手性磷酸識別吲哚喹唑啉類生物堿的應(yīng)用研究
發(fā)布時間：2018-12-20 08:54
【摘要】：吲哚喹唑啉類生物堿廣泛存在于天然產(chǎn)物中,具有抗炎、抗菌、抗腫瘤等藥理活性,是重要的合成目標(biāo)。我們課題組之前報道了兩例催化不對稱合成含有手性叔醇結(jié)構(gòu)的吲哚喹唑啉類生物堿(Phaitanthrin A、Cephalanthrin-A及其衍生物)的研究工作。由于吲哚喹唑啉類生物堿存在極性大、溶解度差等諸多缺點(diǎn),因此在利用高效液相色譜檢測其對映體過量(ee值)時,而需要對該類化合物進(jìn)行一步或兩步的衍生以降低產(chǎn)物極性、增加其溶解性,從而大大地增加了篩選反應(yīng)條件的工作量,降低了研究效率。因此,發(fā)展一種快速、簡便、準(zhǔn)確地檢測吲哚喹唑啉類生物堿的光學(xué)純度的方法是十分必要的。近年來,利用手性溶劑化試劑和手性位移試劑與被檢測物的相互作用,核磁共振(1HNMR)光譜已被成功應(yīng)用于對映異構(gòu)體的光學(xué)純度的分析。在此基礎(chǔ)上,本論文主要研究了以手性磷酸作為手性識別劑通過核磁共振(1H NMR)測定吲哚喹唑啉類生物堿的光學(xué)純度。主要研究工作如下:1)以(R) -1,1'-聯(lián)二萘酚(R-BINOL)為手性源,經(jīng)MOM-Cl保護(hù)、碘代、Suzuki反應(yīng)、脫保護(hù)、與三氯氧磷反應(yīng)等多步反應(yīng)制備了手性磷酸。產(chǎn)物分子結(jié)構(gòu)通過NMR等方法確定。2)以色胺酮及其衍生物為起始原料與丙二酸在醋酸鎳、手性VA唑啉配體的作用下基于脫羧-Aldol反應(yīng)得到Cephalanthrin-A及其衍生物。同樣,以色胺酮及其衍生物為起始原料與丙酮在氨基酸鹽的作用下直接發(fā)生Aldol反應(yīng)得到產(chǎn)物Phaitanthrin A及其衍生物。產(chǎn)物分子結(jié)構(gòu)均通過NMR等方法確定。3)以合成得到的手性磷酸作為手性溶劑化試劑通過核磁對Cephalanthrin-A、Phaitanthrin A及它們的衍生物的對映異構(gòu)體進(jìn)行了識別。實(shí)驗(yàn)結(jié)果表明,手性磷酸對含有叔醇結(jié)構(gòu)的吲哚喹唑啉類生物堿具有良好的識別能力,對多類底物的對映異構(gòu)體均可實(shí)現(xiàn)基線分離;其中Cephalanthrin-A及其衍生物產(chǎn)生最大的化學(xué)位移差值達(dá)到0.02 ppm;對Phaitanthrin A及其衍生物識別產(chǎn)生的最大化學(xué)位移差值達(dá)到0.07 ppm。在此基礎(chǔ)上,我們利用該方法對手性的Cephalanthrin-A和Phaitanthrin A的光學(xué)活性進(jìn)行了檢測,取得了準(zhǔn)確的測量結(jié)果和良好的線性效應(yīng)。同時,氨基酸鹽催化條件下色胺酮與丙酮的反應(yīng)混合物可不經(jīng)純化直接在磷酸存在條件下通過核磁分析,可以極高的準(zhǔn)確性獲得產(chǎn)物的對映選擇性。此外,我們也根據(jù)實(shí)驗(yàn)結(jié)果提出了雙氫鍵的識別模型并通過實(shí)驗(yàn)進(jìn)行了初步驗(yàn)證。
[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.
【學(xué)位授予單位】：溫州大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：O629.3
本文編號：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.
【學(xué)位授予單位】：溫州大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：O629.3
【參考文獻(xiàn)】
相關(guān)博士學(xué)位論文 前1條
1 鮑宗必;色譜法拆分手性藥物中間體的應(yīng)用基礎(chǔ)研究[D];浙江大學(xué);2008年
，本文編號：2387751
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