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首页 高等有机合成

高等有机合成.ppt

高等有机合成

hunterli79
2009-02-20 0人阅读 举报 0 0 暂无简介

简介:本文档为《高等有机合成ppt》,可适用于工程科技领域

高等有机合成AdvancedOrganicSynthesis高等有机合成AdvancedOrganicSynthesis绪论一、有机合成的历史回顾二、有机合成化学的发展趋势三、学习内容和方法四、重要参考书及期刊五、课程安排一、有机合成的历史回顾尿素的合成(年德国化学家Wohler)有机化学的开始颠茄酮的合成)年德国化学家Willstatter(年获Noble化学奖)steps,overallyield)年英国化学家Robinson(年获Noble化学奖)steps,overallyieldRobinson为什么能是发现这条合成路线?MannichReaction()维生素B的合成(Woodward,年)在Woodward及Eschenmoser领导下,经过两个实验室多位科学家的共同努力于年完成了维生素B的全合成工作。将有机合成作为一种艺术展现在世人面前。因在年人工合成了奎宁、类固醇、马钱子碱、羊毛甾醇、麦角碱等近种复杂天然产物而年获Noble化学奖EJCorey,(年获Noble化学奖)如果说Woodward一生奋斗的成就是将有机合成作为一种艺术展现在世人面前那么Corey则是将有机合成从艺术转变成为科学的一个关键人物。他的逆合成分析是现代有机合成化学的重要基石推动了世纪年代以来整个有机合成领域的蓬勃发展。逆合成分析(Retrosyntheticanalysis)Woodward()红霉素的全合成YKishi()海葵毒素的全合成SLSchreiberetal()FK的全合成KCNicolaouSLSchreiber()紫杉醇(Taxol)的全合成KCNicolaouSLSchreiberKCNicolaou,etalTheartandscienceoftotalsynthesisatthedawnoftwentyfirstcentury,AngewChemIntEdEngl,,,SLSchreiber,etalTargetorientedanddiversityorientedorganicsynthesisindrugdiscovery,Science,,,高立体选择性(HighStereoselectivity)原子经济性反应(AtomEconomicalReaction)绿色化学(GreenChemistry)二、有机合成化学的发展趋势新试剂、新反应、新方法的发现永无止境Epibatidine的研究Y(OTf)catalyzednovelMannichreactionofNalkoxycarbonylpyrroles,formaldehydeandprimaryaminehydrochloridesCXZhuan,JCDong,TMCheng,RTLi*,TetrahedronLetters,,(),Aldol缩合反应的研究与生命科学和材料科学的联系越来越紧密三、学习内容和方法内容对重要的基础有机反应要能够熟练运用新化合物的合成比葫芦画瓢逆合成分析跟踪文献尽可能将最新的试剂、反应和方法应用于自己的研究工作中。学习别人的思路创造性地借鉴和运用方法四、重要参考书及期刊四、重要参考书及期刊参考书FACarey著王积涛译高等有机化学B反应与合成高等教育出版社。岳保珍李润涛有机合成基础北京医科大学出版社。吴毓林姚祝军现代有机合成化学科学出版社。WCarruthers著李润涛等译有机合成的一些新方法河南大学出版社。黄宪王彦广陈振初新编有机合成化学化学工业出版社。王咏梅等高等有机化学习题解答南开大学出版社。DaleLBoger,ModernOrganicSynthesis,TheScrippsResearchInstitute,TsriPress,ComprehensiveOrganicSynthesis,Vol期刊AngewChemIntEdJAmChemSocJOrgChemOrgLettersChemCommunTetrahedronTetrahedronLettersTetrahedronAsymmSynthesisSynlettSynthCommunEurJChemEurJOrgChemHeterocyclicsJHeterocyclicChemJMedChemBioorgMedChemBioorgMedChemLettEurJMedChemJCombChem五、课程安排五、课程安排进度安排讲授原则复习老反应补充新反应重点讲进展强调学思路。考试)写综述一篇(近年的进展)())笔试()ChapterFormationofCarbonCarbonSingleBonds一、GeneralPrinciples烷化反应:E=烷化剂缩合反应:E=醛、酮、酯等Michael加成:E=Mannich反应二、影响反应的主要因素a 反应底物(Substrate)NO>COR>SOR>CN>COR>Ph,SORA和B至少要有一个是EWGA和B应该能使其碳上的H活化的基团通常为吸电子基(ElectronwithdrawgroupEWG)。b碱(Base)常用的碱:PhC>(MeCH)N>EtO>OH>RN碱的选择取决于底物的反应活性理想的碱:碱性强亲核性弱并不进攻那些较敏感的基团另外能溶于非极性溶剂中。c溶剂(Solvent)SolventOalkylationCalkylation反应速度常用的非质子极性溶剂(polaraproticsolvent):DMFDMSOHMPAd亲电试剂(Electrophilicreagent)所有能与负碳离子发生反应的碳正离子或分子。例:RX,RSOH,RCOEt,RCOR’这四种影响因素之间是相互联系相互影响的。在分析一个具体反应时应该综合分析考虑这四种影响因素。三、烷基化反应(Alkylation)OalkylationCalkylationExampleExampleDegreeofsubstitutionofalkylatingagent:Example区域选择性(Regioselectivity)区域选择性受热力学控制和动力学控制的反应条件影响很大热力学控制条件下主要生成取代基较多的烯醇动力学控制条件下主要生成取代基较少的烯醇ExampleExample立体选择性(Steroselectivity)烯醇化合物的立体选择性形成,将为不对称合成提供平台ExampleExampleExampleExample二羰基化合物的烷基化反应(Alkylationof,dicarbonylcompounds)JAmChemSoc,,,,,,,ExampleExampleExample继承与发展芳基卤化物与烯醇盐的反应(Reactionsofaromatichalidewithenolates)ExampleMechanism关键是要有形成苯炔的条件。