计算化学的方法确定天然产物绝对构型共37页
天然产物的结构鉴定和化学合成
天然产物的结构鉴定和化学合成天然产物是指存在于自然界中的化合物，如植物、动物、微生物等生物体内所含有的化合物。
这些天然产物具有丰富的结构和多样的生物活性，对于药物研发和农业发展具有重要意义。
然而，由于其复杂的结构和多样的化学反应，天然产物的结构鉴定和化学合成一直是有挑战性的课题。
结构鉴定是确定天然产物的分子结构和化学组成的过程。
常用的结构鉴定方法包括质谱、核磁共振和红外光谱等。
质谱分析可以通过测量化合物分子的质荷比来确定其分子量和分子式，通过质谱碎片图可以推断出化合物的结构。
核磁共振可以通过测量核磁共振信号的化学位移和耦合常数来确定化合物的结构。
红外光谱可以通过测量化合物的振动频率和吸收峰位来确定化合物的官能团和结构。
除了这些传统的结构鉴定方法外，现代技术如高分辨质谱、二维核磁共振和X射线晶体学等也被广泛应用于天然产物的结构鉴定。
这些新技术可以提供更准确和详细的结构信息，帮助化学家更好地理解天然产物的结构和性质。
一旦天然产物的结构被确定，化学合成就成为了进一步研究和应用的关键步骤。
天然产物的化学合成可以通过全合成和半合成两种方法实现。
全合成是指从简单的起始物质出发，通过一系列有机合成反应逐步构建目标天然产物的分子骨架。
半合成是指利用天然产物的某些部分结构作为起始物质，通过化学修饰或改造来合成新的天然产物。
天然产物的化学合成是一项复杂而具有挑战性的任务。
由于天然产物的结构复杂性和反应多样性，化学家需要设计和优化一系列合成路线和反应条件。
同时，天然产物的合成还面临着合成效率和产量的问题。
一些天然产物的合成需要多步反应和复杂的分离纯化步骤，这对化学家的技术和耐心提出了很高的要求。
然而，天然产物的结构鉴定和化学合成也为科学家带来了无限的创新和发展机遇。
通过研究和合成天然产物，科学家可以揭示其生物活性和作用机制，为药物研发和农业发展提供新的思路和方法。
此外，天然产物的结构鉴定和化学合成也为有机化学的发展做出了重要贡献，推动了有机合成方法学的不断进步。
7测定绝对构型
变温实验 加入使溶液变稠的物质，使构象转换的速率变低 将样品分子进行化学修饰，以便测得NOE
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应用改进Mosher法应注意的问题
由于非对映异构体的化学位移差值通常较小，所以在 测定这两个非对映异构体的氢谱时，应注意以下几点： R-和S-MTPA酯或酰胺的浓度要相同 在短时间内测定其一维谱 两个溶剂峰的化学位移差值应小于0.002ppm 不能用C6D6、C5D5N等溶剂
H5a H5b CH 2N+(CH3)3 H4
NMR法测定有机化合物绝对构型
NMR法测定有机化合物绝对构型
NMR法测定有机化合物绝对构型
仲醇绝对构型的测定
Mosher法 :
Mosher法的发展过程
upfield relative to
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测定绝对构型的方法
化学相关法 NMR谱学方法测定构型构象（Mosher 法） ORD 法 CD 法 CD激发态手征性方法 X-ray 衍射法
NMR核磁共振方法
化学位移
13C化学位移
取代基的-旁式效应将使-位置的碳原子产生高场位移
2 天然产物的提取分离和结构鉴定课件PPT
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1溶剂法
1、溶剂提取法及其原理
溶剂提取法：是根据天 然产物中各种成分在溶 剂中的溶解性质，选用 对活性成分溶解度大， 对不需要溶出成分溶解 度小的溶剂，而将有效 成分从药材组织内溶解 出来的方法。
原理：根据“相似相溶” 原理，选择与化合物极 性相当的溶剂将化合物 从植物组织中溶解出来， 同时，由于某些化合物 的增溶或助溶作用，其 极性与溶剂极性相差较 大的化合物也可溶解出 来。
Chapter 2
天然产物的提取分离和结构 鉴定
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教学目的与要求：
•了解天然产物化学的预实验与提取 •掌握天然产物化学成分提取分离的原理及方法 •掌握色谱分离方法 •了解天然产物化学结构的测定方法
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主要内容
❖ 一、天然产物化学成分的预实验与提取 ❖ 二、色谱分离分析方法 ❖ 三、结晶和重结晶 ❖ 四、天然产物化学成分的结构鉴定
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煎煮法
操作方法
将天然物原料 粗粉加水加热煮 沸，使其成分提 取出来的方法。
特点
此法简便，原料中大部 分成分被不同程度地提出， 但含挥发性成分及有效成分 遇热易破坏的原料不宜用此 法，对含有多糖类原料，煎 煮后，溶液比较粘稠，过滤 比较困难
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回流提取法：
应用有机溶剂加热提取，需采用回流加热装置，以免 溶剂挥发损失。小量操作时，可在圆底烧瓶上连接 回流冷凝器。溶剂浸过药材表面约1～2cm。在水浴 中加热回流，一般保持沸腾约1小时后放冷过滤，再 在药渣中加溶剂，作第二、三次加热回流分别约半 小时，或至基本提尽有效成分为止。此法提取效率
•极性最大的有机溶剂：甲醇
天然产物绝对构型的确定_英文_孔令义
Chinese Journal of Natural Medicines 2013, 11(3): 0193−0198doi: 10.3724/SP.J.1009.2013.00193Chinese Journal of Natural MedicinesDetermination of the absolute configuration of naturalproductsKONG Ling-Yi 1*, WANG Peng 1, 21State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing210009, China 2School of Pharmacy, Yancheng Teachers University, Yancheng 214002, ChinaAvailable online 20 May 2013[ABSTRACT] Structural elucidation of natural products is always one of the most important tasks for natural product researchers in related fields. Particularly, the absolute configuration (AC), being a great challenge for natural product chemists, has attracted much attention. During the past few decades, many techniques and approaches have been developed to determine the AC of natural products, including direct (or absolute) methods, e.g. X-ray diffraction (XRD), electronic and vibrational circular dichroism (ECD and VCD), and Raman optical activity (ROA), as well as indirect (or relative) methods using a reference or a derivatizing agent with known AC, e.g. CD with empirical rules and nuclear magnetic resonance (NMR) utilizing anisotropic effects of chiral derivatizing agents. How-ever, none of the currently applied techniques is capable of dominating AC determination, since they each have their respective limita-tions corresponding to the different structural features. This mini review summarizes most of the techniques and methods which are commonly used in AC assignment of natural products, or have potential application prospects, and briefly describes their principles, advantages and limitations.[KEY WORDS] Absolute configuration; Natural products; XRD; NMR; ORD; CD; ECCD; ECD, VCD; ROA; ab initio calculations[CLC Number] R284 [Document code] A [Article ID] 1672-3651(2013)03-0193-061 IntroductionEver since the tetrahedral structure of carbon atoms in or-ganic molecules was proposed by van’t Hoff and Lebel in the19th century [1], the spatial orientation of molecules, i.e. theirstereochemistry, has become one of the most important featuresof organic compounds that need to be revealed by chemists. Inthe pharmaceutical sciences, stereochemistry is of prime im-portance in the interaction of drugs and organisms, since allreceptors in the human body are chiral and probably exhibitdifferent pharmacologic effects and pharmacokinetics betweentwo enantiomers [2]. On account of this, in 1992, the US FDArequired that the properties of each enantiomer in a racemateshould be studied separately before the drug was taken to themarket as one pure enantiomer, or as a racemate [3].A large number of commercialized drugs (ca. 40% in the[Received on]05-Apr.-2013 [Research funding] This project was supported by the National Natural Science Foundation of China (No. 21272275), and the Na-tional Key Scientific and Technological Special Projects (No.2009ZX09502-011).