高等有機(jī)合成課件

高等有機(jī)合成

AdvancedOrganicSynthesis高等有機(jī)合成

AdvancedOrganicSynthe1緒論一、有機(jī)合成的歷史回顧二、有機(jī)合成化學(xué)的發(fā)展趨勢(shì)三、學(xué)習(xí)內(nèi)容和方法四、重要參考書(shū)及期刊五、課程安排緒論一、有機(jī)合成的歷史回顧2一、有機(jī)合成的歷史回顧1.尿素的合成（1828年，德國(guó)化學(xué)家Wohler）有機(jī)化學(xué)的開(kāi)始一、有機(jī)合成的歷史回顧1.尿素的合成（1828年，德國(guó)32.顛茄酮的合成

1)1902年，德國(guó)化學(xué)家Willstatter(1915年獲Noble化學(xué)獎(jiǎng)）21steps,overallyield0.7%2.顛茄酮的合成1)1902年，德國(guó)化學(xué)家Will42）1917年，英國(guó)化學(xué)家Robinson(1947年獲Noble化學(xué)獎(jiǎng)）3steps,overallyield90%Robinson為什么能是發(fā)現(xiàn)這條合成路線？MannichReaction(1912)2）1917年，英國(guó)化學(xué)家Robinson(1947年獲53.維生素B12的合成（Woodward,1977年）在Woodward及Eschenmoser領(lǐng)導(dǎo)下,經(jīng)過(guò)兩個(gè)實(shí)驗(yàn)室，100多位科學(xué)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(jī)合成作為一種藝術(shù)展現(xiàn)在世人面前。因在1945-1954年人工合成了奎寧、類(lèi)固醇、馬錢(qián)子堿、羊毛甾醇、麥角堿等近20種復(fù)雜天然產(chǎn)物而1965年獲Noble化學(xué)獎(jiǎng)3.維生素B12的合成（Woodward,19776E.J.Corey,(1990年獲Noble化學(xué)獎(jiǎng))

如果說(shuō)Woodward一生奮斗的成就是將有機(jī)合成作為一種藝術(shù)展現(xiàn)在世人面前，那么Corey則是將有機(jī)合成從藝術(shù)轉(zhuǎn)變成為科學(xué)的一個(gè)關(guān)鍵人物。他的逆合成分析是現(xiàn)代有機(jī)合成化學(xué)的重要基石，推動(dòng)了20世紀(jì)70年代以來(lái)整個(gè)有機(jī)合成領(lǐng)域的蓬勃發(fā)展。逆合成分析(Retrosyntheticanalysis)E.J.Corey,(1990年獲Noble化學(xué)獎(jiǎng))7Woodward(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Woodward(1981)紅霉素的全合成Y.8高等有機(jī)合成ppt課件9高等有機(jī)合成ppt課件10高等有機(jī)合成ppt課件115.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(jīng)濟(jì)性反應(yīng)（AtomEconomicalReaction)綠色化學(xué)（GreenChemistry)5.K.C.Nicolaou&S.L.Sch12二、有機(jī)合成化學(xué)的發(fā)展趨勢(shì)1.新試劑、新反應(yīng)、新方法的發(fā)現(xiàn)永無(wú)止境Epibatidine的研究二、有機(jī)合成化學(xué)的發(fā)展趨勢(shì)1.新試劑、新反應(yīng)、新方法的發(fā)13高等有機(jī)合成ppt課件14

Y(OTf)3-catalyzednovelMannichreactionofN-alkoxy-carbonylpyrroles,formaldehydeandprimaryaminehydrochloridesC.X.Zhuan,J.C.Dong,T.M.Cheng,R.T.Li*,TetrahedronLetters,2001,43(3),461-463Y(OTf)3-catalyzednovelMa15Aldol縮合反應(yīng)的研究Aldol縮合反應(yīng)的研究162.與生命科學(xué)和材料科學(xué)的聯(lián)系越來(lái)越緊密2.與生命科學(xué)和材料科學(xué)的聯(lián)系越來(lái)越緊密17三、學(xué)習(xí)內(nèi)容和方法內(nèi)容三、學(xué)習(xí)內(nèi)容和方法內(nèi)容181.對(duì)重要的基礎(chǔ)有機(jī)反應(yīng)要能夠熟練運(yùn)用新化合物的合成比葫蘆畫(huà)瓢逆合成分析跟蹤文獻(xiàn)，盡可能將最新的試劑、反應(yīng)和方法應(yīng)用于自己的研究工作中。3.學(xué)習(xí)別人的思路，創(chuàng)造性地借鑒和運(yùn)用方法1.對(duì)重要的基礎(chǔ)有機(jī)反應(yīng)要能夠熟練運(yùn)用新化合物的合成比葫19四、重要參考書(shū)及期刊參考書(shū)F.A.Carey著，王積濤譯，高等有機(jī)化學(xué)，B.反應(yīng)與合成，高等教育出版社，1986。岳保珍，李潤(rùn)濤，有機(jī)合成基礎(chǔ)，北京醫(yī)科大學(xué)出版社，2000。吳毓林，姚祝軍，現(xiàn)代有機(jī)合成化學(xué)，科學(xué)出版社，2001。W.Carruthers著，李潤(rùn)濤等譯，有機(jī)合成的一些新方法，河南大學(xué)出版社，1991。黃憲，王彥廣，陳振初，新編有機(jī)合成化學(xué)，化學(xué)工業(yè)出版社，2003。王詠梅等，高等有機(jī)化學(xué)習(xí)題解答，南開(kāi)大學(xué)出版社，2002。DaleL.Boger,ModernOrganicSynthesis,TheScrippsResearchInstitute,TsriPress,1999.ComprehensiveOrganicSynthesis,Vol.1-9四、重要參考書(shū)及期刊參考書(shū)F.A.Carey著，王20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.期刊Angew.Chem.Int.Ed.21五、課程安排進(jìn)度安排

