高等有機合成

AdvancedOrganicSynthesis高等有機合成緒論一、有機合成的歷史回顧二、有機合成化學的發展趨勢三、學習內容和方法四、重要參考書及期刊五、課程安排高等有機合成一、有機合成的歷史回顧1.尿素的合成（1828年，德國化學家Wohler）有機化學的開始高等有機合成2.顛茄酮的合成

1)1902年，德國化學家Willstatter(1915年獲Noble化學獎）21steps,overallyield0.7%高等有機合成2）1917年，英國化學家Robinson(1947年獲Noble化學獎）3steps,overallyield90%Robinson為什么能是發現這條合成路線？MannichReaction(1912)高等有機合成3.維生素B12的合成（Woodward,1977年）

在Woodward及Eschenmoser領導下,經過兩個實驗室，100多位科學家的共同努力，于1977年完成了維生素B12的全合成工作。將有機合成作為一種藝術展現在世人面前。

因在1945-1954年人工合成了奎寧、類固醇、馬錢子堿、羊毛甾醇、麥角堿等近20種復雜天然產物而1965年獲Noble化學獎高等有機合成E.J.Corey,(1990年獲Noble化學獎)

如果說Woodward一生奮斗的成就是將有機合成作為一種藝術展現在世人面前，那么Corey則是將有機合成從藝術轉變成為科學的一個關鍵人物。他的逆合成分析是現代有機合成化學的重要基石，推動了20世紀70年代以來整個有機合成領域的蓬勃發展。

逆合成分析(Retrosyntheticanalysis)高等有機合成Woodward(1981)紅霉素的全合成Y.Kishi(1987)?？舅氐娜铣蒘.L.Schreiberetal(1993)FK-1012的全合成K.C.Nicolaou&S.L.Schreiber（1994）紫杉醇（Taxol)的全合成高等有機合成高等有機合成高等有機合成高等有機合成5.K.C.Nicolaou&S.L.Schreiber

K.C.Nicolaou,etal.

Theartandscienceoftotalsynthesisatthedawnoftwenty-firstcentury,Angew.Chem.Int.Ed.Engl.,2002,39,44

S.L.Schreiber,etal.

Target-orientedanddiversity-orientedorganicsynthesisindrugdiscovery,Science,2000,287,1964高立體選擇性（HighStereoselectivity)原子經濟性反應（AtomEconomicalReaction)綠色化學（GreenChemistry)高等有機合成二、有機合成化學的發展趨勢1.新試劑、新反應、新方法的發現永無止境Epibatidine的研究高等有機合成高等有機合成

Y(OTf)3-catalyzednovelMannichreactionofN-alkoxy-carbonylpyrroles,formaldehydeandprimaryaminehydrochloridesC.X.Zhuan,J.C.Dong,T.M.Cheng,R.T.Li*,TetrahedronLetters,2001,43(3),461-463高等有機合成Aldol縮合反應的研究高等有機合成2.與生命科學和材料科學的聯系越來越緊密高等有機合成三、學習內容和方法

內容高等有機合成1.對重要的基礎有機反應要能夠熟練運用新化合物的合成比葫蘆畫瓢逆合成分析跟蹤文獻，盡可能將最新的試劑、反應和方法應用于自己的研究工作中。3.學習別人的思路，創造性地借鑒和運用

方法高等有機合成四、重要參考書及期刊

參考書F.A.Carey著，王積濤譯，高等有機化學，B.反應與合成，高等教育出版社，1986。岳保珍，李潤濤，有機合成基礎，北京醫科大學出版社，2000。吳毓林，姚祝軍，現代有機合成化學，科學出版社，2001。W.Carruthers著，李潤濤等譯，有機合成的一些新方法，河南大學出版社，1991。黃憲，王彥廣，陳振初，新編有機合成化學，化學工業出版社，2003。王詠梅等，高等有機化學習題解答，南開大學出版社，2002。DaleL.Boger,ModernOrganicSynthesis,TheScrippsResearchInstitute,TsriPress,1999.ComprehensiveOrganicSynthesis,Vol.1-9高等有機合成

期刊Angew.Chem.Int.Ed.J.Am.Chem.Soc.J.Org.Chem.Org.LettersChem.Commun.TetrahedronTetrahedronLetters.TetrahedronAsymm.SynthesisSynlett11.Synth.Commun.12.Eur.J.Chem.13.Eur.J.Org.Chem.14.Heterocyclics15.J.HeterocyclicChem.16.J.Med.Chem.Bioorg.Med.Chem.Bioorg.Med.Chem.Lett.Eur.J.Med.Chem.20.J.Comb.Chem.高等有機合成五、課程安排進度安排

2.講授原則復習老反應，補充新反應，重點講進展，強調學思路?？荚?/p>

1）寫綜述一篇（近5年的進展）（40%）

2）筆試（60%）高等有機合成Chapter2FormationofCarbon-CarbonSingleBonds高等有機合成一、GeneralPrinciples烷化反應：E=烷化劑縮合反應：E=醛、酮、酯等Michael加成：E=Mannich反應高等有機合成二、影響反應的主要因素

a.