[*Corresponding author] KONG Ling-Yi: Prof., Tel:86-25-83271405, E-mail: cpu_lykong@These authors have no conflict of interest to declare. last 25 years) directly or indirectly came from natural prod-ucts [4], and natural product chemistry is still one of the majorfields of interest for medicinal chemists in searching for lead compounds. As a result, the structural elucidation of novel natural products, including the characterization of constitu-tion, relative configuration (RC) and absolute configuration (AC), is essential in this field. In current natural product re-search, single-crystal X-ray diffraction (XRD) [5-6], nuclear magnetic resonance (NMR) [7-9] and chiroptical methods [10-13] are the most important and popular tools for determining the AC of novel natural products. From another perspective, the currently used methods can be classified into direct (or abso-lute) or indirect (or relative) according to whether a reference with a known AC has been used or not. For example, Mosher’s method is a well-known indirect one in establishing the AC of natural products containing hydroxyl, amino or carboxyl groups, while XRD is a direct and predominantmethod for molecules having anomalous scattering effects.This mini review will briefly introduce the above mentioned techniques and describe their advantages and limitations, respectively.It should be pointed out that this paper does not cover allaspects in AC determination, and focuses on the instrumental methods. For example, total synthesis, which has a long-history and is an ultimate approach, but with great chal-194 Chin J NatMed May 2013 V ol. 11 No.32013年5月 第11卷 第3期lenges, is still considered the most reliable means in AC de-termination. However, it exceeds the scope of the present review. An up-to-date review on this topic was presented by Maier in 2009 [14].2 Single-Crystal X-Ray Diffraction (XRD)Over the years, XRD of single crystals has been em-ployed as a preferable and reliable technique by chemists to establish the AC of natural products, for it has the ability to “see” the arrangement of atoms in a single crystal. In practice, the application of XRD may be divided into two forms: direct and indirect [5]. Anomalous scattering effect (also called anomalous dispersion or resonant scattering effect), which was first introduced by Bijvoet in 1951 [15], and could be used to distinguish a structure from its mirror image on an absolute basis, is the key point in the direct determination of AC. However, only heavy atoms (e.g. S, P, halogen, etc.) exhibit obvious anomalous scattering, while most natural products simply comprise C, H, O and N, which barely exhibit ob-servable anomalous scattering. Fortunately, the magnitude of anomalous scattering is related to the atomic number and to the radiation wavelength. In general, the anomalous scatter-ing effect increases with the atomic number and the wave-length. For those molecules containing only light atoms (C, H, O and N), the anomalous scattering under Mo K α radiation is rather small, and by contrast Cu K α radiation may be a good choice [16]. A large number of determinations are available on the basis of Cu radiation [17-20]. Alternatively, heavy atoms can be introduced into a sample to endow it the ability of exhibiting strong anomalous scattering under Mo radiation, e.g. forming hydrochlorides or hydrobromides for alka-loids [21-23].Flack suggested a parameter x (known as Flack parame-ter and obtained by some numerical procedures, 0 ≤ x ≤ 1) to account for twinning by inversion in a crystal [24], which can be used to evaluate the reliability of AC assignment com-bined with its standard uncertainty u in practical use [25].In spite of the advances in computers, CCD diffractome-ter and other hardware, obtaining a high-quality crystal is always the prerequisite, in another words, a limitation, for XRD analysis. This art used to be practiced by most organic chemists, and is still vital in some present structural determi-nations of complex natural products, e.g. compounds from marine sources with highly flexible structures and an array of complicated asymmetric moieties [26], because XRD is some-times the technique of last resort.In some cases, however, one can introduce a small chiral molecule with a known AC to the sample, e.g. based on the formation of acid-base salts [27-28], covalent bonds [29] (esters, amides, ethers, etc.), or even complexes [30], and produce a single crystal for XRD analysis. Since a reference center exists within the crystal, the AC of the sample can be unam-biguously obtained, regardless of anomalous scattering. This application is considered indirect due to the introduction of references with known AC. It should be remembered that screening of an appropriate reference might be in conflict with the small amount of sample available [2].3 Nuclear Magnetic Resonance (NMR)An NMR-based method for AC determination was originally proposed by Mosher in 1973 [31], and subsequently developed by Ohtani [32], Seco [9], and many other researchers [8]. The principle for this method lies in the difference in ani-sotropic effects between two diastereomers which are pre-pared from the substrate with a pair of enantiomeric chiral derivatizing agents (CDAs), respectively. In practical use, it is the differences in chemical shifts (ΔδRS or ΔδSR ) between the two derivatives of a substrate that are used to assign the AC. The CDAs are the keys to the method, and generally incorporate: (1) a polar