Preparative and Stereoselective Synthesis of the Versatile Intermediate for Carbocyclic Nucleosides文献综述

课题名称 Preparative and Stereoselective Syntheisis of the Versatile Intermediate for Carbocyclic Nucleosides课题性质 radic;基础研究应用课题 设计型 调研综述 理论研究开题报告内容：一、课题背景The virus is the main cause of infectious diseases, which is very harmful and has a wide range of influence. In the rapid development of science, it is still one of the greatest puzzles in developed countries and many developing countries. In recent years, due to the spread of the virus, antiviral drugs have developed rapidly and have become an important variety of anti infectious drugs.Tumor is a new organism formed by the proliferation of local tissue cells under the action of various oncogenic factors, because this new organism is mostly occupied by massive lump, also called superfluous organisms. Anti-neoplastic drugs are anti-malignant drugs. Tumor is a disease that threatens the safety of human life. It is concealed in the early stage of the disease and is not easily found by people. So the best time for treatment is missed. Advanced tumors are more difficult to control their growth and have a fatal risk of cancer cell metastasis.A naturally occurring nucleoside, neplanocin A (1) is a representative of the carbocyclic nucleosides and shows potent antiviral and antitumor activities by inhibiting S-adenosylhomocysteine hydrolase. Its fluorocyclopentene analogue,fluoroneplanocin A (2), was also reported to be a potent irreversible inhibitor of S-adenosylhomocysteine hydrolase and exhibit potent antitumor and antiviral activities.On the other hand, the cytidine analogue 3 showed potent antitumor activity by reducing cytidine-5-triphosphate (CTP) pools and in addition displayed potent antiviral activity by inhibiting CTP synthetase.二、要解决的问题However, although a variety of biological activities of these carbocyclic nucleosides have stimulated medicinal chemists to carry out structure-activity relationship (SAR) studies in carbocyclic nucleosides,synthetic difficulties in preparing the D-carbocycle have hampered them from pursuing the extensive SAR study. Thus, modifications have mainly been done on the base moiety, not on the cyclopentenyl sugar part. Although many synthetic methods to the carboclic moiety have been reported so far, they sometimes suffered from inconsistent and low overall yields,lengthy synthetic routes,racemization, lack of large-scale preparations,and sensitive to reaction condition such as temperature and moisture.Thus,a shortand efficient procedure to the D-carbocycle is highly desirable. Thus, we are very interested in developing a new and efficient synthetic route to the D-cyclopentenone derivative with a 3-hydroxymethyl side chain for the extensive modification of the cyclopentenyl sugar moiety.三、可行性分析 Jacobson and co-workers have published the elegant synthesis of the carbocycle moiety of neplanocin A from D-ribono-gamma;-lactone using olefin ring closing metathesis (RCM) as a key step. More recently, short and efficient syntheses of D- and L-3-unsubstituted cyclopentenones, which employ RCM as the key step, have been reported, and these substrates serve as versatile precursors for the synthesis of D- and L-carbocyclic nucleosides. These provide a reference for the research of the subject, so it is reasonable and feasible to study the subject.四、研究方法和内容 The research method is mainly based on consulting literature and conducting experiments. Yields are improved by optimizing experimental conditions. Using TLC and NMR methods to monitor and test the experiment. Some of the main reactions in the experiment are as follows:①TheGrignard reaction is anorganometallicchemical reactionin whichalkyl,vinyl, oraryl-magnesiumhalides(Grignard reagents) add to acarbonylgroup in analdehydeorketone.This reaction is an important tool for the formation ofcarboncarbon bonds.The Grignard reagent functions as anucleophile, attacking theelectrophiliccarbon atom that is present within thepolar bondof a carbonyl group. The addition of the Grignard reagent to the carbonyl typically proceeds through a six-membered ring transition state.In reactions involving Grignard reagents, it is important to exclude water and air, which rapidly destroy the reagent by protonolysis or oxidation. Since most Grignard reactions are conducted in anhydrous diethyl ether or tetrahydrofuran, side-reactions with air are limited by the protective blanket provided by solvent vapors. Small-scale or quantitative preparations should be conducted.②Ring-closing metathesis, orRCM, is a widely used variation ofolefin metathesisin organic chemistry for the synthesis of variousunsaturatedrings via the intramolecularmetathesisof two terminalalkenes, which forms the cycloalkene as theE-orZ-isomersandvolatileethylene.③TheWittig reactionor Wittig olefination is achemical reactionof analdehydeorketonewith a triphenylphosphonium ylide(often called aWittig reagent) to give analkeneandtriphenylphosphine oxide.Wittig reagents are usually prepared from aphosphonium salt, which is in turn prepared by thequaternizationoftriphenylphosphinewith analkyl halide. The alkylphosphonium salt is deprotonated with a strong base such asn-butyllithium:[Ph3P CH2R]X C4H9Li → Ph3P=CHR LiX C4H10One of the simplest ylide ismethylenetriphenylphosphorane(Ph3P=CH2). It is also a precursor to more elaborate Wittig reagents. Alkylation of Ph3P=CH2with a primaryalkyl halideRCH2X, produces substituted phosphonium salts:Ph3P=CH2 RCH2X→ Ph3P CH2CH2R XThese salts can bedeprotonatedin the usual way to give Ph3P=CHCH2R.