反應底物（Substrate)-NO2>-COR>SO2R>-CN>-CO2R>-Ph,SOR

A和B至少要有一個是EWGA和B應該能使其

-碳上的H活化的基團，通常為吸電子基（ElectronwithdrawgroupEWG）。高等有機合成b.堿（Base）常用的堿：Ph3C->(Me2CH)2N->EtO->OH->R3N

堿的選擇取決于底物的反應活性理想的堿：堿性強，親核性弱，并不進攻那些較敏感的基團，另外能溶于非極性溶劑中。高等有機合成高等有機合成c.溶劑（Solvent)SolventO-alkylationC-alkylation反應速度常用的非質子極性溶劑（polaraproticsolvent):DMFDMSOHMPA高等有機合成d.親電試劑（Electrophilicreagent)所有能與負碳離子發生反應的碳正離子或分子。例：RX,R-SO3H,RCO2Et,RCOR’

這四種影響因素之間是相互聯系，相互影響的。在分析一個具體反應時，應該綜合分析考慮這四種影響因素。

高等有機合成三、烷基化反應(Alkylation)1.O-alkylation&C-alkylationExample1高等有機合成Example2Degreeofsubstitutionofalkylatingagent:高等有機合成Example3高等有機合成2.區域選擇性（Regioselectivity)

區域選擇性受熱力學控制和動力學控制的反應條件影響很大.熱力學控制條件下主要生成取代基較多的烯醇;動力學控制條件下主要生成取代基較少的烯醇;Example1高等有機合成Example2高等有機合成3.立體選擇性（Steroselectivity)

烯醇化合物的立體選擇性形成,將為不對稱合成提供平臺.高等有機合成Example1高等有機合成Example2高等有機合成Example3高等有機合成Example4高等有機合成4.二羰基化合物的

-烷基化反應(-Alkylationof1,3-dicarbonylcompounds)J.Am.Chem.Soc.,1974,90,1082;1963,85,3237;1965,87,82.Example1高等有機合成Example2高等有機合成Example3繼承與發展高等有機合成5.芳基鹵化物與烯醇鹽的反應(Reactionsofaromatichalidewithenolates)ExampleMechanism高等有機合成關鍵是要有形成苯炔的條件。高等有機合成6.酮和酯的烷基化反應(Alkylationsofketonesandesters)避免Aldol縮合反應發生的方法：烷化劑要待酮完全轉化為烯醇式后再加入。常用的堿：NaNH2,KNH2,NaH,Ph3CNa等；有副產物。

LDA,LTMP,LHMDS等效果很好。高等有機合成Example1Example2高等有機合成

不對稱酮的選擇性烷基化反應(Selectivealkylationofasymmetricketones)

在一個

-位引入一個活化基(略）如：DieckmannReaction;Claisencondensation

制成結構專屬性的烯醇負離子高等有機合成

在取代基較多的

-位烷基化(烯醇硅醚法)堿性條件高等有機合成酸性條件高等有機合成

在取代基較少的

-位烷基化(烯胺法,StorkEnamineSynthesis)

通常，用活潑的鹵代烷，可以高產率生成C-烷基化產物；但對于一般的鹵代烴，C-烷基化產物收率較底。若用

LDA在低溫下反應，則對各種鹵代烴均可得到高收率的

C-烷基化產物。對于不對稱酮，主要在取代基較少的

-位發生烷基化。高等有機合成Example1Example2高等有機合成7.對映選擇性烷基化反應（Enantioselectivealkylations)

利用手性胺高等有機合成

利用二甲基肼高等有機合成

擴展：二甲基腙鋰化合物的另一應用

二甲基腙鋰化合物容易轉化成有機銅化合物，而有機銅化合物在C-C鍵的形成中很有用。高等有機合成

利用SAMP和RAMP若用RAMP，則得到另一種對映異構體。高等有機合成

羧酸的

-不對稱烷基化高等有機合成Example高等有機合成8.極性翻轉（Umpolung)

