高等有機合成

高等有機合成第1頁/共674頁緒論一、有機合成的歷史回顧二、有機合成化學的發(fā)展趨勢三、學習內容和方法四、重要參考書及期刊五、課程安排第2頁/共674頁一、有機合成的歷史回顧1.尿素的合成（1828年，德國化學家Wohler）有機化學的開始第3頁/共674頁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%第4頁/共674頁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(fā)現這條合成路線？MannichReaction(1912)第5頁/共674頁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化學獎第6頁/共674頁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(fā)展。

逆合成分析(Retrosyntheticanalysis)第7頁/共674頁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)的全合成第8頁/共674頁第9頁/共674頁第10頁/共674頁第11頁/共674頁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)第12頁/共674頁二、有機合成化學的發(fā)展趨勢1.新試劑、新反應、新方法的發(fā)現永無止境Epibatidine的研究第13頁/共674頁第14頁/共674頁

Y(OTf)3-catalyzednovelMannichreactionofN-alkoxy-carbonylpyrroles,formaldehydeandprimaryaminehydrochloridesC.X.Zhuan,J.C.Dong,T.M.Cheng,R.T.Li*,TetrahedronLetters,2001,43(3),461-463第15頁/共674頁Aldol縮合反應的研究第16頁/共674頁2.與生命科學和材料科學的聯系越來越緊密第17頁/共674頁三、學習內容和方法

內容第18頁/共674頁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(chuàng)造性地借鑒和運用

方法第19頁/共674頁四、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(yī)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(yè)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第20頁/共674頁

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.第21頁/共674頁五、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%）第22頁/共674頁Chapter2FormationofCarbon-CarbonSingleBonds第23頁/共674頁一、GeneralPrinciples烷化反應：E=烷化劑縮合反應：E=醛、酮、酯等Michael加成：E=Mannich反應第24頁/共674頁二、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）。第25頁/共674頁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。第26頁/共674頁第27頁/共674頁c.溶劑（Solvent)SolventO-alkylationC-alkylation反應速度常用的非質子極性溶劑（polaraproticsolvent):DMFDMSOHMPA第28頁/共674頁d.親電試劑（Electrophilicreagent)所有能與負碳離子發(fā)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。

第29頁/共674頁三、烷基化反應(Alkylation)1.O-alkylation&C-alkylationExample1第30頁/共674頁Example2Degreeofsubstitutionofalkylatingagent:第31頁/共674頁Example3第32頁/共674頁2.區(qū)域選擇性（Regioselectivity)

區(qū)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第33頁/共674頁Example2第34頁/共674頁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.第35頁/共674頁Example1第36頁/共674頁Example2第37頁/共674頁Example3第38頁/共674頁Example4第39頁/共674頁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第40頁/共674頁Example2第41頁/共674頁Example3繼承與發(fā)展第42頁/共674頁5.芳基鹵化物與烯醇鹽的反應(Reactionsofaromatichalidewithenolates)ExampleMechanism第43頁/共674頁關鍵是要有形成苯炔的條件。第44頁/共674頁6.酮和酯的烷基化反應(Alkylationsofketonesandesters)避免Aldol縮合反應發(fā)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。第45頁/共674頁Example1Example2第46頁/共674頁

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第47頁/共674頁

在取代基較多的-位烷基化(烯醇硅醚法)堿性條件第48頁/共674頁酸性條件第49頁/共674頁

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(fā)生烷基化。第50頁/共674頁Example1Example2第51頁/共674頁7.對映選擇性烷基化反應（Enantioselectivealkylations)

利用手性胺第52頁/共674頁

利用二甲基肼第53頁/共674頁

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。第54頁/共674頁

利用SAMP和RAMP若用RAMP，則得到另一種對映異構體。第55頁/共674頁

羧酸的-不對稱烷基化第56頁/共674頁Example第57頁/共674頁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安息香縮合第58頁/共674頁Example2醛氰醇法第59頁/共674頁Example31,3–二噻烷法不易發(fā)生Michael加成反應。第60頁/共674頁Example4乙基乙硫甲基亞砜法1,4–二酮第61頁/共674頁四、縮合反應(Condensation)AldolReactionMichaelAdditionMannichReactionClaisenCondensationDieckmannCondrnsationDarzen’sReactionReformatslyreaction第62頁/共674頁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；立體選擇性差第63頁/共674頁2)定向醇醛縮合反應（DirectedAldolcondensation)Metood1PreformedLithiumEnolates

Z-enolatesgivepredominantlysyn(orthreo)aldolproducts(thermodynamicenolates).

