侧链取代trityl自由基的合成及性能表征

发布时间：2018-07-07 12:59

本文选题：电子顺磁共振 + 侧链取代　；参考：《天津医科大学》2017年硕士论文

【摘要】：目的:近年来,全取代三苯甲基(trityl)自由基在磁共振领域备受关注,相较于氮氧自由基此类自由基具有以下优点:较高的生物稳定性、狭窄的电子顺磁共振(EPR)单线信号、较长的弛豫时间(无氧条件下10μs at 25℃)和较高的检测敏感性等。目前,trityl自由基在电子顺磁共振(EPR)波谱和成像领域具有广泛的应用,包括细胞内和细胞外氧气水平、O2·-、p H、氧化还原态等参数的检测;此外,它们在动态核极化(DNP)增强的核磁波谱与成像和自旋标记等领域的应用也受到密切关注。Trityl自由基OX063具有良好的水溶性和生物相容性,是最受关注的探针之一,但是它的合成是一个巨大的挑战,限制了其广泛的应用。因此,具有成熟合成路线的CT-03自由基成为研究者们的首要选择。但是CT-03作为自旋探针存在一些不足,例如对芳环上羧基的修饰缺乏选择性,且修饰后会降低其水溶性和弛豫时间,从而改变它的氧化还原性质和EPR谱线,并且可能带来超精细裂分等问题。针对上述问题,本文开展了侧链单(或双)取代trityl自由基的工作,设计合成了多个侧链可修饰的trityl自由基,并对其性质进行研究,以期得到具有狭窄EPR信号的高水溶性、可选择性修饰的trityl自由基。方法:以1,2,4,5-四(叔丁基硫代)苯、丙酮和丙酮酸乙酯为起始原料,经缩酮化反应、还原反应、羟基保护3步反应,合成了侧链单(或双)羟基取代的trityl单体,并考察加料顺序、溶剂、温度以及反应物的当量比对反应的影响。通过“1+2”的策略即侧链单(或双)取代的单体与芳基酮反应制备三苯甲醇中间体,并对侧链单取代中间体利用手性试剂进行了构型拆分,探讨构型对性质的影响。然后经n-Bu Li拔氢与碳酸二甲酯反应、水解、脱保护基、引入官能团和变自由基等步骤得到侧链具有不同官能团取代的trityl自由基,并用EPR方法对其进行表征。结果:实现了侧链单(或双)取代trityl自由基的高效合成。(1)得到了5个含有不同官能基团的侧链单取代trityl自由基的前体,并用NMR、HPLC等方法确认其结构和纯度;选择其中2个前体转变成自由基,并研究侧链修饰对trityl自由基EPR性质的影响;用(-)-氯代樟脑酸作为拆分试剂,实现了外消旋化合物7的分离,得到4个组分,采用NMR和圆二色谱(CD)的方法对其结构进行表征,并用EPR方法研究了相应的trityl自由基。(2)合成得到了反式和顺式侧链双取代三苯甲醇中间体,并得到了顺式侧链双羟基取代单体的单晶结构。结论:(1)本论文实验方案中所使用的合成路径,具有方法简单、操作简便、重现性好、条件温和等优点。(2)实现了结构新颖的侧链单取代trityl自由基的首次合成,证实trityl自由基的侧链单取代基本不影响其EPR性质,并解决了trityl自由基的衍生化无选择性的问题。(3)手性拆分得到了4个组分,NMR和EPR研究均表明trityl的螺旋桨构型对其性质有影响。(4)该研究对于设计合成新型trityl自由基母核、trityl自由基的功能化、研究三苯甲基衍生物的螺旋桨构型及拓展trityl自由基的生物医学应用具有重要的意义。
[Abstract]:Objective: in recent years, the total substitution of three benzyl (trityl) free radicals has attracted much attention in the field of magnetic resonance. Compared with the free radical of nitrogen and oxygen free radicals, the free radical has the following advantages: high biological stability, narrow electronic paramagnetic resonance (EPR) single line signal, longer relaxation time (10 s at 25 C under oxygen free conditions) and higher detection sensitivity. At present, trityl free radicals are widely used in the field of electron paramagnetic resonance (EPR) spectroscopy and imaging, including intracellular and extracellular oxygen levels, O2 -, P H, redox states and other parameters. In addition, their applications in the field of dynamic nuclear polarization (DNP) enhanced nuclear magnetic spectroscopy, imaging and spin labeling have also been closely concerned with.Tri Tyl free radical OX063 has good solubility in water and biocompatibility, it is one of the most concerned probes, but its synthesis is a huge challenge, limiting its wide application. Therefore, the CT-03 free radical with mature synthetic route has become the primary choice for researchers. But there are some shortcomings of CT-03 as a spin probe, for example. The modification of the carboxyl group on the aromatic ring is lack of selectivity, and the modification will reduce its water solubility and relaxation time, which will change its redox properties and EPR lines, and may bring about hyperfine splitting and other problems. In this paper, the work of side chain single (or double) substitution of trityl radical is carried out, and multiple side chain repairable is designed and synthesized. The trityl free radical is decorated and its properties are studied in order to obtain the highly water-soluble and selective modified trityl radical with a narrow EPR signal. Method: with 1,2,4,5- four (tert butyl thiosulfate) benzene, acetone and ethyl pyruvate as starting materials, the side chain single (or double) is synthesized by the ketone reaction, reduction reaction and hydroxyl protection of the 3 step reaction. The hydroxyl substituted trityl monomers were used to investigate the effects of the addition order, the solvent, temperature and the equivalent ratio of the reactants. The three benzyl alcohol intermediates were prepared by the reaction of "1+2" strategy, the monomers of side chain single (or double) substituted with aryl ketones, and the configuration of the side chain mono substituted intermediates by the chiral reagent. The effect of the properties. Then by n-Bu Li extraction with two methyl carbonate, hydrolysis, deprotection, the introduction of functional groups and variable free radicals, the side chain with different functional groups to replace the trityl radical, and EPR method to characterize it. Results: the realization of side chain single (or double) substitution of trityl free radical high efficient synthesis. (1) obtained 5 A side chain with different functional groups was substituted for the precursor of single substituent trityl radical, and its structure and purity were confirmed by NMR, HPLC. 2 of the precursors were transformed into free radicals, and the effect of side chain modification on the EPR properties of trityl radicals was studied. The separation of racemic compound 7 was realized by using (-) - chlorocamphor acid as a resolution reagent. To 4 components, the structure was characterized by NMR and circular two chromatography (CD), and the corresponding trityl radical was studied by EPR method. (2) the trans cis side chain double substituted three benzyl alcohol intermediate was synthesized and the single crystal structure of the cis side chain dihydroxyl substituted monomer was obtained. Conclusion: (1) the experimental scheme used in this paper is used. The synthesis path has the advantages of simple method, simple operation, good reproducibility and mild conditions. (2) the first synthesis of the novel side chain single substituent trityl free radical is realized. It is proved that the single substitution of the side chain of the trityl radical does not affect its EPR properties, and solves the problem of the non selectivity of the derivative of the trityl radical. (3) chiral separation 4 components are obtained. The NMR and EPR studies show that the propeller configuration of trityl has an effect on its properties. (4) the study is of great significance for the design and synthesis of a new type of trityl free radical, the functionalization of trityl radical, the study of the propeller configuration of three benzyl derivatives and the development of the biomedical applications of trityl radical.
【学位授予单位】：天津医科大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：O621.146

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