手性磷酸识别吲哚喹唑啉类生物碱的应用研究
发布时间：2018-12-20 08:54
【摘要】：吲哚喹唑啉类生物碱广泛存在于天然产物中,具有抗炎、抗菌、抗肿瘤等药理活性,是重要的合成目标。我们课题组之前报道了两例催化不对称合成含有手性叔醇结构的吲哚喹唑啉类生物碱(Phaitanthrin A、Cephalanthrin-A及其衍生物)的研究工作。由于吲哚喹唑啉类生物碱存在极性大、溶解度差等诸多缺点,因此在利用高效液相色谱检测其对映体过量(ee值)时,而需要对该类化合物进行一步或两步的衍生以降低产物极性、增加其溶解性,从而大大地增加了筛选反应条件的工作量,降低了研究效率。因此,发展一种快速、简便、准确地检测吲哚喹唑啉类生物碱的光学纯度的方法是十分必要的。近年来,利用手性溶剂化试剂和手性位移试剂与被检测物的相互作用,核磁共振(1HNMR)光谱已被成功应用于对映异构体的光学纯度的分析。在此基础上,本论文主要研究了以手性磷酸作为手性识别剂通过核磁共振(1H NMR)测定吲哚喹唑啉类生物碱的光学纯度。主要研究工作如下:1)以(R) -1,1'-联二萘酚(R-BINOL)为手性源,经MOM-Cl保护、碘代、Suzuki反应、脱保护、与三氯氧磷反应等多步反应制备了手性磷酸。产物分子结构通过NMR等方法确定。2)以色胺酮及其衍生物为起始原料与丙二酸在醋酸镍、手性VA唑啉配体的作用下基于脱羧-Aldol反应得到Cephalanthrin-A及其衍生物。同样,以色胺酮及其衍生物为起始原料与丙酮在氨基酸盐的作用下直接发生Aldol反应得到产物Phaitanthrin A及其衍生物。产物分子结构均通过NMR等方法确定。3)以合成得到的手性磷酸作为手性溶剂化试剂通过核磁对Cephalanthrin-A、Phaitanthrin A及它们的衍生物的对映异构体进行了识别。实验结果表明,手性磷酸对含有叔醇结构的吲哚喹唑啉类生物碱具有良好的识别能力,对多类底物的对映异构体均可实现基线分离;其中Cephalanthrin-A及其衍生物产生最大的化学位移差值达到0.02 ppm;对Phaitanthrin A及其衍生物识别产生的最大化学位移差值达到0.07 ppm。在此基础上,我们利用该方法对手性的Cephalanthrin-A和Phaitanthrin A的光学活性进行了检测,取得了准确的测量结果和良好的线性效应。同时,氨基酸盐催化条件下色胺酮与丙酮的反应混合物可不经纯化直接在磷酸存在条件下通过核磁分析,可以极高的准确性获得产物的对映选择性。此外,我们也根据实验结果提出了双氢键的识别模型并通过实验进行了初步验证。
[Abstract]:Indole quinazoline alkaloids widely exist in natural products and have anti-inflammatory, antibacterial, anti-tumor and other pharmacological activities, which is an important target of synthesis. Two cases of catalytic asymmetric synthesis of indolequinazoline alkaloids (Phaitanthrin A Cephalanthrin-A and its derivatives) with chiral tertiary alcohols were reported. Because the indolequinazoline alkaloids have many disadvantages, such as high polarity and poor solubility, the enantiomeric excess (ee) of indole quinazoline alkaloids is detected by high performance liquid chromatography (HPLC). In order to reduce the polarity and increase the solubility of the product, the one-step or two-step derivatization is needed, which greatly increases the workload of screening reaction conditions and reduces the research efficiency. Therefore, it is necessary to develop a rapid, simple and accurate method for determining the optical purity of indole quinazoline alkaloids. In recent years, using chiral solvation reagents and chiral shift reagents to interact with the detected compounds, nuclear magnetic resonance (1HNMR) spectroscopy has been successfully applied to the analysis of the optical purity of enantiomers. On this basis, the optical purity of indole quinazoline alkaloids was determined by 1H NMR using chiral phosphoric acid as chiral recognition agent. The main research work is as follows: 1) Chiral phosphoric acid was prepared by MOM-Cl protection, iodide, Suzuki reaction, deprotection, and reaction with phosphorus oxychloride, using R-BINOL as chiral source. The molecular structure of the product was determined by NMR and other methods. 2) Cephalanthrin-A and its derivatives were synthesized by decarboxylation and Aldol reaction of tryptophan and its derivatives with malonic acid in the presence of nickel acetate and chiral VA azoline ligands. Similarly, the product Phaitanthrin A and its derivatives were obtained by Aldol reaction of tryptophan and its derivatives with acetone under the action of amino acid salt. The molecular structures of the products were determined by NMR and other methods. 3) the enantiomers of Cephalanthrin-A,Phaitanthrin A and their derivatives were identified by NMR using the synthesized chiral phosphoric acid as chiral solvent reagent. The experimental results show that chiral phosphoric acid has good recognition ability for indole quinazoline alkaloids with tertiary alcohol structure, and the enantiomers of multiple substrates can be separated at baseline. The maximum difference of chemical shift produced by Cephalanthrin-A and its derivatives was 0.02 ppm;. The maximum difference of chemical shift between Phaitanthrin A and its derivatives was 0.07 ppm.. On this basis, we use the chiral Cephalanthrin-A and Phaitanthrin A to detect the optical activity of the method, and obtain accurate measurement results and good linear effect. At the same time, the mixture of tryptamine and acetone can be obtained by NMR analysis without purification in the presence of phosphoric acid, and the enantioselectivity of the product can be obtained with high accuracy. In addition, based on the experimental results, we also proposed a double hydrogen bond recognition model and verified it by experiments.
