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1、以硫代酰胺为合成子合成嚷嗖咻类和二嘎姻类衍生物的方法学研究及新型CETP抑制剂的合成学位论文完成日期：%指导教师签字：答辩委员会成员签字：oMS 朵以硫代酰胺为合成子合成曝理咻类和二嚷姻类衍生物的方法学研究及新型CETP抑制剂的合成在过去的十几年当中，碘催化逐渐成为有机合成中的热点之一，关于用碘做催 化剂或引发剂的报道已经很多。碘催化之所以在有机合成中如此重要，主要是因为 碘催化具有反应条件温和，区域选择性高，反应时间短等优点。硫代酰胺在有机合 成中是一类重要的中间体，而且最近几年硫代酰胺在有机合成中的应用越来越广泛。芳甲酰硫代酰胺(KTAs)作为硫代酰胺类化合物最典型的代表己成为合成杂环类化
2、 合物的重要中间体，由于夕-芳甲酰硫代酰胺具有四个活泼的反应中心，所以可以与 亲电中心以四种不同的模式进行反应。睡畦咻类化合物具有广泛的生物医药活性，并广泛存在于药物化学中，唆哇咻 类化合物具有潜在的治疗类风湿性关节炎和其他炎症的作用，而且有一些被报道可 作为大麻素受体配体。例如，芳香的2.酰基亚乙基3-甲基噬噗咻具有消炎和止痛的 作用。由于嘎噗咻类化合物的生物医药活性，所以探索唯吐咻类化合物的合成方法 具有重要的意义。本文探索了一种碘催化芳甲酰硫代酰胺自身缩合反应合成曝嗖 咻类化合物2的新方法。我们对反应所需的催化剂、溶剂、温度进行了优化，确定 最优反应条件为：0.5equiv硬作为氧化剂，
3、1 equivDABCO作为碱，乙醇作溶剂， 室温搅拌3 h,并在最优反应条件下，对底物进行了拓展，最终合成14种哩喋咻类 化合物。1,4-二噬姻类化合物是一类重要的杂环化合物，许多1,4-二噬姻类化合物具有重 要的生物医药活性，例如被用作杀菌剂、打虫药、抗菌素、人类甘丙肽受体抑制剂 等。另外，多环的1,4-二哩姻类化合物被广泛用作染料和光电功能材料。因此，引 起了人们广泛的兴趣。虽然1,4二噪姻类化合物己被发现100多年，但是利用硫代 酰胺为合成子合成1,4二哩姻类化合物的方法尚未报道。我们在碘催化硫代酰胺自 身缩合合成嚏哇哪类化合物的基础上，通过改变碘的用量和硫代酰胺的类型，探索 出一种碘
4、催化夕芳甲酰硫代酰胺自身缩合反应合成1,4-二哩姻类化合物3的新方法。 通过反应条件的优化，确定最优反应条件为：lequiv碘作氧化剂，lequivDABCO 作为碱，乙醇作溶剂，室温搅拌3 h,并在最优反应条件卜，对底物进行了拓展，合 成一系列新型的1,4 .二噬姻类化合物。我们探索出一种通过调控碘的用量引发3+2或3+3环化反应催化硫代酰胺自 身缩合合成噬噗咻和1,4二睡姻类化合物的高效方法。9所合成的化合物的结构均经IR、iHNMR、”CNMR和HRMS验证，并对化合 物2a和3e进行了 X-单晶衍射分析，确定了其精确的空间结构。研究表明胆固醇酯转运蛋白(CETP)抑制剂具有较强的升高H
5、DL和抗动脉粥样硬 化作用。新型的CETP抑制剂是天津药物研究院根据CETP靶标设计的具有潜在活性 的一个骨架结构。我们设计了新型CETP抑制剂的合成路线，并通过8步反应成功合 成了最终产物，而且各步的产物通过核磁和高分辨质谱确定了结构，最终确定了一 条合理的、成熟的合成路线。关键词：睡哇咻类化合物，1,4-二哩姻类化合物，CETP抑制剂，硫代酰股，碘 催化。#STUDY ON THE SYNTHESIS OF THIAZOLINES AND1,4-DITHIINES BY USING -KETOTHIOAMIDES ANDSYNTHESIS OF NOVEL CETP INHIBITORAB
6、STRACTOver the past decades, many reactions have been reported using iodine as a promoter or a catalyst, and many of the iodine-mediated reactions feature mild reaction conditions, good selectivities, and short reaction times. A rapidly increasing recognition of the rich and fascinating chemistry of
7、 the yS-keteneacetals in organic synthesis has been brought out in the past decades. -Ketothioamides (KTAs) as the typical representative of S-keteneacetals have been proven to be important building blocks in the construction of heterocyclic systems. Due to the presence of four active centers, the r
8、eactions of KTAs with dielectrophilic reagents may proceed as the four different ways.Thiazoline derivatives are of general interest in medicinal chemistry with therapeutic properties such as rheumatoid arthritis and other inflammatory diseases. Some of them have been reported as a basis for cannabi
9、noid receptor ligands. For example, aromatic 2-acylmethylidene-3-methyl thiazolines are known to possess anti-inflammatory and analgesic properties. Due to the biological and pharmacological importance, exploring and improving the synthetic methods of thiazolylidene derivatives are very significant.
10、 We developed an efficient synthesis of thiazolylidenes 2 by self-condensation reactions of KTAs catalyzed by L. To improve the yield of this reaction, the reaction conditions were optimized with various bases, oxidants and solvents at different temperatures, and the optimum reaction conditions were
11、 L (0.5 equiv) as catalyst5 DABCO (1 equiv) as base and EtOH as solvent at room temperature. The more extensive scope of substrates was investigated under the optimized conditions to test the generality of this reaction, and 14 kinds of new thiazoline derivatives were obtained.Functionalized 1,4-dit
12、hiines are of interest because they represent an important class of heterocycles, many of them exhibit useful biological activities such as fungicides, antibacterials, anthelmintics, antimicrobials and nonpeptide antagonists of the human Galanin hGAL-1 receptors. In addition, polycyclic 1,4-dithiine
13、 derivatives arc useful as pigments and functional materials for electrooptical applications. Although 1,4-dithiines have been known for more than 100 years, careful literature search shows that there have been no reports on the synthetic application of KTAs to synthesize 1,4-dithiines. On the basis
14、 of the synthesis of thiazoline derivatives by selfcondensation reactions of KTAs catalyzed by I2, we report an efficient synthesis of 1,4-dithiines 3 by h-catalyzed self-condensation reactions of different types of KTAs. To improve the yield of this reaction, the reaction conditions were optimized,
15、 and the optimum reaction conditions were L (1 equiv) as catalyst, DABCO (1 equiv) as base and EtOH as solvent at room temperature. In order to justify this observation was not an exception, the reactions of more KTAs were investigated, and the results are satisfactory.An efficient h-catalyzed synth
16、esis of highly thiazolylidenes and 1,4-dithiines from -ketothioamides (KTAs) has been developed only by controlling the amount of I： that triggers diflerent cascade reaction sequences via 3+2 or 3+3-cycIocondensation in one step process.The structures of all compounds were unequivocally established by spectroscopic methods (IR, H and l3C NMR) and HRMS, and unequivocally established by the X-ray single crystal diffract