E-enolatesgivepredominantlyanti(orerythro)aldolproducts(kineticenolates).第64頁/共674頁Example1-StericsizeofR1affectsdiastereoselectivity第65頁/共674頁第66頁/共674頁OriginofDiastereoselectivitya.Z-enolatesDiastereoselectivityforZ-enolate(givingsynaldolproduct)ismaximizedwhenR1andR3arestericallydemanding(R1/R3interactionismaximized).Diastereoselectivityalsoincreasesasmetalischangedtoboron.ThisisattritubtedtoatighterT.S.(B–Obondshorter,soR1/R3stericinteractionsaremagnifiedinT.S.forantiproduct).

WhenR2isverylargetheR3/R2gaucheinteraction>R1/R31,3-diaxialinteraction(Why?).第67頁/共674頁b.E-enolatesDiastereoselectivityincreasesasR1andR3becomestericallylarge,andaswitchtotheboronenolatewillincreaseselectivity.DiastereoselectivitymayswitchwhenR2isverylarge(Why?).第68頁/共674頁EffectofR1第69頁/共674頁EffectofR3第70頁/共674頁EffectofR2第71頁/共674頁Metood2PreformedBoronEnolates第72頁/共674頁第73頁/共674頁a.Z-enolatePreparationandReactions第74頁/共674頁b.E-enolatePreparationandReactions第75頁/共674頁-Originallydifficulttocontrolbut:第76頁/共674頁c.Examplesofmorerecentmethodstocontrolboronenolategeometry第77頁/共674頁第78頁/共674頁AldolCondensationwithChiralEnolates第79頁/共674頁第80頁/共674頁TienolatepromotedEvansaldol(non-Evanssynaldol)第81頁/共674頁Chelatedandnon-chelatedTienolates第82頁/共674頁Metood3Acid-CatalysedDirectedAldolReactions

該方法是在酸性條件下反應；但立體選擇性較差。第83頁/共674頁3)有機小分子催化醇醛縮合反應（SmallOrganicMoleculesCatalystedAldolReactions)第84頁/共674頁第85頁/共674頁第86頁/共674頁第87頁/共674頁第88頁/共674頁第89頁/共674頁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第90頁/共674頁第91頁/共674頁第92頁/共674頁第93頁/共674頁2.MichaelAdditionReactionApplications:Synthesisof1,5-dicarbonylcompoundsGeneralScheme第94頁/共674頁Development:AsymmetryMichaelAdditionReaction

手性金屬配位化合物催化第95頁/共674頁MacmillanGroup’sWorkSmallOrganicMoleculecatalyzedasymmetricMichaelreactions第96頁/共674頁第97頁/共674頁第98頁/共674頁TheFirstEnantioselectiveOrganocatalyticMukaiyama-MichaelReaction:第99頁/共674頁S.P.Brown,N.C.Goodwin,andD.W.C.MacMillan*,

J.Am.Chem.Soc.2003,125(5),1192-1194第100頁/共674頁3.MannichReactionGeneralScheme

胺組份氨、伯胺、仲胺

醛組份HCHO,PhCHO,RCHO可分別發(fā)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(huán)、炔等。第101頁/共674頁Example2Example1第102頁/共674頁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.

第103頁/共674頁(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第104頁/共674頁第105頁/共674頁第106頁/共674頁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第107頁/共674頁Three-componentMannichreactionwithvariousacceptoraldehydesN-methyl-2-pyrrolidinone(NMP)第108頁/共674頁Three-componentMannichreactionwithvariousdonoraldehydes.第109頁/共674頁4.ClaisenCondensationGeneralSchemeMechanism第110頁/共674頁

