Choi N, Tanaka M. Oxidative Addition of HP(O)Ph2to Platinum(0)and Palladium(0) Complexes and Palladium-Catalyzed Regio andStereoselective Hydrophosphinylation of Alkynes. Organometallics,1996,15:3259-3261.
[147] Stockland R A, Levine A M, Giovine M T, et al. Reductive Elimination fromMetal Phosphonate Complexes: Circumvention of Competing ProtonolysisReactions. Organometallics,2004,23:647-656.
[148] Han L B, Zhang C, Yazawa H, et al. Efficient and Selective Nickel-CatalyzedAddition of H-P(O) and H-S Bonds. Journal of the American Chemical Society,2004,126:5080-5081.
[149] Zhao C Q, Han L B, Tanaka M, et a1. Rhodium-CatalyzedHydrophosphorylation of Terminal Alkynes Leading to Highly SelectiveFormation of (E)-Alkenylphosphonates: Complete Reversal of Regioselectivityto the Palladium-Catalyzed Counterpart. Angewandte Chemie InternationalEdition,2001,40:1929-1933.
[150] Han L B, Zhao C Q, Tanaka M. Rhodium-Catalyzed Regio-and StereoselectiveAddition of Diphenylphosphine Oxide to Alkynes. The Journal of OrganicChemistry,2001,66:5929-5932.
[151] Reichwein J F, Patel M C, Pagenkopf B L. Rhodium-Catalyzed RegioselectiveOlefin Hydrophosphorylation. Organic Letters,2001,3(26):4303-4306.
[152] Han L B, Tanaka M. Palladium-Catalyzed Hydrophosphorylation of Alkynesvia Oxidative Addition of HP(O)(OR)2. Journal of the American ChemicalSociety,1996,118:1571-1572.
[153] Han L B, Zhao C Q, Onozawa S Y. Retention of configuration on the oxidativeaddition of P-H bond to platinum(0) complexes: The first straightforwardsynthesis of enantiomerically pure P-chiral alkenylphosphinates viapalladium-catalyzed stereospecific hydrophosphinylation of alkynes. Journal ofthe American Chemical Society,2002,124:3842-3843.
[154] Han L B, Zhao C Q. Stereospecific addition of P-H bond to alkenes: Asimplemethod for the preparation of (Rp)-phenylphinates. The Journal of OrganicChemistry,2005,70:10121-10123.
[155] Han L B, Mirzaei F, Zhao C Q, et al. High reactivity of a five-membered cyclichydrogen phosphonate leading to development of facile palladium-catalyzedhydrophosphorylation of alkenes. Journal of the American Chemical Society,2000,122:5407-5408.
[156] Han L B, Ono Y, Shimada S. Palladium-catalyzed dehydrogenative cis doublephosphorylation of alkynes with H-Phosphonate leading to(Z)-bisphosphoryl-1-alkenes. Journal of the American Chemical Society,2008,130:2752-2753.
[157] Xu Q, Han L B. Palladium-catalyzed asymmetric hydrophosphorylation ofnorbornenes. Organic letters,2006,8:2099-2101.
[158] Zhao C Q, Han L B, Tanaka M. Palladium-catalyzed hydrophosphorylation ofallenes leading to region-and stereoselective formation of allylphosphonates.Organometallics,2000,19:4196-4198.
[159] Mirzaei F, Han L B, Tanaka M. Palladium-catalyzed hydrophosphorylation of1,3-dienes leading to allylphosphonates. Tetrahedron Letters,2001,42:297-299.
[160] Asanuma T, Gotoh T, Tsuchida A, et al. Photosensitized dimerization ofstyrene derivatives by a cation radical transfer mechanism. Journal of theChemical Society, Chemical Communications,1977,14:485-486.
[161] Leung P S W, Teng Y, Toy P H. Chromatography-free wittig reactions using abifunctional polymeric reagent. Organic letters,2010,12:4996-4999.