④TheSwern oxidation is achemical reactionwhereby a primary or secondaryalcoholisoxidizedto analdehydeorketoneusingoxalyl chloride,dimethyl sulfoxide(DMSO) and an organic base, such astriethylamine.The reaction is known for its mild character and wide tolerance offunctional groups.The by-products aredimethyl sulfide(Me2S),carbon monoxide(CO),carbon dioxide(CO2) andwhen triethylamine is used as basetriethylammonium chloride(Et3NHCl). Of the volatile by-products, dimethyl sulfide has a strong, pervasive odour and carbon monoxide is acutely toxic, so the reaction and the work-up needs to be performed in a fume hood. Dimethyl sulfide is a volatile liquid (B.P. 37C) with an unpleasant odour at high concentrations.When using oxalyl chloride as thedehydrationagent, the reaction must be kept colder than 60C to avoid side reactions. Withcyanuric chlorideortrifluoroacetic anhydrideinstead of oxalyl chloride, the reaction can be warmed to 30C without side reactions.The test method in the experiment is as follows:①Thin layer chromatography:TLC is a chromatography technique used to separate non-volatile mixtures.Thin-layer chromatography is performed on a sheet of glass, plastic, or aluminium foil, which is coated with a thin layer of adsorbent material, usually silica gel, aluminium oxide (alumina), or cellulose. This layer of adsorbent is known as the stationary phase.After the sample has been applied on the plate, a solvent or solvent mixture (known as the mobile phase) is drawn up the plate via capillary action. Because different analytes ascend the TLC plate at different rates, separation is achieved.[2] The mobile phase has different properties from the stationary phase. For example, with silica gel, a very polar substance, non-polar mobile phases such as heptane are used. The mobile phase may be a mixture, allowing chemists to fine-tune the bulk properties of the mobile phase.After the experiment, the spots are visualized. Often this can be done simply by projecting ultraviolet light onto the sheet; the sheets are treated with a phosphor, and dark spots appear on the sheet where compounds absorb the light impinging on a certain area. Chemical processes can also be used to visualize spots; anisaldehyde, for example, forms colored adducts with many compounds, and sulfuric acid will char most organic compounds, leaving a dark spot on the sheet.To quantify the results, the distance traveled by the substance being considered is divided by the total distance traveled by the mobile phase. (The mobile phase must not be allowed to reach the end of the stationary phase.) This ratio is called the retardation factor (Rf). In general, a substance whose structure resembles the stationary phase will have low Rf, while one that has a similar structure to the mobile phase will have high retardation factor. Retardation factors are characteristic, but will change depending on the exact condition of the mobile and stationary phase.②Nuclear magnetic resonance spectroscopy, most commonly known as NMR spectroscopy or magnetic resonance spectroscopy (MRS), is a spectroscopic technique to observe local magnetic fields around atomic nuclei. The sample is placed in a magnetic field and the NMR signal is produced by excitation of the nuclei sample with radio waves into nuclear magnetic resonance, which is detected with sensitive radio receivers. The intramolecular magnetic field around an atom in a molecule changes the resonance frequency, thus giving access to details of the electronic structure of a molecule and its individual functional groups. As the fields are unique or highly characteristic to individual compounds, in modern organic chemistry practice, NMR spectroscopy is the definitive method to identify monomolecular organic compounds. Similarly, biochemists use NMR to identify proteins and other complex molecules. Besides identification, NMR spectroscopy provides detailed information about the structure, dynamics, reaction state, and chemical environment of molecules. The most common types of NMR are proton and carbon-13 NMR spectroscopy, but it is applicable to any kind of sample that contains nuclei possessing spin.NMR spectra are unique, well-resolved, analytically tractable and often highly predictable for small molecules. Different functional groups are obviously distinguishable, and identical functional groups with differing neighboring substituents still give distinguishable signals.五、工作计划起止日期 工作内容和要求2018.02.25-2018.03.04 确定选题并查阅文献搜集资料2018.03.05-2016.03.09 完成开题报告2018.03.10-2018.04.01 进行调查、收集资料，并进行实验2018.04.02-2018.04.15 根据实验结果对实验进行分析改进2018.04.16-2018.05.01 根据改进后的实验方案和结果进行整理分析得出结论2018.05.02-2018.05.05 根据实验结论，提交论文初稿2018.05.06-2018.05.12 修改论文，完善系统2018.05.13-2018.05.30 提交正式毕业论文，并进行论文答辩准备[参考文献] [1] Yaginuma,S.; Muto,N; Tsujino,M.; Sudate,Y;Hayashi,M.; Otani,M.J.Antibiot.(Tokyo) 1980,34,359.[2] Yaginuma, S.; Yoshioka, H;Nakatsu, K. J. Antibiot. (Tokyo) 1981, 34, 675.[3]]Arita, M.;Adachi, K.;Ito, Y; Sawai, H; Ohno, M. J. Am. Chem. Soc. 1983, 105, 4049.[4] Medich, J. R.; Kunnen, K. B ; Johnson, C. R. Tetrahedron lett. 1987, 28, 4131.[5]Marquez, V. E;Lim, M. -I.; Treanor, S. P.; Plowman, J.; Priest, M. A.; Markovac, A.; Khan, M.S.; Kaskar, B.; Driscol, J. S. J. Med. 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