or bulky group to maintain a particu-lar conformation, (2) a functional group (e.g. carboxyl) for combination with the substrate, and (3) a group (e.g. an aro-matic moiety) producing a strong and space-oriented anisot-ropic effect that selectively affects different regions of the substrate [9]. MTPA (α-methoxy-α- trifluoromethylphenylace-tic acid), known as Mosher’s reagent, was the initially used, and is the most popular CDA along with its acid chloride (MTPA-Cl). Attention should be paid to the stereochemistry of the corresponding MTPA esters because (R )-MTPA pro-duces the (R )-MTPA ester, whereas (R )-MTPA-Cl produces the (S )-MTPA ester. The other commonly used CDAs include MPA [33], 9-AMA [34], and M αNP [5], etc., and sometimes show preferable results in practical use. For example, both 9-AMA and M αNP have a larger aromatic group that exhibits stronger anisotropic effect. The MPA ester is more reliable due to the preferred conformation that results in larger shiel-ding effect from the phenyl group [8].Monofunctional molecules, e.g. alcohols [9], amines [35] and carboxylic acids [36], are the most commonly analyzed substrates using this method, while polyfunctional com-pounds involve a more complex situation on account of the superposition of anisotropic effects produced by two or more aromatic groups in CDAs, and do not agree with the models of monofunctional substrates [37]. Seco has given a compre-hensive review on this topic. In some cases, polyfunctional substrates with hydroxyl, amino or carboxyl groups far away from one another, of course, can be treated as monofunctional in this regard [38].The NMR method generally comprises double derivati-zation of substrates with two enantiomers of CDA, and re-quires relatively large quantity of samples. More recently, however, the application of single derivatization, i.e . prepar-ing a derivative from only one enantiomer of CDA and com-paring the NMR spectrum of the derivative with that re-corded at a lower temperature (or the spectrum of the deriva-tive after forming a barium complex) [39-40], has received a great deal of attention due to the higher efficiency and the consumption of only half of the precious substrate. Anotherup to date application involves the experimental improve-ment in preparation of derivatives, e.g. using polymer sup-ported CDAs to react with the substrate in the NMR tubing, which eliminates the purification process, decreases the loss of sample and greatly shortens the experimental time [41-43].Besides the application of CDAs, there is another un-common approach to determine AC by NMR, i.e . adding chiral solvating agents (CSAs), ion-pairing agents, or metal complexes [8] to the substrate, and comparing the differences in chemical shifts of two enantiomers. In this way, the sub-strate does not react with the added reagents and therefore exhibits very small differences in chemical shifts by contrast to its enantiomer, which is the main limitation for this method. Additionally, no clear-cut correlations between the AC and the NMR spectra can be established [37]. As a result, this method is practically used to determine the enantiomeric purity.4 Chiroptical MethodsOptical rotation (or rather specific rotation), a physical constant characterizing optically active molecules, was originally discovered by Arago and Biot in the early 19th century [44]. After that, a variety of chiroptical methods based on the different interactions of chiral molecules with left- and right-circularly polarized light have emerged, e.g. optical rotatory dispersion (ORD), electronic circular dichroism (ECD), vibrational circular dichroism (VCD) and Raman optical activity (ROA). However, they involve a distinct na-ture: OR and ORD are based on the difference in velocity of circularly polarized lights through the medium (Δn ), while CD (including ECD, VCD and ROA) depends on the differ-ence in absorption (ΔA or Δε). In addition, ECD concerns the absorption of UV-Vis light (electronic transition), while VCD and ROA involve the absorption at mid-IR region (vibrational transition and Raman scattering, respectively).OR is measured at a single wavelength (often at 589 nm, the Na D-line), and its successive measurement across the scanning wavelengths gives the so-called ORD spectrum, which is especially suitable for those compounds having no chromophores in the UV-Vis region [45]. The advance in quantum mechanical methods in recent years has brought about a renaissance of OR (ORD) in structural elucidation [46-47]. Although OR (ORD) has its place in current research, yet, it is much less popular than CD due to the easier inter-pretation of spectra for the latter.The early application of CD relied on empirical or semi-empirical rules, e.g. the famous octant rule [48], which has been used in some cases until now, despite known limita-tions and exceptions [49-50]. Another empirical, but robust, application of CD involves the formation of a CD-active transition metal complex (Mo, Rh or Ru) [51-52], and is espe-cially powerful for UV-Vis transparent or acyclic alcohols [53] (or amines, diols, aminols, etc.) without interference from other electron-donating groups. Exciton chirality CD (ECCD), a widely used non-empirical chiroptical method developed byHarada and Nakanishi in the 1970s [54], and has been consid-ered a reliable, but scope-limited, CD method. The