Synthesis of D-cyclopentenone derivatives：the versatile intermediates for the synthesis of carbocyclic nucleosides.文献综述

课题名称 Synthesis of D-cyclopentenone derivatives课题性质 □基础研究□应用课题 □设计型□ 调研综述radic; 理论研究Ⅰ.Subject Backgrounds Neplanocin A and aristeromycin are representatives of naturally occurring carbocyclic nucleosides,which exhibit interesting biological activity.these compounds act as potent inhibitors of S-adenosylhomocysteine （SAH）hydrolase,which catalyzes the hydrolysis of S-adenosylhomocysteine into adenosine andhomocysteine.Inhibition of the SAH hydrolase accumulates S-adenosylhomocysteine in the cell,which intern inhibits S-adenosylmethionine (SAM) transferase resulting in the inhibition of viral mRNA capping.Thus,SAH hydrolase inhibitors such as neplanocin A and aristeromycin have received great attention in the development of broad spectrum antiviral agents.Although neplanocin A andaristeromycin act as good inhibitors of SAH hydrolase,they were too cytotoxic to be clinically useful agents.Thus,in the search of less toxic and more potent inhibitors of SAH hydrolase than these compounds,many D-carbocyclic analogues have been synthesized and evaluated for SAH hydrolase inhibitory activity.Abacavir is the first D-carbocyclic nucleoside which has been approved by the Food and Drug Administration(FDA) for the treatment of AIDS and AIDS-related complex(ACR).Since the discovery of abacavir ,extensive efforts on carbocyclic nucleosides like neplanocin A and aristeromycin have been made with a view to the development of new antiviral and antitumor agents. Most D-nucleosides suffer from the lactic acidosis caused by mitochondrial DNA toxicity.On the other hand, since the discovery of (-)-3TC(lamivudine) as a potent anti-HIV and anti-HBV agent,nucleoside chemists turned their attention to the development of L-nucleosides.Several L-nucleosides were found to be less cytotoxic than the corresponding D-nucleosides while maintaining more potent antiviral activity such as (-)-3TC.Recently,on the basis of these foundings,L-carbocyclic nucleosides such as L-aristeromycin and L-carbovir analogues have been synthesized to search for less toxic and more potent antiviral agents than the counterpart D-nucleosides.Although most of the synthesized nucleosides did not exhibit significant antiviral activities,systematic structure-activity relationship study of L-carbocyclic nucleosides should be continued to find novel antiviral agents.The key intermediates can be derived from the lactol,which is easily obtained from the cheap and commercially available D-isoascorbic acid. These intermediates represent convenient synthons for the synthesis of D-and L-carbocyclic nucleosides,respectively.However,in these syntheses,several steps such as selective oxidation and reduction turned out to be major drawbacks for large scale synthesis.This prompted us to improve our procedure.And our procedure highlights mild reaction conditions,no enzymatic resolution,and improved overall yields when compared to the previously published procedures. Ⅱ.Problems to be Solved1.Using ring-closing metathesis(RCM) reaction as a key step starting from the cheap and commercially available D-isoascorbic acid.2.To find a procedure with less step.The reaction should be mild,no enzymatic resolution,higher overall yields.3.The reaction should be fit to the large reaction. Ⅲ.Feasibility AnalysisThe reaction raw materials are easy to obtain,and the reaction is mild as well as the byproducts are few.It should be proved to be good for large-scale synthesis. (-)Aristeromycin,isolated from Streptomyces citricolor ,is a representative carbocyclic nucleoside that exists in Nature . This compound is a potent inhibitor of S-adenosylhomocysteine(AdoHcy) hydrolase and shows potent antiviral activities against several RNA and DNA viruses.It was first synthesis as a racemate by Clayton and his co-worker,and its enantioselective synthesis has since been reported.Based on a bioisosteric rationale ,racemic mixtures of 6-substituted aristeromycin analogues were also synthesized and evaluated for their inhibitory activity against AdoHcy hydrolase.Among these ,()-6-beta;-fluoro-aristeromycin exhibited the most potent inhibitory activity against AdoHcy hydrolase .Thus ,the synthesis of optically pure (-)-6-beta;-fluoro-aristeromycin is an interesting objective because the biological activity is generally only found in one enantiomer ,the D-isomer.Previous work demonstrated that racemic ()-2^5a as well as