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第111頁/共674頁DirectedClaisencondensation第112頁/共674頁5.DickmannCondensation第113頁/共674頁第114頁/共674頁第115頁/共674頁Chapter3FormationofCarbon-CarbonDouleBonds第116頁/共674頁1.-Eleminationreactions（-消去反應）I.TheSyntheticMethodsofAlklenes第117頁/共674頁2.Pyrolyticsyneliminations（順式熱消去反應）Applications:SynthesisofterminalalkenesfromprimaryacetatesDisadvantages:Highreactiontemperature第118頁/共674頁CopereactionChugavereaction反應條件比對應的酯熱消去溫和。第119頁/共674頁3.Wittigandrelatedreactions（Wittig及有關反應）WittigReactionG.Wittigreceivedthe1979NobelPrizeinChemistryfor"manysignificantcontributionstoOrganicChemistry"whichincludednotonlytheWittigreaction,butalsoPhLipreparedbymetal-halogenexchange,benzyne,andtheWittigrearrangement.第120頁/共674頁GeneralSchemeMildreactionconditions;

Thepositionofthedoublebondisunambiguous.Features第121頁/共674頁RepresentativeExamplesExample1Example2第122頁/共674頁Example3Example4第123頁/共674頁Mechanism[2+2]cycloaddition.第124頁/共674頁InfluenceofsolventontheselectivityActivityandstereoselectivityofYild第125頁/共674頁Schl?ssermodification:allowsthepreparationoftransvs.cisolefins.Schl?sserAngew.Chem.,Int.Ed.Eng.1966,5,126.第126頁/共674頁StabilizedYlides-Stabilizedylidesaresolid;stabletostorage,notparticularlysensitivetomoisture,andcanevenbepurifiedbychromatography.-Becausetheyarestabilized,theyaremuchlessreactivethanalkylylides.Theyreactwellwithaldehydes,butonlyslowlywithketones.-Thefirststep,involvingtheadditiontothealdehyde,isslowandreversiblewithstabilizedylides.第127頁/共674頁第128頁/共674頁Influenceofsolventontheselectivity第129頁/共674頁

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.第130頁/共674頁PreparationofPhosphonateEstersArbuzovJ.Russ.Phys.Chem.Soc.1906,38,687.-ArbuzovRearragement-Thesameapproachtothepreparationof-ketophosphonatesisnotsuccessful:第131頁/共674頁-ButcanusevariationonClaisenconditions:第132頁/共674頁ModificationsandScope-LiCl/tertiaryamines(DBU,iPr2NEt,Et3N)Masamune,RoushTetrahedronLett.1984,25,2183.Cansubstituteforconventionalconditionsandisespeciallygoodforbasesensitivesubstrates.第133頁/共674頁-HinderedphosphonatesandhinderedaldehydesincreaseE-selectivity(trans).-Still–GennarimodificationselectiveforZ-alkenes(cis):第134頁/共674頁-AdditionalZ-selectivestabilizedphosphonates.SelecteddiarylphosphonatesprovideHighZ-selectivityaswell.第135頁/共674頁PetersonReactionReviews:Org.React.1990,38,1.PetersonreactionoffersanalternativetoWittigprocedure.TheyaremorereactiveandstericallylessdemandingthanaWittigreagentandthevolatilebyproduct(Me3SiOH/Me3SiOSiMe3)issimplertoremovethanPh3PO.Itdoes,however,requireasecondsteptopromoteeliminationofthe-hydroxysilane.第136頁/共674頁-Theeliminationisstereospecific:acid-promotedbeingantiandbase-promotedbeingsyn.Hudrlik,PetersonJ.Am.Chem.Soc.1975,97,1464.第137頁/共674頁StabilizedPetersonReagents-ThestabilizedPetersonreagentsgivepredominantlythemoststabletransolefins(E)第138頁/共674頁-Additionalexamples:第139頁/共674頁4.TheTebbeReactionandRelatedTitanium-stabilizedMethylenations(Tebbe反應及與有關穩(wěn)定化鈦試劑的亞甲基化反應）第140頁/共674頁-Toleratesketalandalkenederivatives.