mecha-nism can be briefly described as follows: if a chiral molecule incorporates (or can be combined with) two identical or similar chromophores, there will be an exciton couplet be-tween the two equivalent transitions on the two chromopho-res, which gives rise to a couplet of Cotton effects of two chromophores in the CD spectrum. The couplet is either pos-itive or negative according to the absolute angle of twist between the two transition dipoles. Given that a particular natural product has two chromophores and a single prevailing conformation, ECCD supplies a convenient and reliable ap-proach to establish the AC [55-57].CD is concerned with the electronic transition (ECD) or vibrational transition (VCD), and therefore can be theoreti-cally predicted by quantum chemical calculation. By com-paring the measured CD spectrum (mostly in solution) with the time-dependent density functional theory (TD DFT) cal-culated CD spectrum of an assumed configuration, one can easily assign the AC of a chiral compound, which represents a state-of-the-art technique for direct AC determination, and has led to the boom period of chiroptical methods in the past decade [58]. The most popular software for DFT calculation is Gaussian with typical functional and basis set B3YLP/6-31G ∗, which has been found to be a good balance between accuracy and time cost [12].Among the chiroptical methods addressed in this review, ECD has been most widely used over the past decade [59-62]. From an experimental standpoint, ECD measures the differ-ential response of a chiral molecule to the modulation of UV/Vis radiation between left- and right-circularly polarized states [45]. Compared with ORD, VCD and ROA, ECD has one or two orders of magnitude higher sensitivity, and the measurement of ECD needs only sub-μg amounts of sample. The presence of UV-Vis active chromophores in the molecule is a prerequisite, which is a limitation for ECD. In addition, highly flexible or large molecules are not practical for ab initio calculation in the state of the art due to the large cost in computation. VCD and ROA require no chromophores in the UV-Vis region, and therefore have a larger scope than ECD [63]. Furthermore, they show abundant signals, high resolution and good conformational sensitivity, which lead to high reli-ability. As a result, VCD and ROA have attracted increasing attention in recent years.CD spectra are generally recorded in solution for natural products, and conformational analysis is the most important, but inevitable, step in the whole process. However, for those molecules having high conformational flexibility, conforma-tional analysis might become a very time-consuming, even impossible, mission due to the large number of calculations necessary. In addition, the inclusion of a solvent effect is always inevitable. These limitations can be eliminated by recording CD spectra in the solid state for crystalline com-pounds, and then comparing the spectra with the predicted196 Chin J NatMed May 2013 V ol. 11 No.32013年5月 第11卷 第3期ones via ab initio calculation, which adopts the XRD geome-try as input [2]. This strategy totally eliminates the step of conformational search, greatly reduces the calculation pro-cedure, and improves the accuracy. As the most potent and popular techniques in AC determination, chiroptical methods have been utilized by more and more laboratories. Polava-rapu, however, has argued that many determinations have used only one chiroptical method to derive the molecular structural information, which gave an ambiguous or even a mis-assigned configuration in some cases. So the routine application of more than one chiroptical method for any chiral molecule was recommended [64].5 Other MethodsResearchers found that lipases show high stereoselectiv-ity toward many secondary alcohols, and proposed an em-pirical rule for AC determination of secondary alcohols. The rule was based on the X-ray structures of lipases and the rela-tive sizes of substituents of alcohols. Jing reviewed the AC determination of secondary alcohols by lipase-catalyzed ki-netic resolution in 2008 [65]. In addition, biosynthetic infer-ences also have been utilized in stereochemical investigation, in combination with spectroscopic methods [66].Fig. 1 Strategies in choosing a preferable AC determination method for a given natural product6 ConclusionsAlthough a variety of methods or techniques have been used in AC assignment, they each have their respective scopes and limitations as aforementioned. Thus, when a nov-el natural product is ready for AC assignment, one should carefully study the chemical structure and consider the phys-icochemical properties of this compound before a preferable method is chosen (Fig. 1). For example, XRD is often the optimal choice for crystalline sample; NMR is especially suitable for rapid analysis of small amount of alcohols (or amines); and ECD has overwhelming superiority for axial and planar chiral molecules having UV-Vis active chromo-phores. 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Three new germacrane-typesesquiterpene stereoisomers from the flowers of Chrysanthemum indicum [J]. Fitoterapia , 2012, 83(8): 1675-1679.[20] Tong Y , Luo JG , Wang R, et al . New cyclic peptides withosteoblastic proliferative activity from Dianthus superbus [J]. Bioorg Med Chem Lett , 2012, 22(5): 1908-1911.