二氢菲类化合物赫尔西酚的手性异构体研究

目的研究中华石仙桃(Pholidota chinensis Lindl)全草中分离得到的二氢菲类化合物赫尔西酚(hircinol)的立体结构并进行手性异构体的分离。方法采用多种柱色谱法进行分离纯化,并根据比旋光度和圆二色谱数据进行构型确定。利用手性色谱柱对分离得到的赫尔西酚进行手性异构体的拆分。结果与结论得到赫尔西酚A、赫尔西酚B两种手性异构体,两种异构体比例为78.9∶22.1,两种异构体的比旋光度分别为+25.4°和-25.4°。本文首次报道赫尔西酚是具有旋光性的对映体,经圆二色谱(CD)测定和解析证明赫尔西酚A为S构型、赫尔西酚B为R构型。     

圆二色谱测定技术在小分子化合物与DNA相互作用研究中的应用

圆二色谱(CD)是研究DNA构象随环境条件(如温度、离子强度和pH)的改变而变化的检测技术,也是研究DNA与配基(包括小分子和蛋白质等大分子)相互作用的有力工具。DNA的圆二色谱是由其骨架结构中的不对称糖分子和由这些糖分子的构型决定的螺旋结构产生的。根据配基对原有的DNA圆二色谱信号的影响,以及诱导产生的圆二色谱新信号(ICD)的不同特点,不仅可以得知配基与DNA具有相互作用,还可以推断配基与DNA结合的不同模式。研究表明这些ICD信号是由配基的电子跃迁偶极矩与DNA的碱基电子跃迁偶极矩在DNA不对称环境中发生偶合产生的。如果使用不同序列的短链DNA进行深入的研究,还可获知配基与DNA相互作用中的序列特异性。实验已经证明,圆二色谱法虽然灵敏度较低,但它具有快速、简便、样品用量少、对构象变化敏感及不受分子大小的限制等特点,可以作为核磁共振(NMR)和X-光单晶衍射技术的补充。本文将介绍圆二色谱技术在研究DNA与小分子化合物相互作用中的应用以及本实验室利用圆二色谱技术研究抗肿瘤新药的初步结果。由于圆二色谱可作为新药研究中发现先导化合物辅助筛选的手段,因此可用于发现更多以DNA为靶点的药物,如抗肿瘤药、抗菌药、抗病...     

麦冬中几种二氢高异黄酮的立体结构

目的研究麦冬中几种二氢高异黄酮的立体结构。方法采用光谱方法,并用圆二色谱确定立体结构。结果确定6个二氢高异黄酮的立体结构,鉴定结果为:5,7-d ihydroxy-6-m ethyl-8-m ethoxy-3(R)-(2-′hydroxy-4′-m ethoxy-benzyl)chroman-4-one(Ⅰa);5,7-d ihydroxy-6-methyl-8-methoxy-3(S)-(2′-hydroxy-4′-methoxybenzyl)chroman-4-one(Ⅰb);5,7-d ihydroxy-6,8-d im ethyl-3(R)-(3-′m ethoxy-4-′hydroxybenzyl)chrom an-4-one(Ⅱa);5,7-d ihydroxy-6,8-d im ethyl-3(S)-(3′-m ethoxy-4′-hydroxybenzyl)chrom an-4-one(Ⅱb);R-m ethyloph iopogonanone B(Ⅲ)和R-m ethyloph iopogonanone A(Ⅳ)。结论首次确定了6个二氢高异黄酮(Ⅰ~Ⅳ)的立体构型。     

绣毛酮和款冬酮的圆二色谱研究

报道了五个绣毛酮类(化合物1～5)和三个款冬酮类(化合物6～7,都是新化合物)的圆二色谱和八区律图,应用酮的八区律、平面环己烯酮规则和β,γ-不饱和酮等规则,确定了它们的AB环和BC环的稠合方式,从而决定了它们的绝对构型。     

大黄酸和大黄素与过氧化氢酶相互作用的研究

目的 研究大黄酸(RH)和大黄素(EM)与过氧化氢酶(CAT)的相互作用.方法 采用荧光光谱法、紫外光谱法和圆二色谱法进行研究.结果 确定了静态猝灭和非辐射能量转移是导致CAT荧光猝灭的主要原因,圆二色谱表明CAT中α-螺旋含量改变,热力学参数表明了药物分子与CAT之间的作用力类型.结论 药物分子与CAT之间有较强的结合作用,以疏水作用为主,反应自发进行,其中EM对CAT作用较强.     