俞凌翀，劉志昌，極性轉換及其在有機合成中的應用，科學出版社，1991Example1安息香縮合高等有機合成Example2醛氰醇法高等有機合成Example31,3–二噻烷法不易發生Michael加成反應。高等有機合成Example4乙基乙硫甲基亞砜法1,4–二酮高等有機合成四、縮合反應(Condensation)AldolReactionMichaelAdditionMannichReactionClaisenCondensationDieckmannCondrnsationDarzen’sReactionReformatslyreaction高等有機合成AldolReaction(condensation)1)經典Aldol反應的兩大缺點

不同醛、酮之間的反應常得到混合產物；立體選擇性差高等有機合成2)定向醇醛縮合反應（DirectedAldolcondensation)Metood1PreformedLithiumEnolates

Z-enolatesgivepredominantlysyn(orthreo)aldolproducts(thermodynamicenolates).

E-enolatesgivepredominantlyanti(orerythro)aldolproducts(kineticenolates).高等有機合成Example1-StericsizeofR1affectsdiastereoselectivity高等有機合成高等有機合成OriginofDiastereoselectivitya.Z-enolatesDiastereoselectivityforZ-enolate(givingsynaldolproduct)ismaximizedwhenR1andR3arestericallydemanding(R1/R3interactionismaximized).Diastereoselectivityalsoincreasesasmetalischangedtoboron.ThisisattritubtedtoatighterT.S.(B–Obondshorter,soR1/R3stericinteractionsaremagnifiedinT.S.forantiproduct).

WhenR2isverylargetheR3/R2gaucheinteraction>R1/R31,3-diaxialinteraction(Why?).高等有機合成b.E-enolatesDiastereoselectivityincreasesasR1andR3becomestericallylarge,andaswitchtotheboronenolatewillincreaseselectivity.DiastereoselectivitymayswitchwhenR2isverylarge(Why?).高等有機合成EffectofR1高等有機合成EffectofR3高等有機合成EffectofR2高等有機合成Metood2PreformedBoronEnolates高等有機合成高等有機合成a.Z-enolatePreparationandReactions高等有機合成b.E-enolatePreparationandReactions高等有機合成-Originallydifficulttocontrolbut:高等有機合成c.Examplesofmorerecentmethodstocontrolboronenolategeometry高等有機合成高等有機合成AldolCondensationwithChiralEnolates高等有機合成高等有機合成TienolatepromotedEvansaldol(non-Evanssynaldol)高等有機合成Chelatedandnon-chelatedTienolates高等有機合成Metood3Acid-CatalysedDirectedAldolReactions

該方法是在酸性條件下反應；但立體選擇性較差。高等有機合成3)有機小分子催化醇醛縮合反應（SmallOrganicMoleculesCatalystedAldolReactions)高等有機合成高等有機合成高等有機合成高等有機合成高等有機合成高等有機合成NovelSmallOrganicMoleculesforaHighlyEnantioselectiveDirectAldolReactionJ.AM.CHEM.SOC.2003,125,5262-5263ZhuoTang,?,?FanJiang,§Luo-TingYu,?XinCui,?Liu-ZhuGong,*,?Ai-QiaoMi,?Yao-ZhongJiang,?andYun-DongWu*KeyLaboratoryforAsymmetricSynthesisandChirotechnologyofSichuanProvince,ChengduInstituteofOrganicChemistry,ChineseAcademyofSciences,Chengdu,610041,China,CollegeofChemicalEngineering,SichuanUniVersity,Chengdu,610065,China,andStateKeyLaboratoryofMolecularDynamicsandStableStructures,CollegeofChemistryandMolecularEngineering,PekingUniVersity,Beijing,100871,China高等有機合成高等有機合成高等有機合成高等有機合成2.MichaelAdditionReactionApplications:Synthesisof1,5-dicarbonylcompoundsGeneralScheme高等有機合成Development:AsymmetryMichaelAdditionReaction

手性金屬配位化合物催化高等有機合成MacmillanGroup’sWorkSmallOrganicMoleculecatalyzedasymmetricMichaelreactions高等有機合成高等有機合成高等有機合成TheFirstEnantioselectiveOrganocatalyticMukaiyama-MichaelReaction:高等有機合成S.P.Brown,N.C.Goodwin,andD.W.C.MacMillan*,