酮和酯的烷基化反应(Alkylationsofketonesandesters)避免Aldol缩合反应发生的方法:烷化剂要待酮完全转化为烯醇式后再加入。常用的碱:NaNH,KNH,NaH,PhCNa等有副产物。LDA,LTMP,LHMDS等效果很好。ExampleExample不对称酮的选择性烷基化反应(Selectivealkylationofasymmetricketones)在一个位引入一个活化基(略)如:DieckmannReactionClaisencondensation制成结构专属性的烯醇负离子在取代基较多的位烷基化(烯醇硅醚法)碱性条件酸性条件在取代基较少的位烷基化(烯胺法,StorkEnamineSynthesis)通常用活泼的卤代烷可以高产率生成C烷基化产物但对于一般的卤代烃C烷基化产物收率较底。若用LDA在低温下反应则对各种卤代烃均可得到高收率的C烷基化产物。对于不对称酮主要在取代基较少的位发生烷基化。ExampleExample对映选择性烷基化反应(Enantioselectivealkylations)利用手性胺利用二甲基肼扩展:二甲基腙锂化合物的另一应用二甲基腙锂化合物容易转化成有机铜化合物而有机铜化合物在CC键的形成中很有用。利用SAMP和RAMP若用RAMP则得到另一种对映异构体。羧酸的不对称烷基化Example极性翻转(Umpolung)俞凌翀刘志昌极性转换及其在有机合成中的应用科学出版社Example安息香缩合Example醛氰醇法Example,–二噻烷法不易发生Michael加成反应。Example乙基乙硫甲基亚砜法,–二酮四、缩合反应(Condensation)AldolReactionMichaelAdditionMannichReactionClaisenCondensationDieckmannCondrnsationDarzen’sReactionReformatslyreactionAldolReaction(condensation))经典Aldol反应的两大缺点不同醛、酮之间的反应常得到混合产物立体选择性差)定向醇醛缩合反应(DirectedAldolcondensation)MetoodPreformedLithiumEnolatesZenolatesgivepredominantlysyn(orthreo)aldolproducts(thermodynamicenolates)Eenolatesgivepredominantlyanti(orerythro)aldolproducts(kineticenolates)ExampleStericsizeofRaffectsdiastereoselectivityOriginofDiastereoselectivityaZenolatesDiastereoselectivityforZenolate(givingsynaldolproduct)ismaximizedwhenRandRarestericallydemanding(RRinteractionismaximized)DiastereoselectivityalsoincreasesasmetalischangedtoboronThisisattritubtedtoatighterTS(B–Obondshorter,soRRstericinteractionsaremagnifiedinTSforantiproduct)WhenRisverylargetheRRgaucheinteraction>RR,diaxialinteraction(Why)bEenolatesDiastereoselectivityincreasesasRandRbecomestericallylarge,andaswitchtotheboronenolatewillincreaseselectivityDiastereoselectivitymayswitchwhenRisverylarge(Why)EffectofREffectofREffectofRMetoodPreformedBoronEnolatesaZenolatePreparationandReactionsbEenolatePreparationandReactionsOriginallydifficulttocontrolbut:cExamplesofmorerecentmethodstocontrolboronenolategeometryAldolCondensationwithChiralEnolatesTienolatepromotedEvansaldol(nonEvanssynaldol)ChelatedandnonchelatedTienolatesMetoodAcidCatalysedDirectedAldolReactions该方法是在酸性条件下反应但立体选择性较差。)有机小分子催化醇醛缩合反应(SmallOrganicMoleculesCatalystedAldolReactions)NovelSmallOrganicMoleculesforaHighlyEnantioselectiveDirectAldolReactionJAMCHEMSOC,,ZhuoTang,†,‡FanJiang,§LuoTingYu,‡XinCui,†LiuZhuGong,*,†AiQiaoMi,†YaoZhongJiang,†andYunDongWu*KeyLaboratoryforAsymmetricSynthesisandChirotechnologyofSichuanProvince,ChengduInstituteofOrganicChemistry,ChineseAcademyofSciences,Chengdu,,China,CollegeofChemicalEngineering,SichuanUniVersity,Chengdu,,China,andStateKeyLaboratoryofMolecularDynamicsandStableStructures,CollegeofChemistryandMolecularEngineering,PekingUniVersity,Beijing,,ChinaMichaelAdditionReactionApplications:Synthesisof,dicarbonylcompoundsGeneralSchemeDevelopment:AsymmetryMichaelAdditionReaction手性金属配位化合物催化MacmillanGroup’sWorkSmallOrganicMoleculecatalyzedasymmetricMichaelreactionsTheFirstEnantioselectiveOrganocatalyticMukaiyamaMichaelReaction:SPBrown,NCGoodwin,andDWCMacMillan*,JAmChemSoc,(),MannichReactionGeneralScheme胺组份氨、伯胺、仲胺醛组份HCHO,PhCHO,RCHO可分别发生三、双、单Mannich反应活泼H组份醛、酮、活泼亚甲基化合物、酚类化合物、杂环、炔等。ExampleExampleDevelopment:AsymmetryMannichReactionLewisacidcatalyzedasymmetricMannichreactions(a)Fujii,AHagiwara,ESodeoka,MJAmChemSoc,,(b)Ishitani,HUeno,MKobayashi,SJAmChemSoc,,(c)Ishihara,KMiyata,MHattori,KYamamoto,HJAmChemSoc,,(d)Ishitani,HUeno,MKobayashi,SJAmChemSoc,,(e)Ferraris,DYong,BDudding,TLeckta,TJAmChemSoc,,(f)Ferraris,DYoung,BCox,CDudding,TDrury,WJ,IIIRyzhkov,LTaggi,AELectka,TJAmChemSoc,,(g)Kobayashi,SHamada,TManabe,KJAmChemSoc,,(a)Notz,WSakthivel,KBui,TZhong,GBarbas,CF,IIITetrahedronLett,,(b)Juhl,KGathergood,NJorgensen,KAAngewChem,IntEd,,(c)Yamasaki,SIida,TShibasaki,MTetrahedron,,(d)List,BJAmChemSoc,,(e)Co´rdova,ANotz,WZhong,GBetancort,JMBarbas,CF,IIIJAmChemSoc,,(f)Co´rdova,AWatanabe,SiTanaka,FNotz,WBarbas,CF,IIIJAmChemSoc,,SmallOrganicMoleculecatalyzedasymmetricMannichreactionsTheDirectandEnantioselective,OnePot,ThreeComponent,CrossMannichReactionofAldehydesAngewChemIntEd,,–YHayashi,WTsuboi,IAshimine,TUrushima,DrMShojiDepartmentofIndustrialChemistry,FacultyofEngineeringTokyoUniversityofScience,KagurazakaThreecomponentMannichreactionwithvariousacceptoraldehydesNmethylpyrrolidinone(NMP)ThreecomponentMannichreactionwithvariousdonoraldehydesClaisenCondensationGeneralSchemeMechanism一种酯的自身缩合Scopeofapplication一种含H的酯与一种不含H的酯之间的缩合ExamplesDirectedClaisencondensationDickmannCondensationChapterFormationofCarbonCarbonDouleBondsEleminationreactions(消去反应)ITheSyntheticMethodsofAlklenesPyrolyticsyneliminations(顺式热消去反应)Applications:SynthesisofterminalalkenesfromprimaryacetatesDisadvantages:HighreactiontemperatureCopereactionChugavereaction反应条件比对应的酯热消去温和。Wittigandrelatedreactions(Wittig及有关反应)WittigReactionGWittigreceivedtheNobelPrizeinChemistryfor"manysignificantcontributionstoOrganicChemistry"whichincludednotonlytheWittigreaction,butalsoPhLipreparedbymetalhalogenexchange,benzyne,andtheWittigrearrangementGeneralSchemeMildreactionconditionsThepositionofthedoublebondisunambiguousFeaturesRepresentativeExamplesRepresentativeExamplesExampleExampleExampleExampleMechanismcycloadditionInfluenceofsolventontheselectivityActivityandstereoselectivityofYildSchlössermodification:allowsthepreparationoftransvscisolefinsSchlösserAngewChem,IntEdEng,,StabilizedYlidesStabilizedylidesaresolidstabletostorage,notparticularlysensitivetomoisture,andcanevenbepurifiedbychromatographyBecausetheyarestabilized,theyaremuchlessreactivethanalkylylidesTheyreactwellwithaldehydes