CD在木脂素类化合物绝对构型测定中的应用

目的介绍圆二色谱(circular dichroism,CD)在木脂素类化合物绝对构型测定中的应用规律。方法在查阅国内外相关文献的基础上,对CD在芳基萘类、联苯环辛烯类、二苄基丁内酯类、双四氢呋喃类、苯并呋喃类等木脂素类化合物绝对构型测定中的应用规律进行综述。结果 CD在木脂素类化合物绝对构型测定中的应用具有一定的规律性。结论初步总结了CD在木脂素类化合物绝对构型测定中的应用规律,以期为该类化合物绝对构型测定提供有益的参考。     

用旋光谱和圆二色谱研究青蒿素降解产物失碳倍半萜内酯的立体化学

本文研究了青蒿素降解产物失碳倍半萜内酯(Ⅰ)的旋光谱和圆二色谱,推断了它的绝对构型。并用旋光谱和圆二色谱研究了(Ⅰ)的最终氧化产物(Ⅲ)和还原产物(Ⅳ)的立体化学及青蒿乙素的氢化产物(Ⅴ)的立体化学。根据这些结果并结合化学反应论证了(Ⅰ)的绝对构型。     

用旋光谱和圆二色谱研究青蒿素降解产物失碳倍半萜内酯的立体化学

本文研究了青蒿素降解产物失碳倍半萜内酯(Ⅰ)的旋光谱和圆二色谱,推断了它的绝对构型。并用旋光谱和圆二色谱研究了(Ⅰ)的最终氧化产物(Ⅲ)和还原产物(Ⅳ)的立体化学及青蒿乙素的氢化产物(Ⅴ)的立体化学。根据这些结果并结合化学反应论证了(Ⅰ)的绝对构型。     

应用圆二色谱法验证银杏内酯的绝对构型及银杏提取物的化学成分

目的验证银杏内酯A、B的绝对构型,并对银杏提取物的化学成分进行研究。方法应用圆二色谱法并依据Klyne内酯八区-扇形区律对银杏内酯A、B的绝对构型进行分析讨论;采用反复硅胶柱色谱、聚酰胺柱色谱、Sephadex LH-20柱色谱、高效液相色谱、重结晶等方法分离化学成分,1H-NMR1、3C-NMR等方法进行结构鉴定。结果从银杏提取物中分离得到11个化合物,分别鉴定为:芫花素(genkwanin,1)、异鼠李素(isorhamnetin,2)、山奈酚(kaempferol,3)、槲皮素(quercetin,4)、白果内酯(bilobalide,5)、银杏内酯A(ginkgolide A,6)、银杏内酯B(ginkgolide B,7)、银杏内酯C(ginkgolide C,8)、芦丁(rutin,9)、β-谷甾醇(-βsitosterol,10)、胡萝卜苷(daucosterol,11)。结论银杏内酯A、B的绝对构型与文献报道相符。     

箭根酮内酯化合物的圆二色谱研究

首次报道了九个箭根酮内酯类型化合物(都是新化合物)的圆二色谱。应用烯烃和酮的八区律、平面环己烯酮规则及γ-内酯的扇形规则,指定了它们的绝对构型。     

Assignment of absolute stereostructures through quantum mechanics electronic and vibrational circular dichroism calculations

Elucidation of absolute configuration of chiral molecules including structurally complex natural products remains a challenging problem in organic chemistry. A reliable method for assigning the absolute stereostructure is to combine the experimental circular dichroism (CD) techniques such as electronic and vibrational CD (ECD and VCD), with quantum mechanics (QM) ECD and VCD calculations. The traditional QM methods as well as their continuing developments make them more applicable with accuracy. Taking some chiral natural products with diverse conformations as examples, this review describes the basic concepts and new developments of QM approaches for ECD and VCD calculations in solution and solid states.     

Study on the absolute configuration of levetiracetam via density functional theory calculations of electronic circular dichroism and optical rotatory dispersion

Theoretical calculation of chiroptical properties has been a powerful tool for the absolute configuration assignment of chiral compounds including synthetic drugs and natural products. In the present work, time-dependent density functional theory (TDDFT) calculations of electronic circular dichroism (ECD) and optical rotatory dispersion (ORD) were employed to investigate the absolute configuration of levetiracetam, which is a widely used anticonvulsant drug. Nine conformers were generated by conformation search using the MMFF94 molecular mechanics force field, and the geometries were then optimized using the Becke 3-Lee-Yang-Parr (B3LYP) exchange-correlation functional. The population-averaged ECD spectrum was obtained by adding ECD spectrum of each conformer using Boltzmann statistics. The predicted ECD spectrum is in excellent agreement with the measured ECD spectrum of levetiracetam. Theoretical ORD spectra show the same tendency as the experimental data of levetiracetam, further confirming the absolute configuration derived from the ECD spectra. Our results demonstrated that the only chiral carbon atom of levetiracetam is unambiguously to be S configuration.     