ScopedefinedbyEvansandGrubbsJ.Am.Chem.Soc.1980,102,3270.ExtendedtotertiaryamidesbyPineJ.Org.Chem.1985,50,1212.ForananalogoususeofCp2TiMe2:PetasisJ.Am.Chem.Soc.1990,112,6392.第141頁/共674頁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第142頁/共674頁-alkylationofallylicalcohlosExample1Example2第143頁/共674頁6.Alkenesfromsulphones(由砜制備烯烴）-JuliaOlefinationReview:ComprehensiveOrg.Syn.,Vol.1,792.-Example:JuliaTetrahedronLett.1973,4833.第144頁/共674頁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:第145頁/共674頁-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.第146頁/共674頁7.Decarboxylationof-lactones(-內酯的脫羧反應）ReformatskyReactionNote:NostilbenewasformedSynthesisoftri-ortetrasubsitutedalkenesExample1第147頁/共674頁FehrC.etal.TetrahedronLett.,1992,33,2465MolbierW.R.etal.J.Org.Chem.,1995,60,5378Example2Example3第148頁/共674頁MulzerJ.,etal.,J.Chem.Soc.Chem.Commun.,1979,52第149頁/共674頁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第150頁/共674頁DevelopmentMethod1Corey,E.J.etal.,J.Am.Chem.Soc.,1967,89,4246.第151頁/共674頁Example(54%;97%E)第152頁/共674頁Method2Example:R=Et,Yield72%Zweifel,G.etal.,J.Am.Chem.Soc.,1967,89,2754.第153頁/共674頁Zweifel,G.etal.,J.Am.Chem.Soc.,1967,89,5085.第154頁/共674頁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(huán)狀烯烴的好方法。Example1第155頁/共674頁TanzawaT.etal.TetrahedronLett.,1992,33,6783Example2Example3第156頁/共674頁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第157頁/共674頁LesssubstitutedalkeneExample1Example2第158頁/共674頁11.FragmentationReactions(裂解反應）X=leavinggroup,e.g.:-OSO2C6H4CH3-p,-OSO2CH3100%stereospecificExample第159頁/共674頁第160頁/共674頁第161頁/共674頁12.OlefinInversionReactions(烯烴構型轉換反應）Deoxygenationofepoxides(withretentionofgeometry)第162頁/共674頁Otherexamples第163頁/共674頁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.第164頁/共674頁EastwoodAust.J.Chem.1964,17,1392.EastwoodTetrahedronLett.1970,5223.Burgstahler,BogerTetrahedron1976,32,309.第165頁/共674頁14.[3,3]-SigmatropicRearrangementsClaisenandCopeRearrangement第166頁/共674頁ExamplesEvansJ.Am.Chem.Soc.1975,97,4765.BurgstahlerJ.Am.Chem.Soc.1961,83,198.第167頁/共674頁CarnduffJ.Chem.Soc.,Chem.Commun.1967,606.第168頁/共674頁Thio-ClaisenRearrangementAnadvantageofthethio-Claisenrearrangementisthattheprecursorcanbedeprotonatedandalkylated.CoreyJ.Am.Chem.Soc.1970,92,5522.YamamotoJ.Am.Chem.Soc.1973,95,2693and4446.BlockJ.Am.Chem.Soc.1985,107,6731.第169頁/共674頁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.第170頁/共674頁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.第171頁/共674頁LythgoeJ.Chem.Soc.,Chem.Commun.1972,757.EvansTetrahedronLett.1973,4691.第172頁/共674頁Amino-ClaisenRearrangement-Thisreactionoccursbestwhennitrogenisconvertedtotheammoniumsalt.GilbertTetrahedronLett.1984,25,2303.StilleJ.Org.Chem.1991,56,5578.NakaiChem.Lett.1990,2069.第173頁/共674頁SatoJ.Am.Chem.Soc.1990,112,1999.第174頁/共674頁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:第175頁/共674頁(1).TrostSynthesisWadsworth–Horner–EmmonsReaction第176頁/共674頁Stereoselectivity-notmuchdifferencebetweenMeandH(secondatomstericeffect)-bothisomersobtainedfromtheWadsworth–Horner–Emmonsreaction(Modernimprovementsnowavailable)RetrosyntheticAnalysis-repeatingsubunitsrecognized-repeatingreactionsutilizedJ.Am.Chem.Soc.1967,89,5292.