【学位授予单位】：温州大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：O629.3
本文编号：2387751
[Abstract]:Indole quinazoline alkaloids widely exist in natural products and have anti-inflammatory, antibacterial, anti-tumor and other pharmacological activities, which is an important target of synthesis. Two cases of catalytic asymmetric synthesis of indolequinazoline alkaloids (Phaitanthrin A Cephalanthrin-A and its derivatives) with chiral tertiary alcohols were reported. Because the indolequinazoline alkaloids have many disadvantages, such as high polarity and poor solubility, the enantiomeric excess (ee) of indole quinazoline alkaloids is detected by high performance liquid chromatography (HPLC). In order to reduce the polarity and increase the solubility of the product, the one-step or two-step derivatization is needed, which greatly increases the workload of screening reaction conditions and reduces the research efficiency. Therefore, it is necessary to develop a rapid, simple and accurate method for determining the optical purity of indole quinazoline alkaloids. In recent years, using chiral solvation reagents and chiral shift reagents to interact with the detected compounds, nuclear magnetic resonance (1HNMR) spectroscopy has been successfully applied to the analysis of the optical purity of enantiomers. On this basis, the optical purity of indole quinazoline alkaloids was determined by 1H NMR using chiral phosphoric acid as chiral recognition agent. The main research work is as follows: 1) Chiral phosphoric acid was prepared by MOM-Cl protection, iodide, Suzuki reaction, deprotection, and reaction with phosphorus oxychloride, using R-BINOL as chiral source. The molecular structure of the product was determined by NMR and other methods. 2) Cephalanthrin-A and its derivatives were synthesized by decarboxylation and Aldol reaction of tryptophan and its derivatives with malonic acid in the presence of nickel acetate and chiral VA azoline ligands. Similarly, the product Phaitanthrin A and its derivatives were obtained by Aldol reaction of tryptophan and its derivatives with acetone under the action of amino acid salt. The molecular structures of the products were determined by NMR and other methods. 3) the enantiomers of Cephalanthrin-A,Phaitanthrin A and their derivatives were identified by NMR using the synthesized chiral phosphoric acid as chiral solvent reagent. The experimental results show that chiral phosphoric acid has good recognition ability for indole quinazoline alkaloids with tertiary alcohol structure, and the enantiomers of multiple substrates can be separated at baseline. The maximum difference of chemical shift produced by Cephalanthrin-A and its derivatives was 0.02 ppm;. The maximum difference of chemical shift between Phaitanthrin A and its derivatives was 0.07 ppm.. On this basis, we use the chiral Cephalanthrin-A and Phaitanthrin A to detect the optical activity of the method, and obtain accurate measurement results and good linear effect. At the same time, the mixture of tryptamine and acetone can be obtained by NMR analysis without purification in the presence of phosphoric acid, and the enantioselectivity of the product can be obtained with high accuracy. In addition, based on the experimental results, we also proposed a double hydrogen bond recognition model and verified it by experiments.
【学位授予单位】：温州大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：O629.3
【参考文献】
相关博士学位论文 前1条
1 鲍宗必;色谱法拆分手性药物中间体的应用基础研究[D];浙江大学;2008年
，本文编号：2387751
本文链接：https://www.wllwen.com/kejilunwen/huaxue/2387751.html
教材专著