Electronic circular dichroism behavior of chiral Phthiobuzone

Phthiobuzone is a bis(thiosemicarbazone) derivative with a single chiral center which has been used as a racemate in the clinical treatment of herpes and trachoma diseases. In this study, its two enantiomers were prepared from chiral amino acids and their absolute configurations were investigated by electronic circular dichroism (ECD) combined with modern quantum-chemical calculations using time-dependent density functional theory. It was found that solvation changed both the conformational distribution and the ECD spectrum of each conformer. The theoretical ECD spectra of the two enantiomers were in good agreement with the experimentally determined spectra of the corresponding isomers in dimethyl sulfoxide. The ECD behavior of the bis(thiosemicarbazone) chromophore in a chiral environment is also discussed. Our results indicate that ECD spectroscopy may be a useful tool for the stereochemical evaluation of chiral drugs.Key words: Electronic circular dichroism, Chiral drugs, Absolute configuration, Time-dependent density functional theory     

Spectroscopic methods for determining enantiomeric purity and absolute configuration in chiral pharmaceutical molecules

Analytical support, such as methods development, along with identification and characterization of intermediates and impurities, are critical in the development of a chemical process. The preparation of a drug substance requires the development of analytical methods for monitoring reactions and identifying impurities. Methods development for a chiral drug molecule is more difficult as the method must be capable of monitoring the overall reaction as well as possible racemization of starting materials and products. Chiral methods are often required to monitor the reaction steps of a synthesis, however, the development of enantiomeric purity methods are time-consuming and expensive. The use of chiroptical detectors, such as circular dichroism (CD), optical rotation (OR) and vibrational circular dichroism (VCD), can help to reduce or eliminate the need to develop chiral monitoring methods and also to predict absolute configuration. Recently, VCD has shown remarkable success with the latter and currently holds the most promise as a general, direct method that can be used as an alternative to X-ray crystallography. Each of the mentioned techniques can help analytical chemists to reduce the time associated with traditional enantiomeric purity methods development and to determine absolute configuration. This review will discuss the scope and limitations of these techniques for the rapid and routine determination of both enantiomeric excess and absolute configuration.     

Circular dichroism calculation for natural products

Determination of the absolute configuration (AC) is often a challenging aspect in the structure elucidation of natural products. When chiral compounds possess appropriate chromophore(s), electronic circular dichroism (ECD) may provide a powerful approach to the determination of their absolute configuration. Recently, ECD calculations by time-dependent density functional theory (TDDFT) have come to be used more commonly. In the present review, we give several examples of recent studies using TDDFT-calculated ECD spectra for the AC determination of natural products.     

Direct HPLC enantioseparation of omeprazole and its chiral impurities: Application to the determination of enantiomeric purity of esomeprazole magnesium trihydrate

Analytical and semipreparative high-performance liquid chromatography (HPLC) enantioseparation of the proton-pump inhibitor omeprazole (OME) and its potential organic chiral impurities were accomplished on the immobilised-type Chiralpak IA chiral stationary phase (CSP) under both polar organic and normal-phase conditions. The (S)-enantiomers were isolated with a purity of >99% ee and their absolute configuration was empirically assigned by circular dichroism (CD) spectroscopy. A chemo- and enantioselective HPLC method was validated to control the enantiomeric purity of the (S)-enantiomer of OME (ESO), an active ingredient contained in drug products, in the presence of chiral and achiral related substances. The precision, linearity and accuracy of the determination of the (R)-impurity as well as the recovery of ESO from a pharmaceutical preparation were determined.     

An evaluation of four commercial HPLC chiral detectors: a comparison of three polarimeters and a circular dichroism detector

With increasing frequency, new drug candidates being introduced into pharmaceutical drug pipelines are chiral. Often only one enantiomer exhibits the desired biological activity and the other enantiomer may exhibit undesired side effects, thereby making chiral purity an important parameter. The introduction of chiral analysis adds additional complications in drug development. The pharmaceutical industry is constantly striving to streamline processes and improve efficiencies in an effort to move molecules to market quickly. In order to simplify the process of chiral method development, chiral screening can be set up, however a successful chiral screen depends on optimizing two factors: the column and the detector. The following work investigated the second factor and evaluated two types of commercially available chiral detectors for their possible use in chiral method development and screening: polarimeters and circular dichroism (CD) detectors. Linearity, precision, and the limit of detection (LD) of six compounds (trans-stilbene oxide, ethyl chrysanthemate, propranolol, 1-methyl-2-tetralone, naproxen, methyl methionine) on four commercial detectors (three polarimeters and one CD detector) were determined experimentally and the limit of quantitation (LQ) calculated from the experimental LD. Trans-stilbene oxide worked well across all the detectors, showing good linearity, precision and low detection limits. However, the other five compounds proved to be more discriminating and showed that the circular dichroism detector performed better as a detector for chiral screens, over the polarimeters.     

圆二色谱在天然产物——二萜双向酯和娃儿藤碱的结构分析中的应用

本文报道了四个二萜双内酯和五个娃儿藤碱的圆二色谱、扇形图和反八区律,其中6和8为新化合物。文中提出的反八区律图首先应用于二萜双内酯的构型测定,我们应用有关的规则,所预测的这些化合物的Cotton效应和实测结果一致,从而指定了它们的绝对构型。     

圆二色谱在天然产物——二萜双向酯和娃儿藤碱的结构分析中的应用

本文报道了四个二萜双内酯和五个娃儿藤碱的圆二色谱、扇形图和反八区律,其中6和8为新化合物。文中提出的反八区律图首先应用于二萜双内酯的构型测定,我们应用有关的规则,所预测的这些化合物的Cotton效应和实测结果一致,从而指定了它们的绝对构型。