[21] Zeng WG, Liang WZ, He CH, et al . An alkaloid fromCorydalis bungeana [J]. Phytochemistry , 1988, 27(2): 599-602. [22] Camps P, Contreras J, Font-Bardia M, et al . Enantioselectivesynthesis of tacrine-huperzine A hybrids. Preparative chiral MPLC separation of their racemic mixtures and absolute configuration assignments by X-ray diffraction analysis [J]. Tetrahedron: Asymmetry , 1998, 9(5): 835-849.[23] Przybyl AK, Flippen-Anderson JL, Jacobson AE, et al .Practical and high-yield syntheses of dihydromorphine from tetrahydrothebaine and efficient syntheses of (8S )-8-bromomorphide [J]. J Org Chem , 2003, 68(5): 2010-2013.[24] Flack HD. On enantiomorph-polarity estimation [J]. Acta CrystA , 1983, 39(6): 876-881. [25] Flack HD, Bernardinelli G. Reporting and evaluatingabsolute-structure and absolute-configuration determinations [J]. J Appl Crystallogr , 2000, 33: 1143-1148.[26] Molinski TF, Morinaka BI. Integrated approaches to theconfigurational assignment of marine natural products [J]. Tetrahedron , 2012, 68(46): 9307-9343.[27] Li YX, Ma HY, Lin ZY, et al . Synthesis and determination ofabsolute configuration of (R )-(+)-5-{4-[2-(5-chloroindazol- 2-yl)ethoxy]benzyl}-5-methyl-2,4-oxazolidinedione [J]. Chin J Org Chem , 2009, 29(8): 1254-1258.[28] Faigl F, Vas-Feldhoffer B, Kubinyi M, et al . Efficient synthesisof optically active 1-(2-carboxymethyl-6-ethylphenyl)-1H- pyrrole-2-carboxylic acid: a novel atropisomeric 1-arylpyrrole derivative. [J] Tetrahedron: Asymmetry , 2009, 20(1): 98-103. [29] Kosaka M, Watanabe M, Harada N. Enantioresolution by thechiral phthalic acid method: absolute configurations of substituted benzylic alcohols [J]. Chirality , 2000, 12(5-6):362-365.[30] Toda F, Tanaka K, Miyahara I, et al . Role of methanol in chiralcombinations of host-guest molecules in the inclusion crystal: structure determination by X-ray crystallography [J]. J Chem Soc Chem Commun 1994, (15): 1795-1796.[31] Dale JA, Mosher HS. Nuclear magnetic resonance enantiomerregents. Configurational correlations via nuclear magnetic resonance chemical shifts of diastereomeric mandelate, O-methylmandelate, and α-methoxy-α-trifluoromethyl phenylacetate (MTPA) esters [J]. J Am Chem Soc . 1973, 95(2): 512-519.[32] Ohtani I, Kusumi T, Kashman Y , et al . High-field FT NMRapplication of Mosher’s method. The absolute configurations of marine terpenoids [J]. J Am Chem Soc , 1991, 113(11): 4092-4096.[33] Latypov SK, Seco JM, Quiñoá E, et al . MTPA vs MPA in thedetermination of the absolute configuration of chiral alcohols by 1H NMR [J]. J Org Chem , 1996, 61(24): 8569-8577.[34] Seco JM, Quiñoá E, Riguera R. 9-Anthrylmethoxyacetic acidesterification shifts-correlation with the absolute stereochemistry of secondary alcohols [J]. Tetrahedron , 1999, 55(2): 569-584.[35] Fujiwara T, Segawa M, Fujisawa H, et al . Reliable assignmentof absolute configuration of chiral amines based on the analysis of 1H NMR spectra of their CFTA amide diastereomers [J]. Tetrahedron: Asymmetry , 2008, 19(7): 847-856.[36] Hoye TR, Hamad AS, Koltun DO, et al . An NMR method fordetermination of configuration of β-substituted carboxylic acids [J]. Tetrahedron Lett , 2000, 41(14): 2289-2293.[37] Seco JM, Quiñoá E, Riguera R. Assignment of the absoluteconfiguration of polyfunctional compounds by NMR using chiral derivatizing agents [J]. Chem Rev , 2012, 112(8): 4603-4641.[38] Zhang Y, Wang JS, Wang XB, et al . Polystanins A-D, fournew protolimonoids from the fruits of Aphanamixis polystachya [J]. Chem Pharm Bull , 2013, 61(1): 75-81.[39] Latypov, SK, Seco, JM, Quiñoá E, et al . Are both the (R )- andthe (S )-MPA esters really needed for the assignment of the absolute configuration of secondary alcohols by NMR? The use of a single derivative [J]. J Am Chem Soc , 1998, 120(5): 877-882.[40] García R, Seco JM, Vázquez SA, et al . Role of Barium(II) inthe determination of the absolute configuration of chiral amines by 1H NMR spectroscopy [J]. J Org Chem , 2006, 71(3): 1119-1130.[41] Arnauld T, Barrett AGM, Hopkins BT, et al . Facile andpurification free synthesis of Mosher amides utilizing a ROMPgel supported reagent [J]. Tetrahedron Lett , 2001, 42 (46): 8215-8217.[42] Gao JH, Haas H, Wang KY, et al . The use of MPA amide forthe assignment of absolute configuration of a sterically hindered cyclic secondary amine by 'mix and shake' NMR method [J]. Magn Reson Chem , 2008, 46(1): 17-22.[43] Porto S, Seco JM, Espinosa J, et al . Resin-bound chiralderivatizing agents for assignment of configuration by NMR Spectroscopy [J]. J Org Chem , 2008, 73(15): 5714-5722.[44] Xing QY , Pei WW, Xu RQ, et al . Organic Chemistry [M].Higher Education Press, 2005: 100.[45] Petrovic AG , Navarro-Vazquez A, Alonso-Gomez LJ. Fromrelative to absolute configuration of complex natural products: interplay between NMR, ECD, VCD, and ORD assisted by ab initio calculations [J]. Curr Org Chem , 2010, 14(15):198 Chin J NatMed May 2013 V ol. 11 No.32013年5月 第11卷 第3期1612-1628. [46] Polavarapu PL. Optical rotation: Recent advances indetermining the absolute configuration [J]. Chirality , 2002, 14 (10): 768-781.[47] Zhao SD, Shen L, Luo DQ, et al . Progression of absoluteconfiguration determination in natural product chemistry using optical rotation (dispersion), matrix determinant and electronic circular dichroism methods [J]. Curr Org Chem , 2011, 15(11): 1843-1862.