optically active (-)-2^5b could be synthesized via the key fluoroazide 5,which was synthesized by treating the azido alcohols 4a and 7a with triflic anhydride followed by fluorination with tris (dimethylamino) sulfur (trimethylsilyl) difluoride (TASF).the key fluoroazide was converted to the desired product 2 using a the linear base buildup approach.However,these fluorination-containing approaches required many steps to prepare the substrates 4a and 7a for fluorination and had low overall yields.Furthermore,the opining of racemic epoxide 3 with sodium azide was not regioselective (4a:4b=1:1) and the opening of chiral epoxide 6 was only moderately regioselective (7a:7b=4:1)^5b.Thus ,it was highly desired to develop a stereoselective fluorination method with a substrate that could be efficiently prepared.In the present work,stereoselective electrophilic fluorination of the silyl enol ether 13 was employed for the synthesis of the key fluoroketone 9beta; ,which could be elaborated to the desired (-)-2.It was also previously reported that the 6-alpha;-fluoro epoxide derived from3 was opened with an adenine anion,but this method showed poor regioselectivity (2:1 ratio) and low yield^5a.We thought that these drawbacks might be overcome by employing a cyclic sulfate as a carbafuranosyl donor,because of its high electrophilicity and its capacity for regioselectivity under mild conditions. Herein,we report a stereoselective synthesis of optically pure (-)-6-beta;-fluoroaristeromycin(2) via a stereocontrolled electrophilic fluorination and the regioselective synthesis of 5- -beta;-fluoro-aristeromycin using cyclic sulfate chemistry,starting from D-ribose.In the synthesis of D-cyclopentenone derivative,D-ribose was protected as the 2,3-acetonide(93%)which was treated with vinylmagnesium bromide to give triol (81%).And this step is called the Grignard reaction.[Grignard is most noted for devising a new method for generating carbon-carbon bonds using magnesium to couple ketones and alkyl halides.This reaction is valuable in organic synthesis. It occurs in two steps:Formation of the 'Grignard reagent', which is an organomagnesium compound made by the reaction an organohalide, R-X (R = alkyl or aryl; and X is a halide, usually bromide or iodide) with magnesium metal. The Grignard reagent is usually described with the general chemical formula R-Mg-X, although its structure is more complex.Addition of the carbonyl, in which a ketone or an aldehyde is added to the solution containing the Grignard reagent. The carbon atom that is bonded to Mg transfers to the carbonyl carbon atom, and the oxygen of the carbonyl carbon becomes attached to the magnesium to give an alkoxide. The process is an example of anucleophilic addition to a carbonyl. After the addition, the reaction mixture is treated with aqueous acid to give an alcohol, and the magnesium salts are subsequently discarded.The Grignard reaction is an important means of preparing organic compounds from smaller precursor molecules. For this work, Grignard was awarded the Nobel Prize in Chemistry in 1912 jointly with fellow Frenchman Paul Sabatier.]Oxidative cleavage of triol with sodium metaperiodated gave the lactol in 85% yield.[Oxidative cleavage is the cleavage of carbon-carbon bonds to generate carbon-oxygen bonds. Sometimes CC bonds are oxidized, and sometimes CC and CH are oxidized.Classical reductions include alkene reduction to alkanes and classical oxidations include oxidation of alcohols to aldehydes. In oxidations electrons are removed and the electron density of a molecule is reduced. In reductions electron density increases when electrons are added to the molecule. This terminology is always centered on the organic compound. For example, it is usual to refer to the reduction of a ketone by lithium aluminium hydride, but not to the oxidation of lithium aluminium hydride by a ketone. Many oxidations involve removal of hydrogen atoms from the organic molecule, and the reverse, reduction adds hydrogens to an organic molecule.Many reactions classified as reductions also appear in other classes. For instance conversion of the ketone to an alcohol by lithium aluminium hydride can be considered a reduction but the hydride is also a good nucleophile in nucleophilic substitution. Many redox reactions in organic chemistry have coupling reaction reaction mechanism involving free radical intermediates. True organic redox chemistry can be found in electrochemical organic synthesis or electrosynthesis. Examples of organic reactions that can take place in an electrochemical cell are the Kolbe electrolysis.In disproportionation reactions the reactant is both oxidised and reduced in the same chemical reaction forming two separate compounds.Asymmetric catalytic reductions and asymmetric catalytic oxidations are important in asymmetric synthesis.]Wittig reaction of the former product with triphenylphosphonium methylidene produced the diene in 88% yield.