2.講授原則復(fù)習(xí)老反應(yīng)，補(bǔ)充新反應(yīng)，重點(diǎn)講進(jìn)展，強(qiáng)調(diào)學(xué)思路?？荚?）寫(xiě)綜述一篇（近5年的進(jìn)展）（40%）2）筆試（60%）五、課程安排進(jìn)度安排22Chapter2FormationofCarbon-CarbonSingleBondsChapter223一、GeneralPrinciples烷化反應(yīng)：E=烷化劑縮合反應(yīng)：E=醛、酮、酯等Michael加成：E=Mannich反應(yīng)一、GeneralPrinciples烷化反應(yīng)：E=24二、影響反應(yīng)的主要因素

a.

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

A和B至少要有一個(gè)是EWGA和B應(yīng)該能使其

-碳上的H活化的基團(tuán)，通常為吸電子基（ElectronwithdrawgroupEWG）。二、影響反應(yīng)的主要因素a.

反應(yīng)底物（Substr25b.堿（Base）常用的堿：Ph3C->(Me2CH)2N->EtO->OH->R3N堿的選擇取決于底物的反應(yīng)活性理想的堿：堿性強(qiáng)，親核性弱，并不進(jìn)攻那些較敏感的基團(tuán)，另外能溶于非極性溶劑中。b.堿（Base）常用的堿：Ph3C->26高等有機(jī)合成ppt課件27c.溶劑（Solvent)SolventO-alkylationC-alkylation反應(yīng)速度常用的非質(zhì)子極性溶劑（polaraproticsolvent):DMFDMSOHMPAc.溶劑（Solvent)SolventO-alky28d.親電試劑（Electrophilicreagent)所有能與負(fù)碳離子發(fā)生反應(yīng)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(lián)系，相互影響的。在分析一個(gè)具體反應(yīng)時(shí)，應(yīng)該綜合分析考慮這四種影響因素。