[48] Yamada K, Kunieda T. Studies on optical rotatory dispersionand cicular dichroism. I. Absolute configuration of cyclic alpha-amino-ketones and octant rule [J]. Chem Pharm Bull , 1967, 15(4): 490-498.[49] Wang YQ, Bao L, Yang XL, et al . Four new cuparene-typesesquiterpenes from Flammulina velutipes [J]. Helv Chim Acta , 2012, 95(2): 261-267.[50] Krohn K, Sohrab MH, van Ree T, et al . Dinemasones A, B andC - new bioactive metabolites from the endophytic fungus Dinemasporium strigosum [J]. Eur J Org Chem , 2008, (33): 5638-5646.[51] Di Bari L, Pescitelli G , Pratelli C, et al . Determination ofabsolute configuration of acyclic 1,2-diols with Mo 2(OAc)4. I. Snatzke's method revisited [J]. J Org Chem , 2001, 66(14): 4819-4825.[52] Frelek J, Klimek A, Ruskowska P. Dinuclear transition metalcomplexes as auxiliary chromophores in chiroptical studies on bioactive compounds [J]. Curr Org Chem , 2003, 7(11): 1081-1104.[53] Yin H, Luo JG , Kong LY . Tetracyclic diterpenoids withisomerized isospongian skeleton and labdane diterpenoids from the fruits of Amomum kravanh [J]. J Nat Prod , 2013, 76(2): 237-242.[54] Harada N, Nakanishi K. Exciton chirality method and itsapplication to configurational and conformational studies of natural products [J]. Acc Chem Res , 1972, 5(8): 257-263.[55] Luo J, Wang JS, Wang XB, et al . Phragmalin-type limonoidorthoesters from Chukrasia tabularis var. velutina [J]. Chem Pharm Bull , 2011, 59(2): 225-230.[56] Han Z, Luo J, Kong LY . Two new tocopherol polymers fromthe seeds of Euryale ferox [J]. J Asian Nat Prod Res , 2012, 14 (8): 743-747.[57] Zhang M, Linuma M, Wang JS, et al . Terpenoids fromChloranthus serratus and their anti-inflammatory activities [J]. J Nat Prod , 2012, 75(4): 694-698.[58] Bringmann G , Bruhn T, Maksimenka K, et al . The assignmentof absolute stereostructures through quantum chemical circular dichroism calculations [J]. Eur J Org Chem , 2009, (17): 2717-2727.[59] Li X, Luo JG , Wang XB, et al . Phenolics from Leontopodiumleontopodioides inhibiting nitric oxide production [J]. Fitoterapia , 2012, 83(5): 883-887. [60] Zhang F, Wang JS, Gu YC, et al .Cytotoxic andanti-inflammatory triterpenoids from Toona ciliate [J]. J Nat Prod , 2012, 75(4): 538-546. [61] Wang XB, Zhang Y , Wang JS, et al . Spectroscopiccharacterizations, X-ray studies, and electronic circular dichroism calculations of two alkaloid triterpenoids [J]. Struct Chem , 2011, 22(6): 1241-1248.[62] Lv XQ, Luo JG , Wang XB, et al . Four new sesquiterpenoidsfrom the fruits of Alpinia oxyphylla [J]. Chem Pharm Bull , 2011, 59(3): 402-406.[63] Stephens PJ, Devlin FJ, Pan JJ. The determination of theabsolute configurations of chiral molecules using vibrational circular dichroism (VCD) spectroscopy [J]. Chirality , 2008, 20 (5): 643-663.[64] Polavarapu PL. Why is it important to simultaneously use morethan one chiroptical spectroscopic method for determining the structures of chiral molecules [J]. Chirality , 2008, 20(5): 664-672. [65] Jing Q, Kazlauskas RJ. Determination of absoluteconfiguration of secondary alcohols using lipase-catalyzed kinetic resolutions [J]. Chirality , 2008, 20(5): 724-735.[66] Lane AL, Moore BS. A sea of biosynthesis: marine naturalproducts meet the molecular age [J]. Nat Prod Rep , 2011, 28(2): 411-428.[67] Ma L, Gu YC, Luo JG , et al . Triterpenoid saponins fromDianthus versicolor [J]. J Nat Prod , 2009, 72(4): 640-644.天然产物绝对构型的确定孔令义1*, 王 鹏1, 21中国药科大学“天然药物活性组分与药效”国家重点实验室, 天然药物化学教研室, 南京 210009; 2盐城师范学院药学院, 盐城 214002【摘 要】 天然产物结构研究一直是天然药物化学相关领域最重要的工作之一, 尤其对天然产物绝对构型(AC)的确定更是具有挑战性的研究内容, 目前得到国内外学者越来越多的关注。
天然产物立体构型的确定方法
萜类化合物的立体构型确定
总结词
萜类化合物的立体构型可以通过化学 反应和物理方法来确定。
详细描述
萜类化合物的立体构型可以通过化学 反应，如氧化、还原、水解等，以及 通过色谱法、紫外光谱、红外光谱和 核磁共振等物理方法来确定。
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天然产物立体构型确定的 意义与应用
药物研发
要点一
药物设计和优化
确定天然产物的立体构型有助于理解其与靶点的相互作用 ，为药物设计和优化提供关键信息。
要点二
新药发现
了解天然产物的立体构型有助于发现具有新作用机制和靶 点的新药，加速新药研发进程。
生物活性研究
活性机制
确定天然产物的立体构型有助于理解其生物活性机制， 为药物作用机制研究提供重要依据。
质谱法
总结词
一种通过分析离子质量和电荷比来确定分子结构的方法。
详细描述
质谱法是利用电场和磁场将分子电离成离子，通过测量离子的质量和电荷比来确定分子的组成和结构 。该方法具有高灵敏度和高分辨率，适用于各种类型的分子，包括大分子和不易制备晶体的分子。
化学反应法
总结词
一种通过分析化学反应产物来确定分子立体构型的方法。
人工智能技术
总结词
人工智能技术利用机器学习和深度学习算法，对已知化合物立体构型数据进行训练和学 习，实现对未知化合物立体构型的预测。
详细描述
人工智能技术通过建立已知化合物立体构型数据库，利用机器学习和深度学习算法对数 据进行训练和学习，建立预测模型。通过输入未知化合物的相关信息，可以实现对未知
化合物立体构型的预测，为研究提供新的思路和方法。
天然产物立体构型的确定方法
(2) 饱和环酮化合物的八区投影 • 环己酮各原子主要落在c平面“后区”，为判断旋
光分担方便起见采用投影法。
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八区律规则：
• a). C-4的a和e，C-2和C-6的e键取代基均无 贡献。
• b). C-5的a和e，C-2的a键取代基均为正贡献。 • c). C-3的a和e，C-6的a键取代基均为负贡献。 • d). 旋光贡献具有加和性。 • e). 距离羰基越远，贡献越小。 • f). 基团越大，贡献越大。
作用：用来鉴定空间上接近的核，进而确定相对构型。
NOE
H H CH2OH
HO HO
O OR
OH
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NOE最适合应用于刚性分子。在这种情况下，核组之间具 有确定的距离。根据NOE可以得到分子的立体化学信息。
���若样品为柔性分子，相对于核磁共振的时标，这样的分 子在溶液中存在着较快的构象互变，NOE测定的是个平均 的结果，因而无法得到具体的构象信息。
圆二色谱是吸收光谱，具有紫外吸收的手性化合物 可测定圆二色谱。 谱线特征：产生具有峰状或谷状Cotton 效应的图谱。 Cotton效应：平滑曲线在所测化合物的最大吸收波 长处出现的异常的峰状或谷状曲线。峰为正Cotton， 谷为负Cotton。
在化合物紫外最大吸收处，是ORD产生Cotton效 应谱线跨越基线的位置；是CD产生Cotton效应 谱线的位置。
左旋偏振光和右旋偏振光在通过手性介质时不但产生了旋光现象， 而且还产生了因吸收系数不同而导致的“圆二色性”（CD）
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2.旋光性与旋光谱（ORD, Optical Rotatary Dispersion）
在一定温度下，用某一波长测定一光学性物质时，其旋光 性与样品浓度和洗手池的长度有下列关系。
天然产物化学成分提取分离方法
第15页，共137页。
被提取成分的极性
化学成分的极性：是选择提取溶剂最重要的依据。 影响化合物极性的因素：
(1) 化合物分子母核大小（碳数多少）：分子大、碳数多，
极性小；分子小、碳数少，极性大。
(2) 取代基极性大小：在化合物母核相同或相近情况下，化 合物极性大小主要取决于取代基极性大小。 常见基团极性；酸＞酚＞醇＞胺＞醛＞酮＞酯＞醚＞烯＞烷
分稳定. • 2. 临界压力（Pc=7.37 MPa）不太高, 容易操作.