J.Am.Chem.Soc.2003,125(5),1192-1194高等有機合成3.MannichReactionGeneralScheme

胺組份氨、伯胺、仲胺

醛組份HCHO,PhCHO,RCHO可分別發生三、雙、單Mannich

反應

活潑H

組份醛、酮、活潑亞甲基化合物、酚類化合物、雜環、炔等。高等有機合成Example2Example1高等有機合成Development:AsymmetryMannichReactionLewisacid-catalyzedasymmetricMannichreactions(a)Fujii,A.;Hagiwara,E.;Sodeoka,M.J.Am.Chem.Soc.1999,121,5450;(b)Ishitani,H.;Ueno,M.;Kobayashi,S.J.Am.Chem.Soc.2000,122,8180;(c)Ishihara,K.;Miyata,M.;Hattori,K.;Yamamoto,H.J.Am.Chem.Soc.1994,116,10520;(d)Ishitani,H.;Ueno,M.;Kobayashi,S.J.Am.Chem.Soc.1997,119,2060;(e)Ferraris,D.;Yong,B.;Dudding,T.;Leckta,T.J.Am.Chem.Soc.1998,120,4548;(f)Ferraris,D.;Young,B.;Cox,C.;Dudding,T.;Drury,W.J.,III;Ryzhkov,L.;Taggi,A.E.;Lectka,T.J.Am.Chem.Soc.2002,124,67.(g)Kobayashi,S.;Hamada,T.;Manabe,K.J.Am.Chem.Soc.2002,124,5640.

高等有機合成(a)Notz,W.;Sakthivel,K.;Bui,T.;Zhong,G.;Barbas,C.F.,IIITetrahedronLett.2001,42,199;(b)Juhl,K.;Gathergood,N.;Jorgensen,K.A.Angew.Chem.,Int.Ed.2001,40,2995;(c)Yamasaki,S.;Iida,T.;Shibasaki,M.Tetrahedron1999,55,8857;(d)List,B.J.Am.Chem.Soc.2000,122,9336;(e)Co′rdova,A.;Notz,W.;Zhong,G.;Betancort,J.M.;Barbas,C.F.,IIIJ.Am.Chem.Soc.2002,124,1842;(f)Co′rdova,A.;Watanabe,S.-i.;Tanaka,F.;Notz,W.;Barbas,C.F.,IIIJ.Am.Chem.Soc.2002,124,1866.SmallOrganicMoleculecatalyzedasymmetricMannichreactions高等有機合成高等有機合成高等有機合成TheDirectandEnantioselective,One-Pot,Three-Component,Cross-MannichReactionofAldehydesAngew.Chem.Int.Ed.2003,42,3677–3680Y.Hayashi,W.Tsuboi,I.Ashimine,T.Urushima,Dr.M.ShojiDepartmentofIndustrialChemistry,FacultyofEngineeringTokyoUniversityofScience,Kagurazaka高等有機合成Three-componentMannichreactionwithvariousacceptoraldehydesN-methyl-2-pyrrolidinone(NMP)高等有機合成Three-componentMannichreactionwithvariousdonoraldehydes.高等有機合成4.ClaisenCondensationGeneralSchemeMechanism高等有機合成

一種酯的自身縮合Scopeofapplication

一種含-H的酯與一種不含-H的酯之間的縮合Examples高等有機合成DirectedClaisencondensation高等有機合成5.DickmannCondensation高等有機合成高等有機合成高等有機合成Chapter3FormationofCarbon-CarbonDouleBonds高等有機合成1.-Eleminationreactions（

-消去反應）I.TheSyntheticMethodsofAlklenes高等有機合成2.Pyrolyticsyneliminations（順式熱消去反應）Applications:SynthesisofterminalalkenesfromprimaryacetatesDisadvantages:Highreactiontemperature高等有機合成CopereactionChugavereaction反應條件比對應的酯熱消去溫和。高等有機合成3.Wittigandrelatedreactions（Wittig及有關反應）WittigReactionG.Wittigreceivedthe1979NobelPrizeinChemistryfor"manysignificantcontributionstoOrganicChemistry"whichincludednotonlytheWittigreaction,butalsoPhLipreparedbymetal-halogenexchange,benzyne,andtheWittigrearrangement.高等有機合成GeneralSchemeMildreactionconditions;

Thepositionofthedoublebondisunambiguous.Features高等有機合成RepresentativeExamplesExample1Example2高等有機合成Example3Example4高等有機合成Mechanism[2+2]cycloaddition.高等有機合成InfluenceofsolventontheselectivityActivityandstereoselectivityofYild高等有機合成Schl?ssermodification:allowsthepreparationoftransvs.cisolefins.Schl?sserAngew.Chem.,Int.Ed.Eng.1966,5,126.高等有機合成StabilizedYlides-Stabilizedylidesaresolid;stabletostorage,notparticularlysensitivetomoisture,andcanevenbepurifiedbychromatography.-Becausetheyarestabilized,theyaremuchlessreactivethanalkylylides.Theyreactwellwithaldehydes,butonlyslowlywithketones.-Thefirststep,involvingtheadditiontothealdehyde,isslowandreversiblewithstabilizedylides.高等有機合成高等有機合成Influenceofsolventontheselectivity高等有機合成

Wadsworth–Horner–EmmonsReactionHornerChem.Ber.1958,91,61;1959,92,2499.Wadsworth,EmmonsJ.Am.Chem.Soc.1961,83,1733.Reviews:Org.React.1977,25,73–253.ComprehensiveOrg.Syn.,Vol.1,761.高等有機合成PreparationofPhosphonateEstersArbuzovJ.Russ.Phys.Chem.Soc.1906,38,687.-ArbuzovRearragement-Thesameapproachtothepreparationof

-ketophosphonatesisnotsuccessful:高等有機合成-ButcanusevariationonClaisenconditions:高等有機合成ModificationsandScope-LiCl/tertiaryamines(DBU,iPr2NEt,Et3N)Masamune,RoushTetrahedronLett.1984,25,2183.Cansubstituteforconventionalconditionsandisespeciallygoodforbasesensitivesubstrates.高等有機合成-HinderedphosphonatesandhinderedaldehydesincreaseE-selectivity(trans).-Still–GennarimodificationselectiveforZ-alkenes(cis):高等有機合成-AdditionalZ-selectivestabilizedphosphonates.SelecteddiarylphosphonatesprovideHighZ-selectivityaswell.高等有機合成PetersonReactionReviews:Org.React.1990,38,1.PetersonreactionoffersanalternativetoWittigprocedure.TheyaremorereactiveandstericallylessdemandingthanaWittigreagentandthevolatilebyproduct(Me3SiOH/Me3SiOSiMe3)issimplertoremovethanPh3PO.Itdoes,however,requireasecondsteptopromoteeliminationofthe

-hydroxysilane.高等有機合成-Theeliminationisstereospecific:acid-promotedbeingantiandbase-promotedbeingsyn.Hudrlik,PetersonJ.Am.Chem.Soc.1975,97,1464.高等有機合成StabilizedPetersonReagents-ThestabilizedPetersonreagentsgivepredominantlythemoststabletransolefins(E)高等有機合成-Additionalexamples:高等有機合成4.TheTebbeReactionandRelatedTitanium-stabilizedMethylenations(Tebbe反應及與有關穩定化鈦試劑的亞甲基化反應）高等有機合成-Toleratesketalandalkenederivatives.

ScopedefinedbyEvansandGrubbsJ.Am.Chem.Soc.1980,102,3270.ExtendedtotertiaryamidesbyPineJ.Org.Chem.1985,50,1212.ForananalogoususeofCp2TiMe2:PetasisJ.Am.Chem.Soc.1990,112,6392.高等有機合成5.Sulphoxide-sulphenaterearragement:Synthesisofallylalcohols(亞砜-次磺酸酯重排：烯丙醇類化合物的合成)Combinedwithalkylationofsulphoxidesthereactionprovidesaversatilesynthesisofdi-andtri-substitutedallylicalcoholsEvansandAndrews,Acc.Chem.Res.,1974,7,147高等有機合成-alkylationofallylicalcohlosExample1Example2高等有機合成6.Alkenesfromsulphones(由砜制備烯烴）-JuliaOlefinationReview:ComprehensiveOrg.Syn.,Vol.1,792.-Example:JuliaTetrahedronLett.1973,4833.高等有機合成Juliadevelopedamorerecent,single-stepvariantthatavoidsthereductiveeliminationJuliaBull.Soc.Chim.,Fr.1993,130,336.Julia,M.etal.,TetrahedronLett.,1973,4833Kocienski,P.J.etal.,J.Chem.Soc.PerkinI,1978,829.-Example:高等有機合成-Ramberg–BacklundreactionOrg.React.1977,25,1.Base-SO2NicolaouK.C.etal.,J.AmChem.Soc.,1992,114,7360.BoockmanR.K.etal.,J.AmChem.Soc.,1991,113,9682.AlvarzeE.etal.,J.AmChem.Soc.,1995,117,1437.高等有機合成7.Decarboxylationof-lactones(-內酯的脫羧反應）ReformatskyReactionNote:NostilbenewasformedSynthesisoftri-ortetrasubsitutedalkenesExample1高等有機合成FehrC.etal.TetrahedronLett.,1992,33,2465MolbierW.R.etal.J.Org.Chem.,1995,60,5378Example2Example3高等有機合成MulzerJ.,etal.,J.Chem.Soc.Chem.Commun.,1979,52高等有機合成8.Stereoselectivesynthesisoftri-andtetra-substitutedalkenes(

