不对称Michael加成反应合成含巯基手性嘧啶类非环核苷类化合物
发布时间：2018-08-05 19:50
【摘要】：核苷类化合物在化学、医药、生物学方面都有着非凡的意义,并且现今市面上也有很多核苷类药物用于各种疾病的研究。由于核苷类化合物在人体内可以直接影响核糖和蛋白类化合物的生成过程,从而影响癌细胞或者病毒的繁殖,有着很好的抗癌和抗病毒活性,所以核苷类类化合物在药物领域中有着极其重要的意义。在多种核苷类化合物中,非环核苷类化合物是其中极其重要的一大类。非环核苷类化合物指在核苷结构中核糖位置取代为其他含羟基烷基侧链的核苷类化合物。传统上合成手性的非环核苷类化合物主要有以下几种方案:第一,先合成手性的含羟基侧链然后连接到碱基上;其二,利用不对称诱导用手性的原料进一步合成目标化合物;其三,通过不对称催化合成手性非环核苷类化合物。前两种方法,需要手性侧链化合物和其它手性的原料,极大地增加了合成的成本,因此这两种方法的应用受到很大的限制。基于课题组以往对核苷类化合物的研究以及对文献的调研,发现嘧啶非环核苷类化合物的不对称催化合成方法鲜有报道。本文首先设计并合成了一系列的各种取代的嘧啶1位丙烯酸酯化合物,然后在有机小分子催化剂的催化下,研究了其与硫代乙酸的不对称Michael加成反应,合成了一系列含有SH的非环核苷类化合物,期望这一系列化合物具有一定的潜在的抗病毒和抗肿瘤活性。本文研究了嘧啶1位丙烯酸酯取代的非环核苷的不对称Michael加成反应。从有机小分子催化剂、反应溶剂、反应温度和反应添加剂的选择等方面对该反应条件进行考察,并在最优条件下进行了反应普适性的扩展。经过考察发现:在零下20℃,3%mol催化剂量,乙醚作为溶剂,并且添加4A分子筛作为添加剂时可以达到大于99的分离产率和99%的对映选择性。在对反应普适性的初步考察中,发现反应的ee值有一定的下降,经过再次对反应条件的优化,并且考察了嘧啶3位取代基和1位丙烯酸酯中酯基的影响,找到了对其他反应底物具有较好活性的反应条件,同时扩展了多种不同类型的反应底物。并且培养出来的单晶进行衍射数据分析确定该加成产物的绝对构型,此外,以获得的手性加成产物为原料,经过2步合成了含有羟基和巯基的非环核苷类化合物。本文提出了一种不对称合成手性非环核苷类化合物的新方法,并且进一步发展了通过碱基位取代丙烯酸酯来合成非环核苷的新方法。
[Abstract]:Nucleoside compounds are of great significance in chemistry, medicine and biology, and there are also many nucleoside drugs in the market for the study of various diseases. Because nucleoside compounds can directly affect the formation of ribose and protein compounds in the human body, thus affecting the proliferation of cancer cells or viruses, they have good anticancer and antiviral activities. Therefore, nucleosides are of great significance in the field of drugs. Among the various nucleoside compounds, acyclic nucleosides are one of the most important ones. Acyclic nucleoside compounds refer to nucleosides which are substituted for other hydroxyl alkyl side chains in the nucleoside structure of nucleosides. Traditionally, there are several schemes for the synthesis of chiral acyclic nucleosides: first, the chiral hydroxyl side chains are synthesized and then connected to the bases; secondly, the chiral materials are used to further synthesize the target compounds by asymmetric induction. Third, chiral acyclic nucleosides were synthesized by asymmetric catalysis. The first two methods require chiral side chain compounds and other chiral raw materials, which greatly increase the cost of synthesis, so the application of these two methods is greatly limited. Based on the previous studies on nucleosides and literatures, it is found that the asymmetric catalytic synthesis of pyrimidine acyclic nucleosides is rarely reported. In this paper, a series of substituted pyrimidine acrylates were first designed and synthesized. Then the asymmetric Michael addition reaction of thioacetic acid with acrylates was studied under the catalysis of small organic catalysts. A series of acyclic nucleosides containing SH have been synthesized, which are expected to have potential antiviral and antitumor activities. The asymmetric Michael addition reaction of acrylated acrylates substituted by pyrimidine was studied in this paper. The reaction conditions were investigated from the aspects of organic small molecule catalyst, reaction solvent, reaction temperature and reaction additive, and the universality of the reaction was extended under the optimum conditions. It is found that the separation yield and enantioselectivity of > 99% can be achieved when the amount of catalyst is 3 mol at minus 20 鈩，
本文编号：2166841
[Abstract]:Nucleoside compounds are of great significance in chemistry, medicine and biology, and there are also many nucleoside drugs in the market for the study of various diseases. Because nucleoside compounds can directly affect the formation of ribose and protein compounds in the human body, thus affecting the proliferation of cancer cells or viruses, they have good anticancer and antiviral activities. Therefore, nucleosides are of great significance in the field of drugs. Among the various nucleoside compounds, acyclic nucleosides are one of the most important ones. Acyclic nucleoside compounds refer to nucleosides which are substituted for other hydroxyl alkyl side chains in the nucleoside structure of nucleosides. Traditionally, there are several schemes for the synthesis of chiral acyclic nucleosides: first, the chiral hydroxyl side chains are synthesized and then connected to the bases; secondly, the chiral materials are used to further synthesize the target compounds by asymmetric induction. Third, chiral acyclic nucleosides were synthesized by asymmetric catalysis. The first two methods require chiral side chain compounds and other chiral raw materials, which greatly increase the cost of synthesis, so the application of these two methods is greatly limited. Based on the previous studies on nucleosides and literatures, it is found that the asymmetric catalytic synthesis of pyrimidine acyclic nucleosides is rarely reported. In this paper, a series of substituted pyrimidine acrylates were first designed and synthesized. Then the asymmetric Michael addition reaction of thioacetic acid with acrylates was studied under the catalysis of small organic catalysts. A series of acyclic nucleosides containing SH have been synthesized, which are expected to have potential antiviral and antitumor activities. The asymmetric Michael addition reaction of acrylated acrylates substituted by pyrimidine was studied in this paper. The reaction conditions were investigated from the aspects of organic small molecule catalyst, reaction solvent, reaction temperature and reaction additive, and the universality of the reaction was extended under the optimum conditions. It is found that the separation yield and enantioselectivity of > 99% can be achieved when the amount of catalyst is 3 mol at minus 20 鈩，
本文编号：2166841
本文链接：https://www.wllwen.com/kejilunwen/huaxue/2166841.html
教材专著