碳＞正己烷≈石油醚。
第17页，共137页。
（3）溶解规律：
①水可以溶解：氨基酸、糖类、无机盐等。 ②亲水性有机溶剂（与水任意比例混溶 ）:甲醇、乙醇、
丙酮等。可溶解苷类、生物碱、鞣质等.溶解范围较广.
乙醇是提取天然产物化学成分最常用的溶剂。
特点： 介电常数较大，水溶性较大 对植物细胞穿透能力较强 对许多成分的溶解性能好，提取完全
石油醚 沸程 30~60℃、60~90℃、90~120℃ 脱脂、脱色常用
与甲醇、乙醇不能任意混溶
第23页，共137页。
3.常用的溶剂提取方法
（1）浸渍法：在常温或温热（60℃~80℃）条件下,将天 然材料粗粉以适当的溶剂(水或稀醇)浸泡。适用于遇热 易破坏及含大量淀粉、黏液质、树胶、果胶的天然材 料的提取。
•
溶剂消耗量大
连续回流法:提取效率高 热敏性成分易破坏 溶解度极小的成分
第28页，共137页。
（二）水蒸气蒸馏法 ： 适用于挥发性成分 （主要是挥发油）的提取
• 将原材料粗粉或碎片浸泡润湿后，通入水蒸气
蒸馏（也可在多功能提取器中边煎煮边蒸馏），原材料
天然产物化学刘湘版 天然产物的结构鉴定技术
感应磁场对质子的屏蔽作用
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质子外围的电子云密度稍有不同, 质子的共振吸收位置就不同, 这就给测 定有机物的结构提供了有用的信息, 我 们就是根据这些信息来推测有机化合 物的结构。
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在外磁场作用下，质子外围价电子环流产 生的感应磁场对外磁场有干扰作用：
屏蔽效应：HN=H0 – H'
去屏效应： HN= H0+ H'
当电磁波的能量与核自旋能级的能量差相等 时，处于低能态的自旋核吸收一定频率的电磁波 跃迁到高能态上去的这种现象就叫核磁共振。
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将上式变形得：
0
2
h
H0
H0
h
2
(1) 固定磁场强度 H0, 改变无线电频率 V0 。（扫频）
(2) 固定无线电频率 V0, 改变磁场强度 H0 。（扫场） 固定 V0 改变 H0 更方便, 故现在大多数仪器是 采取扫场的方式。
非一级谱（二级谱） ❖一般情况下，谱峰数目超过n+1规律所计算的数目 ❖组内各峰之间强度关系复杂 ❖一般情况下， 和J不能从谱图中可直接读出
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五、化学等价质子与磁等价质子
1 、化学等价质子：具有相同化学位移的质 子叫化学等价（性）质子。
吸收峰的数目等于分子中不等性质子的数 目；换言之：有多少组吸收峰就表示分子中 有多少种不同类型的质子。
H0：外加磁场的强度 H' : 感应磁场的强度 HN ：质子真正感受到的磁场强度
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分子中的质子真正感受到的磁场强度是:
HN = H0－σH0 = H0(1 － σ)
HN: 质子真正感受到的场强 H0:外加磁场的强度 σ: 屏蔽常数随质子外围的电子环境而异
天然产物结构研究法知到章节答案智慧树2023年沈阳药科大学
天然产物结构研究法知到章节测试答案智慧树2023年最新沈阳药科大学第一章测试1.下列原子核中，能够产生核磁共振信号的是（）。
参考答案:null2.以下方法可用于确定苷键构型的是（）。
参考答案:可以根据某些糖端基氢的偶合常数;可根据端基碳的化学位移值来进行判定;可根据糖端基碳氢的偶合常数判定;利用Klyne经验公式计算3.能区分碳的类型的谱学方法是（）谱。
参考答案:HMQC;DEPT;OFR4.下列论述正确的是（）。
参考答案:强心苷类化合物，因C-10，13位的甲基的化学位移值与C-5，14的构型有关，因此在某种条件下，可根据甲基化学位移值的大小来判定环的稠合方式。
;红外光谱除用于推定结构中官能团的有无外，还能应用其研究立体结构。
;齐墩果烷类化合物的UV光谱中，若242nm处有最大吸收，则H-18为α取向。
;因质子之间的偶合常数与其形成的二面角大小有关，因此可利用此参数来判定质子的相对立体取向。
5.能区分碳的类型的谱学方法是（）谱。
参考答案:DEPT;OFR;HMQC6.下列论述正确的是（）。
参考答案:互为反式的双键上两个质子的偶合常数要大于其顺式的偶合常数。
;强心苷类化合物，因C-10，13位的甲基的化学位移值与C-5，14的构型有关，因此在某种条件下，可根据甲基化学位移值的大小来判定环的稠合方式。
;因质子之间的偶合常数与其形成的二面角大小有关，因此可利用此参数来判定质子的相对立体取向。
;因红外光谱只用于推定结构中官能团的有无外，因此不能应用其研究立体结构。
;紫外光谱不仅可用于判定结构中共轭体系的存在与否，还可用于立体构型和构象的判定。
7.影响碳信号化学位移的因素有（）。
参考答案:诱导效应的影响;碳核周围的电子云密度;碳原子的杂化方式;共轭效应的影响8.碳信号的化学位移因受碳的杂化方式影响，故sp3杂化的碳信号比sp2杂化的碳处于低场，化学位移值大。
（）参考答案:错9.脂肪羰基碳信号比处于共轭体系中的羰基碳信号处于高场。
天然产物的结构鉴定与合成研究
天然产物的结构鉴定与合成研究天然产物，是指来源于动植物和微生物的化合物体系。
它们具有广泛的生物活性和天然绿色环保的特点，因此在医药、农药、食品、化妆品等领域有着广泛的应用前景。
而天然产物的结构鉴定与合成研究，则是为了深入理解其生物活性机制和开发新型活性物质所必需的关键步骤。
