發(fā)布時(shí)間：2018-08-05 19:50

【摘要】：核苷類化合物在化學(xué)、醫(yī)藥、生物學(xué)方面都有著非凡的意義,并且現(xiàn)今市面上也有很多核苷類藥物用于各種疾病的研究。由于核苷類化合物在人體內(nèi)可以直接影響核糖和蛋白類化合物的生成過(guò)程,從而影響癌細(xì)胞或者病毒的繁殖,有著很好的抗癌和抗病毒活性,所以核苷類類化合物在藥物領(lǐng)域中有著極其重要的意義。在多種核苷類化合物中,非環(huán)核苷類化合物是其中極其重要的一大類。非環(huán)核苷類化合物指在核苷結(jié)構(gòu)中核糖位置取代為其他含羥基烷基側(cè)鏈的核苷類化合物。傳統(tǒng)上合成手性的非環(huán)核苷類化合物主要有以下幾種方案:第一,先合成手性的含羥基側(cè)鏈然后連接到堿基上;其二,利用不對(duì)稱誘導(dǎo)用手性的原料進(jìn)一步合成目標(biāo)化合物;其三,通過(guò)不對(duì)稱催化合成手性非環(huán)核苷類化合物。前兩種方法,需要手性側(cè)鏈化合物和其它手性的原料,極大地增加了合成的成本,因此這兩種方法的應(yīng)用受到很大的限制�；谡n題組以往對(duì)核苷類化合物的研究以及對(duì)文獻(xiàn)的調(diào)研,發(fā)現(xiàn)嘧啶非環(huán)核苷類化合物的不對(duì)稱催化合成方法鮮有報(bào)道。本文首先設(shè)計(jì)并合成了一系列的各種取代的嘧啶1位丙烯酸酯化合物,然后在有機(jī)小分子催化劑的催化下,研究了其與硫代乙酸的不對(duì)稱Michael加成反應(yīng),合成了一系列含有SH的非環(huán)核苷類化合物,期望這一系列化合物具有一定的潛在的抗病毒和抗腫瘤活性。本文研究了嘧啶1位丙烯酸酯取代的非環(huán)核苷的不對(duì)稱Michael加成反應(yīng)。從有機(jī)小分子催化劑、反應(yīng)溶劑、反應(yīng)溫度和反應(yīng)添加劑的選擇等方面對(duì)該反應(yīng)條件進(jìn)行考察,并在最優(yōu)條件下進(jìn)行了反應(yīng)普適性的擴(kuò)展。經(jīng)過(guò)考察發(fā)現(xiàn):在零下20℃,3%mol催化劑量,乙醚作為溶劑,并且添加4A分子篩作為添加劑時(shí)可以達(dá)到大于99的分離產(chǎn)率和99%的對(duì)映選擇性。在對(duì)反應(yīng)普適性的初步考察中,發(fā)現(xiàn)反應(yīng)的ee值有一定的下降,經(jīng)過(guò)再次對(duì)反應(yīng)條件的優(yōu)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響,找到了對(duì)其他反應(yīng)底物具有較好活性的反應(yīng)條件,同時(shí)擴(kuò)展了多種不同類型的反應(yīng)底物。并且培養(yǎng)出來(lái)的單晶進(jìn)行衍射數(shù)據(jù)分析確定該加成產(chǎn)物的絕對(duì)構(gòu)型,此外,以獲得的手性加成產(chǎn)物為原料,經(jīng)過(guò)2步合成了含有羥基和巰基的非環(huán)核苷類化合物。本文提出了一種不對(duì)稱合成手性非環(huán)核苷類化合物的新方法,并且進(jìn)一步發(fā)展了通過(guò)堿基位取代丙烯酸酯來(lái)合成非環(huán)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，

本文編號(hào)：2166841