[162]喻爱和,冯勋波,陈超越,等.合成-细辛脑的脱水剂选择.合成化学,2006,14:500-502.
[163] Wieczorek D J S, Boduszek B, Wielkopolski W A, et al. Herbicidal9-aminofluorene-9-phosphonates. Journal für Parktische Chemie,1987,329:165-170.
[164] Risi J, Gauvin D. Contribution a letude de lapolymerisation: II proprietes,mecanisme de formation et constitution des distyrenes et des polystyrenes.Canadian Journal of Research,1936,7:255-267.
[165] Schoepfle C S, Ryan J D. The polymerization of asymmetricaldiphenylethylene. The preparation of1,1,3-triphenyl-3-methylhydrindene.Journal of the American Chemistry,1930,52:4021-4030.
[166] Rosen M J. Studies on the dimerization of styrene in aqueous sulfuric acid. TheJournal of Organic Chemistry,1953,18:1701-1705.
[167] Corson B B, Dorsky J, Nickels J E, et al. Dimerization of styrene in thepresence and absence of solvent, The Journal of Organic Chemistry,1954,19:17-26.
[168] Benito A, Corma A, García H, et al. Dimerization of styrene catalyzed by acid12-membered ring zeolites. Applied Catalysis A: General,1994,116:127-135.
[169] Alok B, Gopalakrishna T. The Michaelis-Arbuzov rearrangement. ChemicalReviews,1981,81:415-430.
[170]刘增勋,刘舜尧,杨秀凤,等.一种新有机膦除草剂的合成与试验.化学工业与工程,1991,8:14-17.
[171] Ye M C, Li L P, Zhao Y F. Structural effects on the electrophile inducedcyclization of organophosphorus compounds. Phosphorus and Sulfur,1988,39:79-83.
[172]赵玉芬,尹应武,吉改姣,等.亚膦酸酯的特性及其应用.清华大学学报（自然科学版）,1992,32:75-85.
[173]段军飞,刘西洋,向建南,等.-氨基苯基膦酸酯衍生物的合成,合成化学,2006,14:588-590.
[174] Kubota T, Takahara T, Nagata M, et al. Colorimetric chemosensitivity testingusing sulforhodamine B. Journal of Surgical Oncology,1993,52:83-88.
[175] Lei S, Chien P Y, Sheikh S, et al. Enhanced therapeutic efficacy of a novelliposome-based formulation of Sn-38against human tumor models in SCIDmice. Anticancer Drugs,2004,15:773-778.
[176] Bjorkman K M, Karl D M. A novel method for the measurement of dissolvedadenosine and guanosine triphosphate in aquatic habitats: applications tomarine microbial ecology. Journal of Microbiological Methods,2001,47:159-167.
[177] Trudil D, Loomis L, Pdbon R, et al. Rapid ATP method for the screening andidentification of bacteria in food and water samples. Biocatalysis,2000,41:27-29.
[178]赵俊萍,张慧丽. LDH释放法测定NK细胞活性对红细胞的影响.肿瘤研究与临床,1999,12:203-204.
[179]张志斌,付晓光.紫杉醇对人胰腺癌细胞株BxPC-3增殖抑制作用的研究.中华肿瘤防治杂志,2007,4:1694-1697.
[180]林宜先,江曼,刘铭球,等.紫杉醇对Lewis肺癌抑制作用及其机理的研究.中国肺癌杂志,2000,3:205-207.
[181] Xiao Y C, Carmen P, Ying P H, et al. Synthesis and biological evaluation ofdimeric RGD peptide-paclitaxel conjugate as a model for integrin-targeted drugdelivery. Joural of Medicinal Chemistry,2005,48:1098-1106.
[182] Diergarten K, Dreps A. Taxol: A new antieoplastic agent. Onkologie,1993,16:329-337.
[183] Singla A K, Garg A, Aggarwal D. Paclitaxel and its formulations. InternationalJournal of Pharmaceutics,2002,235:179-192.