一、天然产物结构鉴定的方法天然产物化合物的结构鉴定，是为了确认其分子式、分子量、官能团，以及它们之间的相对位置和绝对构型等信息。
目前，常见的天然产物结构鉴定方法主要包括下面几种。
1. 传统的物理化学分析方法如紫外光谱、红外光谱、核磁共振谱等。
这些方法可以提供光谱图谱来判断分子的特性和含有的官能团，进而推断其结构和构型等信息。
2. 高效液相色谱-质谱联用分析技术该技术包括高效液相色谱、毒理学筛查、拉曼光谱、气相色谱等多种手段，能实现高通量的分析和质谱确定，大大提高了结构鉴定的速度和精度。
3. 生物学方法如DNA探针、蛋白质晶体学等，利用生物学样本和试剂进行分析，进一步对分子结构进行推断。
二、天然产物结构合成的方法天然产物的结构合成，是基于其分子结构和生物活性的研究目标，通过人工合成的方法来获得高品质且具有自主性的产物。
而天然产物结构合成的方法则多种多样，在其中合成化学方法是其中的重要一环。
1. 立体控制天然产物的结构合成中有许多与立体有关的环境、中间体或步骤。
利用对称性或群论，有时可以判断分子哪些具有对称性，并且由路径的不同在空间中产生它们的反应合成产物。
利用手性催化剂和手性配体的知识，可以在合成天然产物过程中完全控制立体化学。
2. 条件控制利用合成中的条件控制可以选择一些特殊反应的方向和位置。
例如，当反应涉及不同位置的官能团或键的标记成分时，可以通过停滞反应或选择性催化剂来实现所需的化学反应。
而各种条件控制点的选择要视化合成的目标产物而定。
3. 基础构建基于对天然产物结构的合成掌握，常用的方法就是步骤构建。
该方法以简单和相对易于合成的分子为起点来构建复杂的中间体和合成路径，以创造性地使用各种人工或天然可用的预制分子。
天然产物的提取和结构鉴定
通过化学反应对天然产物的官能团和结构 特征进行分析，确定其化学结构。
利用各种波谱技术，如红外光谱、核磁共 振谱等，对天然产物的分子结构和组成进 行分析。
X射线晶体学
计算机模拟法
通过X射线分析天然产物的晶体结构和分子 排列，确定其化学结构。
利用计算机模拟技术对天然产物的分子结 构和性质进行预测和模拟。
根据物质之间的相似相溶原理， 选择与目标成分极性相似的溶剂 进行提取，从而提高提取效率。
分子间作用力
利用物质分子之间的作用力，如 范德华力、氢键等，将目标成分 从原料中分离出来。
酸碱性质
利用目标成分的酸碱性质，选择 适当的酸碱溶液进行提取，使目 标成分溶解或释放。
提取过程
原料预处理
对原料进行破碎、粉碎、干燥等预处 理，以便于后续的提取操作。
天然产物的提取和 结构鉴定
目录
• 天然产物提取 • 天然产物结构鉴定 • 天然产物提取与结构鉴定的关系 • 天然产物提取与结构鉴定的应用 • 天然产物提取与结构鉴定的挑战与展望 • 相关文献与资料
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CATALOGUE
天然产物提取
提取方法
溶剂提取法
利用不同溶剂将天然产物从原料中溶解 出来，常用的溶剂包括水、乙醇、甲醇
量子化学原理
利用量子化学方法对天然产物分子进行计算和模拟，预测其性质和结 构。
结构鉴定过程
样品制备
将天然产物样品进行适当处理，以便进行后 续分析。
波谱分析
利用各种波谱技术对天然产物进行分析，获 取分子结构和组成信息。
初步分析
通过物理和化学性质分析，初步判断天然产 物的类型和可能的结构。
结构解析
结合分析结果，对天然产物的化学结构进行 解析和确定。
第2章天然产物的提取分离和结构鉴定课件
➢ 因此大孔吸附树脂在干燥状态下其内部具有较
高的孔隙率，且孔径较大，在100～1000nm之间，
故称为大孔吸附树脂。
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大孔吸附树脂优势
➢ 表面积较大，且交换速度较快 ➢ 机械强度高 ➢ 抗污染能力强，可重复使用 ➢ 理化性质稳定，热稳定好 ➢ 在水溶液和非水溶液中都能使用
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(4) 根据物质的分子大小差别进行分离
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石油醚－苯－氯仿－乙醚－乙酸乙酯－丙酮－乙醇－甲醇－水
----亲水性强的化合物在水中溶解度较大,亲脂性 强的化合物在油中的溶解度较大。这种亲水性或亲 脂性的强弱是和化合物的结构直接相关。简言之, 在多数情况下凡化合物与水的结构相似,就具有亲 水性,与油脂的结构相似,就具有亲脂性。这就是所 谓 “相似相溶”原则。
VaporLeabharlann Boiling flask containing high-density extracting solvent and extracted solute
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Lower-density solvent extraction
Condensate
Extracting solvent
High-density solution being extracted
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➢ 影响液滴逆流分配的主要因素有： ➢ 被分离成分在两相溶剂间的分配系数要大； ➢ 形成大小合适的移动相液滴，这与两相间的界面 张力、密度差、输液管口径和萃取管材料等有关， 可以采用数根萃取管预试液滴的形成情况而确定； ➢ 液滴间的间隔，与泵的送液速度有关，送液速度 过快，液滴间几无间隔变成线流通过固定相，通常 也可经过小样探索而定。
1. 天然产物化学成分的预试验 p11, 天然产物化学成分的预试验流程