,butonlyslowlywithketonesThefirststep,involvingtheadditiontothealdehyde,isslowandreversiblewithstabilizedylidesInfluenceofsolventontheselectivityWadsworth–Horner–EmmonsReactionHornerChemBer,,,,Wadsworth,EmmonsJAmChemSoc,,Reviews:OrgReact,,–ComprehensiveOrgSyn,Vol,PreparationofPhosphonateEstersArbuzovJRussPhysChemSoc,,ArbuzovRearragementThesameapproachtothepreparationofketophosphonatesisnotsuccessful:ButcanusevariationonClaisenconditions:ModificationsandScopeLiCltertiaryamines(DBU,iPrNEt,EtN)Masamune,RoushTetrahedronLett,,CansubstituteforconventionalconditionsandisespeciallygoodforbasesensitivesubstratesHinderedphosphonatesandhinderedaldehydesincreaseEselectivity(trans)Still–GennarimodificationselectiveforZalkenes(cis):AdditionalZselectivestabilizedphosphonatesSelecteddiarylphosphonatesprovideHighZselectivityaswellPetersonReactionReviews:OrgReact,,PetersonreactionoffersanalternativetoWittigprocedureTheyaremorereactiveandstericallylessdemandingthanaWittigreagentandthevolatilebyproduct(MeSiOHMeSiOSiMe)issimplertoremovethanPhPOItdoes,however,requireasecondsteptopromoteeliminationofthehydroxysilaneTheeliminationisstereospecific:acidpromotedbeingantiandbasepromotedbeingsynHudrlik,PetersonJAmChemSoc,,StabilizedPetersonReagentsThestabilizedPetersonreagentsgivepredominantlythemoststabletransolefins(E)Additionalexamples:TheTebbeReactionandRelatedTitaniumstabilizedMethylenations(Tebbe反应及与有关稳定化钛试剂的亚甲基化反应)ToleratesketalandalkenederivativesScopedefinedbyEvansandGrubbsJAmChemSoc,,ExtendedtotertiaryamidesbyPineJOrgChem,,ForananalogoususeofCpTiMe:PetasisJAmChemSoc,,Sulphoxidesulphenaterearragement:Synthesisofallylalcohols(亚砜次磺酸酯重排:烯丙醇类化合物的合成)CombinedwithalkylationofsulphoxidesthereactionprovidesaversatilesynthesisofdiandtrisubstitutedallylicalcoholsEvansandAndrews,AccChemRes,,,alkylationofallylicalcohlosExampleExampleAlkenesfromsulphones(由砜制备烯烃)JuliaOlefinationReview:ComprehensiveOrgSyn,Vol,Example:JuliaTetrahedronLett,Juliadevelopedamorerecent,singlestepvariantthatavoidsthereductiveeliminationJuliaBullSocChim,Fr,,Julia,Metal,TetrahedronLett,,Kocienski,PJetal,JChemSocPerkinI,,Example:Ramberg–BacklundreactionOrgReact,,BaseSONicolaouKCetal,JAmChemSoc,,,BoockmanRKetal,JAmChemSoc,,,AlvarzeEetal,JAmChemSoc,,,Decarboxylationoflactones(内酯的脱羧反应)ReformatskyReactionNote:NostilbenewasformedSynthesisoftriortetrasubsitutedalkenesExampleFehrCetalTetrahedronLett,,,MolbierWRetalJOrgChem,,,ExampleExampleMulzerJ,etal,JChemSocChemCommun,,Stereoselectivesynthesisoftriandtetrasubstitutedalkenes(三、四取代烯烃的立体选择性合成)ThefirststepishighlystereoselectiveTheRandthelargerofthegroupsRandRareantitoeachotherEarlyMethodCornforth,JWetal,JChemSoc,,DevelopmentMethodCorey,EJetal,JAmChemSoc,,,Example(E)MethodExample:R=Et,YieldZweifel,Getal,JAmChemSoc,,,Zweifel,Getal,JAmChemSoc,,,Oxidativedecarboxylationofcarboxylicacids(羧酸的氧化脱羧反应)Sheldon,RA,etal,OrganicReactions,,,Jahngen,BGE,JOrgChem,,,与DiealAlder反应结合是制备环状烯烃的好方法。