第177頁/共674頁(2).SyntexSynthesis第178頁/共674頁J.Am.Chem.Soc.1968,90,6224.RobinsonAnnulationAlkylationDiastereoselectivityDirectedEpoxidationReactionFragmentationReactionSelectiveReduction-saturatedvs.a,b-unsaturatedcarbonyl-ringstrainassociatedwith5-memberedringcarbonylreleasedonreduction-attackfromleasthinderedfaceTHPProtectingGroup-ifRgroupcontainschiralcenters,diastereomersresult-removedbymildacid第179頁/共674頁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第180頁/共674頁Epoxidation-inEt2O,coordinationofperacidtosolventgivesdeliveryfromtheleasthindereda-face-inCH2Cl2,H-bondingofOHtoperacidprovidesdeliverytothelessaccessibleb-face-TeranishiJ.Am.Chem.Soc.1979,101,159.FragmentationReaction-utilizedtocontrolC=Cbondstereochemistry-transperiplanarorientationofbreakingbonds-dictatesZolefingeometryinproduct第181頁/共674頁3.CoreySynthesis第182頁/共674頁DissolvingMetalReductionsCyclicPrecursorstoTrisubstitutedOlefinsOxidativeCleavageofEnolEthersLiAlH4ReductionofPropargylAlcoholsCuprateCouplingReactionsAllylicAlcoholOxidationJ.Am.Chem.Soc.1968,90,5618.StereospecificSynthesisofTrisubstitutedOlefins第183頁/共674頁MnO2Oxidation-mildoxidationofallylicalcohols-direct,mildmethodforoxidationtoamethylesterEpoxidation-selective-inpolarsolventthemoleculefoldsupsuchthattheterminalC=Cismoreaccessible第184頁/共674頁4.JohnsonSynthesis:Trimethylpyridine第185頁/共674頁J.Am.Chem.Soc.1968,90,6225.第186頁/共674頁5.CoreySynthesis:J.Am.Chem.Soc.1970,92,6635,6636.第187頁/共674頁1,5-HShiftDiimideReduction-lesssubstitutedC=Creducedmorerapidly-generatedin-situ第188頁/共674頁6.JohnsonSynthesis:J.Am.Chem.Soc.1970,92,4463.第189頁/共674頁OlefinicKetalClaisenReaction-selectivitydependenton1,3-interactioninchair-likeT.S.-secondClaisenmoreselectiveduetolargerRgroupvs.CO2Me第190頁/共674頁7.Stotter–KondoSynthesis:J.Am.Chem.Soc.1973,95,4444.J.Chem.Soc.,Chem.Commun.1972,1311.第191頁/共674頁第192頁/共674頁8.StillSynthesis:TetrahedronLett.1979,593.[2,3]-SigmatropicRearrangement第193頁/共674頁第194頁/共674頁Chapter4ConversionofFunctionalGroups第195頁/共674頁1.AdditionofCarbon-CarbonDoubleBonds第196頁/共674頁2.HalogenationofAlcoholsGeneralMethods第197頁/共674頁Org.Lett.,2002,4(4),553-555TCT/DMFMethodDevelopment2,4,6-trichloro[1,3,5]triazineTCT第198頁/共674頁Table1.ConversionofAliphaticAlcoholsintotheCorrespondingAlkylHalidesa

Forcompleteconversionofthealcohol.b

Thecorrespondingchlorideisformedalso.第199頁/共674頁Table2.ConversionofDiolsandUnsaturatedand-aminoAlcoholsintotheCorrespondingAlkylHalidesa

Forcompleteconversionofthealcohol.b

Thecorrespondingchlorideisformedalso.第200頁/共674頁Mechanism第201頁/共674頁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第202頁/共674頁3.FormationofAminesGeneralMethods第203頁/共674頁與氮烯有關的重排反應第204頁/共674頁SynthesisprimaryamineGabrielSynthesisHarshhydrolysisconditionsImprovementSynthesis,1990,8,735;1995,7,756Synlett,1996,2,179;Synth.Commun.,1999,29,2685第205頁/共674頁SynthesisofArylaminesfromaminationofArylHalides

Development第206頁/共674頁EarlyPalladium-CatalyzedAmination該反應僅限于仲胺與電中性的鹵代苯。第207頁/共674頁要求等當量的有機鈀催化劑。第208頁/共674頁J.Am.Chem.Soc.,1994,116,5969-5970P.Patt,Hartiget.al.發(fā)現Pd可循環(huán)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。第209頁/共674頁InitialTin-freeAminationofArXHartwigand