三、四取代烯烴的立體選擇性合成）Thefirststepishighlystereoselective.TheR4andthelargerofthegroupsR1andR2areantitoeachother.EarlyMethodCornforth,J.W.etal.,J.Chem.Soc.,1959,112高等有機合成DevelopmentMethod1Corey,E.J.etal.,J.Am.Chem.Soc.,1967,89,4246.高等有機合成Example(54%;97%E)高等有機合成Method2Example:R=Et,Yield72%Zweifel,G.etal.,J.Am.Chem.Soc.,1967,89,2754.高等有機合成Zweifel,G.etal.,J.Am.Chem.Soc.,1967,89,5085.高等有機合成9.Oxidativedecarboxylationofcarboxylicacids(

羧酸的氧化脫羧反應）Sheldon,R.A.,etal.,OrganicReactions,1972,19,279.Jahngen,B.G.E.,J.Org.Chem.,1974,39,1650.

與Dieal-Alder反應結合，是制備環狀烯烴的好方法。Example1高等有機合成TanzawaT.etal.TetrahedronLett.,1992,33,6783Example2Example3高等有機合成10.Alkenesfromarylsulphonylhydrazones(由芳基磺酰腙制備烯烴）KolonkoK.,etal.J.Org.Chem.,1978,43,1404;AdlingtonR.M.,etal.Acc.Chem.Res.,1983,16,55Mechanism高等有機合成LesssubstitutedalkeneExample1Example2高等有機合成11.FragmentationReactions(裂解反應）X=leavinggroup,e.g.:-OSO2C6H4CH3-p,-OSO2CH3100%stereospecificExample高等有機合成高等有機合成高等有機合成12.OlefinInversionReactions(烯烴構型轉換反應）Deoxygenationofepoxides(withretentionofgeometry)高等有機合成Otherexamples高等有機合成13.Srereospecificsynthesisofalkenesfrom1,2-diols(由1,2-二醇立體選擇性地合成烯烴）Corey–WinterOlefinSynthesisCoreyJ.Am.Chem.Soc.1963,85,2677.CoreyJ.Am.Chem.Soc.1965,87,934.高等有機合成EastwoodAust.J.Chem.1964,17,1392.EastwoodTetrahedronLett.1970,5223.Burgstahler,BogerTetrahedron1976,32,309.高等有機合成14.[3,3]-SigmatropicRearrangementsClaisenandCopeRearrangement高等有機合成ExamplesEvansJ.Am.Chem.Soc.1975,97,4765.BurgstahlerJ.Am.Chem.Soc.1961,83,198.高等有機合成CarnduffJ.Chem.Soc.,Chem.Commun.1967,606.高等有機合成Thio-ClaisenRearrangementAnadvantageofthethio-Claisenrearrangementisthattheprecursorcanbedeprotonatedandalkylated.CoreyJ.Am.Chem.Soc.1970,92,5522.YamamotoJ.Am.Chem.Soc.1973,95,2693and4446.BlockJ.Am.Chem.Soc.1985,107,6731.高等有機合成TheCarrollReactionCarrollJ.Chem.Soc.1940,704,1266.HartungJ.Chem.Soc.1941,507.CopeJ.Am.Chem.Soc.1943,65,1992.TanabeJ.Am.Chem.Soc.1980,102,862.高等有機合成15.[2,3]-SigmatropicRearrangementsReview:ComprehensiveOrg.Syn.,Vol.6,pp834,873–908.Org.React.1994,46,105–209.-Analogousto[3,3]-sigmatropicrearrangementexceptitenlistsalocalizedcharge(anion)inplaceofadoublebond.ExamplesJuliaTetrahedronLett.1974,2077.高等有機合成LythgoeJ.Chem.Soc.,Chem.Commun.1972,757.EvansTetrahedronLett.1973,4691.高等有機合成Amino-ClaisenRearrangement-Thisreactionoccursbestwhennitrogenisconvertedtotheammoniumsalt.GilbertTetrahedronLett.1984,25,2303.StilleJ.Org.Chem.1991,56,5578.NakaiChem.Lett.1990,2069.高等有機合成SatoJ.Am.Chem.Soc.1990,112,1999.高等有機合成II.OlefinSynthesisExemplifiedwithJuvenileHormone(保幼激素的合成）JuvenileHormone（HJ)1.TrostSynthesis:J.Am.Chem.Soc.1967,89,5292.2.SyntexSynthesis:J.Am.Chem.Soc.1968,90,6224.3.CoreySynthesis:J.Am.Chem.Soc.1968,90,5618.4.JohnsonSynthesis:J.Am.Chem.Soc.1968,90,6225.5.CoreySynthesis:J.Am.Chem.Soc.1970,92,6635,6636,6637.6.JohnsonSynthesis:J.Am.Chem.Soc.1970,92,4463.7.Stotter–KondoSynthesis:J.Am.Chem.Soc.1973,95,4444.J.Chem.Soc.,Chem.Commun.1972,1311.8.StillSynthesis:TetrahedronLett.1979,593.9.OtherSyntheses:高等有機合成(1).TrostSynthesisWadsworth–Horner–EmmonsReaction高等有機合成Stereoselectivity-notmuchdifferencebetweenMeandH(secondatomstericeffect)-bothisomersobtainedfromtheWadsworth–Horner–Emmonsreaction(Modernimprovementsnowavailable)RetrosyntheticAnalysis-repeatingsubunitsrecognized-repeatingreactionsutilizedJ.Am.Chem.Soc.1967,89,5292.