ExampleTanzawaTetalTetrahedronLett,,,ExampleExampleAlkenesfromarylsulphonylhydrazones(由芳基磺酰腙制备烯烃)KolonkoK,etalJOrgChem,,,AdlingtonRM,etalAccChemRes,,,MechanismLesssubstitutedalkeneExampleExampleFragmentationReactions(裂解反应)X=leavinggroup,eg:OSOCHCHp,OSOCHstereospecificExampleOlefinInversionReactions(烯烃构型转换反应)Deoxygenationofepoxides(withretentionofgeometry)OtherexamplesSrereospecificsynthesisofalkenesfrom,diols(由,二醇立体选择性地合成烯烃)Corey–WinterOlefinSynthesisCoreyJAmChemSoc,,CoreyJAmChemSoc,,EastwoodAustJChem,,EastwoodTetrahedronLett,Burgstahler,BogerTetrahedron,,,SigmatropicRearrangementsClaisenandCopeRearrangementExamplesEvansJAmChemSoc,,BurgstahlerJAmChemSoc,,CarnduffJChemSoc,ChemCommun,ThioClaisenRearrangementAnadvantageofthethioClaisenrearrangementisthattheprecursorcanbedeprotonatedandalkylatedCoreyJAmChemSoc,,YamamotoJAmChemSoc,,andBlockJAmChemSoc,,TheCarrollReactionTheCarrollReactionCarrollJChemSoc,,HartungJChemSoc,CopeJAmChemSoc,,TanabeJAmChemSoc,,,SigmatropicRearrangementsReview:ComprehensiveOrgSyn,Vol,pp,–OrgReact,,–Analogousto,sigmatropicrearrangementexceptitenlistsalocalizedcharge(anion)inplaceofadoublebondExamplesJuliaTetrahedronLett,LythgoeJChemSoc,ChemCommun,EvansTetrahedronLett,AminoClaisenRearrangementThisreactionoccursbestwhennitrogenisconvertedtotheammoniumsaltGilbertTetrahedronLett,,StilleJOrgChem,,NakaiChemLett,SatoJAmChemSoc,,IIOlefinSynthesisExemplifiedwithJuvenileHormone(保幼激素的合成)JuvenileHormone(HJ)TrostSynthesis:JAmChemSoc,,SyntexSynthesis:JAmChemSoc,,CoreySynthesis:JAmChemSoc,,JohnsonSynthesis:JAmChemSoc,,CoreySynthesis:JAmChemSoc,,,,JohnsonSynthesis:JAmChemSoc,,Stotter–KondoSynthesis:JAmChemSoc,,JChemSoc,ChemCommun,StillSynthesis:TetrahedronLett,OtherSyntheses:()TrostSynthesisWadsworth–Horner–EmmonsReactionStereoselectivitynotmuchdifferencebetweenMeandH(secondatomstericeffect)bothisomersobtainedfromtheWadsworth–Horner–Emmonsreaction(Modernimprovementsnowavailable)RetrosyntheticAnalysisrepeatingsubunitsrecognizedrepeatingreactionsutilizedJAmChemSoc,,()SyntexSynthesis()SyntexSynthesisJAmChemSoc,,RobinsonAnnulationAlkylationDiastereoselectivityDirectedEpoxidationReactionFragmentationReactionSelectiveReductionsaturatedvsa,bunsaturatedcarbonylringstrainassociatedwithmemberedringcarbonylreleasedonreductionattackfromleasthinderedfaceTHPProtectingGroupifRgroupcontainschiralcenters,diastereomersresultremovedbymildacidThermodynamicEnolatesevere,diaxialinteractioninchairlikeTSaxialalkylationnostericincumberancetoaxialalkylationonleasthinderedfaceoftwistboatTSLiAlH(OtBu)Reductionlargereagent,usuallyequatorialH–delivery,interaction(torsionalstrain)relativelyinvarianttoNu–size,stericinteractionhighlydependentonNu–sizedueto

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