[The Wittig reaction or Wittig olefination is a chemical reaction of an aldehyde or ketone with a triphenyl phosphonium ylide (often called a Wittig reagent) to give an alkene and triphenylphosphine oxide.Wittig reactions are most commonly used to couple aldehydes and ketones to singly substituted phosphine ylides. With unstabilised ylides this results in almost exclusively the Z-alkene product. In order to obtain the E-alkene, stabilised ylides are used in the HornerWadsworthEmmons reaction or unstabilised ylides are used in the Schlosser modification of the Wittig reaction.]Ring-Closing metathesis of diene using Grubbscatalyst gave the allylic alcohol 90%,which was converted to the D-cyclopentenone in 89% yield.We synthesized the D-cyclopentenone in 45% overall yield and six steps from D-ribose, which is much more improved in view of overall yield and the number of steps,compared to our previously reported procedure.Ⅳ.Research Methods and ContentThe main research method is references reviewing.The main tool will be used is 〞Chemdraw 〞. The final paper will present the synthesis procedures of D-cyclopentenone derivativesⅤ.Work Plan2.283.17：Complete the references review,opening report and other preparatory work.3.185.10：Complete the experiment as required.5.115.20：Complete the paper,master the way to use 'Chemdraw'5.216.03：Complete the review and revision of the paper.6.04Before Reply：Complete proofreading of the paper.Ⅵ.References[1] Won Jun Choi,Jae Gyu Park,Su Jeong Yoo,Hea Ok Kim,Hyung Ryong Moon,Moon Woo Chun ,Young Hoon Jung,and Lak Shin Jeong. Syntheses of D- and L-Cyclopentenone Derivatives Using Ring-Closing Metathesis:Versatile Intermediates for the Synthesis of D- and L-Carbocyclic Nucleosides. J.Org.Chem.2001,66,6490-6494[2] Hyung Ryong Moon,Won Jun Choi,Hea Ok Kim,and Lak Shin Jeong. Improved and alternative synthesis of D- and L-cyclopentenone derivatives,the versatile intermediates for the synthesis of carbocyclic nucleosides. Tetrahedron :Asymmetry 13 (2002) 1189-1193.[3]Won Jun Choi,Hyung Ryong Moon,Hea Ok Kim,Byul Nae Yoo,Jeong A Lee,Dae Hong Shin,and Lak Shin Jeong.Preparative and Stereoselective Synthesis of the Versatile Intermediate for Carbocyclic Nucleosides:Effects of the Bulky Protecting Groups to Enforce Facial Selectivity. JOC Note,November 14,2003.[4]Gyudong Kim,Ji-seong Yoon,Dnyandev B.Jarhad,Young Sup Shin,Mahesh S.Majik,Varughese A.Mulamoottil,Xiyan Hou,Shuhao Qu,Jiyong Park,Mu-Hyun Baik,and Lak Shin Jeong. Asmmetric Synthesis of (-)-6-beta;-Fluoro-aristeromycin via Stereoselective Electrophilic Fluorination. 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[11](a)Chu,C.K.;Ma,T.;Shanmuganathan,K.;Wang,C.;Xiang,Y.;Pai,S.B.;Tao,G.Q.;Sommadossi,J.P.;Cheng,Y.C.Antimicrob. Agents Chemother. 1995,39,979-981;(b) Lin,T.S.;Luo,M.Z.;Liu,M.C.;Zhu,Y.L.;Gullen,E.;Dutschman,G.E.;Cheng,Y.C.J.Med.Chem.1996,39,1757-1769.[12]Choi,W.J.;Park,J.G.;Yoo,S.J.;Kim,H.O.;Moon,H.R.;Chun,M.W.;Jung,Y.H.;Jeong,L.S.J.Org.Chem.2001,66,6490-6494.[13](a)Kiso,M.;Hasegawa,A.Carbohydr.Res.1976,52,95-101;(b)Acevedo,O.L.;Townsend,L.B.In Nucleic Acid Chemistry,Part Three:Improved and New Synthetic Procedures,Methods and Techniques;Townsend,L.B.,Tipson,R.S.,Eds.Synthesis of 2,3-O-isopropylidene-D-ribose.John Wiley pp.35-37; (c)Ewing,D.F.;Humble,R.W.;Mackenzie,G.;Raynor,A.;Shaw,G.Carbohydr.Res.1991,218,233-236;(d)Rauter,A.P.;Ramoa-Ribeiro,F.;Fernandes,A.C.;Figueiredo,J.A.Tetrahedron 1995,51,6529-6540. [14]Shing,T.K.M.;Elsley,D.A.;Gillhouley,J.G.J.Chem.Soc.,Chem.Commun.1989,1,1280-1282;(b)Redlich,H.;Sudau,W.;Szardenings,A.K.; Vollerthun,R.Carbohydr. Res,1992,226,57-78;(c)vanBoggelen, M.P.; van Dommelen,B.F.G.A.; Jiang,S.;Singh,G.Tetrahedron 1997,53,16897-16910.[15](a)Grubbs,R.H.;Chang,S.Tetrahedron1998,54,4413-4450;(b)Ovaa,H.;Codde,J.D.C.;Lastdrager,B.;Overkleeft,H.S.;van der Marel,G.A.;van Boom,J.H.Tetrahedron Lett.1998,39,7987-7990.学生签名：李茵 2017 年 3 月21 日指导教师意见：该生文献调研充分，选题具有实际应用价值，提出了要解决的问题，对完成课题的可行性进行了初步分析，工作计划合理可行，工作量饱满，应能取得预期成果。

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