高等有機合成(2).SyntexSynthesis高等有機合成J.Am.Chem.Soc.1968,90,6224.RobinsonAnnulationAlkylationDiastereoselectivityDirectedEpoxidationReactionFragmentationReactionSelectiveReduction-saturatedvs.a,b-unsaturatedcarbonyl-ringstrainassociatedwith5-memberedringcarbonylreleasedonreduction-attackfromleasthinderedfaceTHPProtectingGroup-ifRgroupcontainschiralcenters,diastereomersresult-removedbymildacid高等有機合成ThermodynamicEnolate-severe1,3-diaxialinteractioninchair-likeT.S.axialalkylation-nostericincumberancetoaxialalkylationonleasthinderedfaceoftwistboatT.S.LiAlH(OtBu)3Reduction-largereagent,usuallyequatorialH–delivery-1,2-interaction(torsionalstrain)relativelyinvarianttoNu–size-1,3-stericinteractionhighlydependentonNu–size-duetoabsenceofaxialC(3)–H,largereagentnowgivesaxialdelivery高等有機合成Epoxidation-inEt2O,coordinationofperacidtosolventgivesdeliveryfromtheleasthindereda-face-inCH2Cl2,H-bondingofOHtoperacidprovidesdeliverytothelessaccessibleb-face-TeranishiJ.Am.Chem.Soc.1979,101,159.FragmentationReaction-utilizedtocontrolC=Cbondstereochemistry-transperiplanarorientationofbreakingbonds-dictatesZolefingeometryinproduct高等有機合成3.CoreySynthesis高等有機合成DissolvingMetalReductionsCyclicPrecursorstoTrisubstitutedOlefinsOxidativeCleavageofEnolEthersLiAlH4ReductionofPropargylAlcoholsCuprateCouplingReactionsAllylicAlcoholOxidationJ.Am.Chem.Soc.1968,90,5618.StereospecificSynthesisofTrisubstitutedOlefins高等有機合成MnO2Oxidation-mildoxidationofallylicalcohols-direct,mildmethodforoxidationtoamethylesterEpoxidation-selective-inpolarsolventthemoleculefoldsupsuchthattheterminalC=Cismoreaccessible高等有機合成4.JohnsonSynthesis:Trimethylpyridine高等有機合成J.Am.Chem.Soc.1968,90,6225.高等有機合成5.CoreySynthesis:J.Am.Chem.Soc.1970,92,6635,6636.高等有機合成1,5-HShiftDiimideReduction-lesssubstitutedC=Creducedmorerapidly-generatedin-situ高等有機合成6.JohnsonSynthesis:J.Am.Chem.Soc.1970,92,4463.高等有機合成OlefinicKetalClaisenReaction-selectivitydependenton1,3-interactioninchair-likeT.S.-secondClaisenmoreselectiveduetolargerRgroupvs.CO2Me高等有機合成7.Stotter–KondoSynthesis:J.Am.Chem.Soc.1973,95,4444.J.Chem.Soc.,Chem.Commun.1972,1311.高等有機合成高等有機合成8.StillSynthesis:TetrahedronLett.1979,593.[2,3]-SigmatropicRearrangement高等有機合成高等有機合成Chapter4ConversionofFunctionalGroups高等有機合成1.AdditionofCarbon-CarbonDoubleBonds高等有機合成2.HalogenationofAlcoholsGeneralMethods高等有機合成Org.Lett.,2002,4(4),553-555TCT/DMFMethodDevelopment2,4,6-trichloro[1,3,5]triazineTCT高等有機合成Table1.ConversionofAliphaticAlcoholsintotheCorrespondingAlkylHalidesa

Forcompleteconversionofthealcohol.b

Thecorrespondingchlorideisformedalso.高等有機合成Table2.ConversionofDiolsandUnsaturatedand

-aminoAlcoholsintotheCorrespondingAlkylHalidesa

Forcompleteconversionofthealcohol.b

Thecorrespondingchlorideisformedalso.高等有機合成Mechanism高等有機合成Me3SiCl

該方法對芐醇、伯醇、烯丙醇、叔醇，室溫下反應迅速，收率高。J.Org.Chem.1995,60,2638高等有機合成3.FormationofAminesGeneralMethods高等有機合成與氮烯有關的重排反應高等有機合成SynthesisprimaryamineGabrielSynthesisHarshhydrolysisconditionsImprovementSynthesis,1990,8,735;1995,7,756Synlett,1996,2,179;Synth.Commun.,1999,29,2685高等有機合成SynthesisofArylaminesfromaminationofArylHalides

Development高等有機合成EarlyPalladium-CatalyzedAmination該反應僅限于仲胺與電中性的鹵代苯。高等有機合成要求等當量的有機鈀催化劑。高等有機合成J.Am.Chem.Soc.,1994,116,5969-5970P.Patt,Hartiget.al.發現Pd可循環使用從1985到1994近10年沒有關于Pd催化胺化反應的報道。存在的問題：1）要將胺變成錫胺化物；

2）不適應于伯胺；

3）反應速度較慢；

4）催化劑用量較大。高等有機合成InitialTin-freeAminationofArXHartwigandBuchwald,Angew.Chem.Int.Edu.,1995,34,1348-1350;TetrahedronLett.1995,36,3609高等有機合成RoomTemperatureCatalyticAminationofArylIodidesJ.Org.Chem.1997,62,6066-6068JohnP.WolfeandStephenL.Buchwald*DepartmentofChemistry,MassachusettsInstituteofTechnology,Cambridge,Massachusetts02139高等有機合成高等有機合成Table2.RoomTemperatureCatalyticAminationofArylIodides高等有機合成Table2.Continued高等有機合成AHighlyActiveCatalystforPalladium-CatalyzedCross-CouplingReactions:Room-TemperatureSuzukiCouplingsandAminationofUnactivatedArylChloridesDavidW.Old,JohnP.Wolfe,andStephenL.Buchwald*J.Am.Chem.Soc.1998,120,9722-9723高等有機合成高等有機合成AminationReactionsofArylHalideswithNitrogen-ContainingReagentsMediatedbyPalladium/ImidazoliumSaltSystemsGabrielaA.Grasa,MihaiS.Viciu,JinkunHuang,andStevenP.Nolan*DepartmentofChemistry,UniversityofNewOrleans,NewOrleans,Louisiana70148J.Org.Chem.2001,66,7729-7737高等有機合成Imes·HClImes:1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylideneIpr:1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene)ImidazoliumChlorideLigands高等有機合成高等有機合成Table2.AminationofArylChlorideswithVariousAmines高等有機合成Table2Continued高等有機合成Table3.AminationInvolvingArylBromidesandIdodideswithVariousAminesMostinterestinginthesestudiesinvolvinganarylbearingbothchloroandiodo(orbromo)substituentsistheobservationthatbromoandiodofunctionalitiescanbeconvertedatroomtemperature(entries3and4)andtheremainingchlorofunctionalitycansubsequentlybeconvertedatmoreelevatedtemperatures.Thiscouldprovetobeasignificantadvantageinprocesschemistry.高等有機合成Table4.InfluenceofPalladium(0)/ImidazoliumSaltRatioonAminationReactions高等有機合成Table5.AminationofChlopyridinesandBromopyridineswithVariousAmines高等有機合成Generalcatalyticcycleforaminationreaction.高等有機合成Table6.AminationofArylChlorideswithBenzophenoneImine高等有機合成Table7.AminationofArylBromideswithBenzophenoneImine高等有機合成Table9.EffectoftheImidazoliumChloridesandBasesonN-Ary