d.親電試劑（Electrophilicreagen29三、烷基化反應(yīng)(Alkylation)1.O-alkylation&C-alkylationExample1三、烷基化反應(yīng)(Alkylation)1.O-alky30Example2Degreeofsubstitutionofalkylatingagent:Example2Degreeofsubstitutio31Example3Example3322.區(qū)域選擇性（Regioselectivity)區(qū)域選擇性受熱力學(xué)控制和動(dòng)力學(xué)控制的反應(yīng)條件影響很大.熱力學(xué)控制條件下主要生成取代基較多的烯醇;動(dòng)力學(xué)控制條件下主要生成取代基較少的烯醇;Example12.區(qū)域選擇性（Regioselectivity)33Example2Example2343.立體選擇性（Steroselectivity)烯醇化合物的立體選擇性形成,將為不對(duì)稱(chēng)合成提供平臺(tái).3.立體選擇性（Steroselectivity)35Example1Example136Example2Example237Example3Example338Example4Example4394.二羰基化合物的-烷基化反應(yīng)(-Alkylationof1,3-dicarbonylcompounds)J.Am.Chem.Soc.,1974,90,1082;1963,85,3237;1965,87,82.Example14.二羰基化合物的-烷基化反應(yīng)(-Alkyla40Example2Example241Example3繼承與發(fā)展Example3繼承與發(fā)展425.芳基鹵化物與烯醇鹽的反應(yīng)(Reactionsofaromatichalidewithenolates)ExampleMechanism5.芳基鹵化物與烯醇鹽的反應(yīng)(Reactionsof43關(guān)鍵是要有形成苯炔的條件。關(guān)鍵是要有形成苯炔的條件。446.酮和酯的烷基化反應(yīng)(Alkylationsofketonesandesters)避免Aldol縮合反應(yīng)發(fā)生的方法：烷化劑要待酮完全轉(zhuǎn)化為烯醇式后再加入。常用的堿：NaNH2,KNH2,NaH,Ph3CNa等；有副產(chǎn)物。LDA,LTMP,LHMDS等效果很好。6.酮和酯的烷基化反應(yīng)(Alkylationsof45Example1Example2Example1Example246不對(duì)稱(chēng)酮的選擇性烷基化反應(yīng)(Selectivealkylationofasymmetricketones)在一個(gè)-位引入一個(gè)活化基(略）如：DieckmannReaction;Claisencondensation制成結(jié)構(gòu)專(zhuān)屬性的烯醇負(fù)離子不對(duì)稱(chēng)酮的選擇性烷基化反應(yīng)(Selectivealk47在取代基較多的-位烷基化(烯醇硅醚法)堿性條件在取代基較多的-位烷基化(烯醇硅醚法)堿性條48酸性條件酸性條件49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(chǎn)率生成C-烷基化產(chǎn)物；但對(duì)于一般的鹵代烴，C-烷基化產(chǎn)物收率較底。若用LDA在低溫下反應(yīng)，則對(duì)各種鹵代烴均可得到高收率的C-烷基化產(chǎn)物。對(duì)于不對(duì)稱(chēng)酮，主要在取代基較少的-位發(fā)生烷基化。在取代基較少的-位烷基化(烯胺法,Stor50Example1Example2Example1Example2517.對(duì)映選擇性烷基化反應(yīng)（Enantioselectivealkylations)利用手性胺7.對(duì)映選擇性烷基化反應(yīng)（Enantioselectiv52利用二甲基肼利用二甲基肼53擴(kuò)展：二甲基腙鋰化合物的另一應(yīng)用二甲基腙鋰化合物容易轉(zhuǎn)化成有機(jī)銅化合物，而有機(jī)銅化合物在C-C鍵的形成中很有用。擴(kuò)展：二甲基腙鋰化合物的另一應(yīng)用二甲基腙54利用SAMP和RAMP若用RAMP，則得到另一種對(duì)映異構(gòu)體。利用SAMP和RAMP若用RAMP，55羧酸的-不對(duì)稱(chēng)烷基化羧酸的-不對(duì)稱(chēng)烷基化56ExampleExample578.極性翻轉(zhuǎn)（Umpolung)俞凌翀，劉志昌，極性轉(zhuǎn)換及其在有機(jī)合成中的應(yīng)用，科學(xué)出版社，1991Example1安息香縮合8.極性翻轉(zhuǎn)（Umpolung)俞凌翀，劉志58Example2醛氰醇法Example2醛氰醇法59Example31,3–二噻烷法不易發(fā)生Michael加成反應(yīng)。Example31,3–二噻烷法不易發(fā)生Mich60Example4乙基乙硫甲基亞砜法1,4–二酮Example4乙基乙硫甲基亞砜法1,4–二酮61四、縮合反應(yīng)(Condensation)AldolReactionMichaelAdditionMannichReactionClaisenCondensationDieckmannCondrnsationDarzen’sReactionReformatslyreaction四、縮合反應(yīng)(Condensation)AldolRea62AldolReaction(condensation)1)經(jīng)典Aldol反應(yīng)的兩大缺點(diǎn)不同醛、酮之間的反應(yīng)常得到混合產(chǎn)物；立體選擇性差A(yù)ldolReaction(condensation)1632)定向醇醛縮合反應(yīng)（DirectedAldolcondensation)Metood1PreformedLithiumEnolates

Z-enolatesgivepredominantlysyn(orthreo)aldolproducts(thermodynamicenolates).

E-enolatesgivepredominantlyanti(orerythro)aldolproducts(kineticenolates).2)定向醇醛縮合反應(yīng)（DirectedAldolco64Example1-StericsizeofR1affectsdiastereoselectivityExample1-StericsizeofR1a65高等有機(jī)合成ppt課件66OriginofDiastereoselectivitya.Z-enolatesDiastereoselectivityforZ-enolate(givingsynaldolproduct)ismaximizedwhenR1andR3arestericallydemanding(R1/R3interactionismaximized).Diastereoselectivityalsoincreasesasmetalischangedtoboron.ThisisattritubtedtoatighterT.S.(B–Obondshorter,soR1/R3stericinteractionsaremagnifiedinT.S.forantiproduct).

WhenR2isverylargetheR3/R2gaucheinteraction>R1/R31,3-diaxialinteraction(Why?).OriginofDiastereoselectivi67b.E-enolatesDiastereoselectivityincreasesasR1andR3becomestericallylarge,andaswitchtotheboronenolatewillincreaseselectivity.DiastereoselectivitymayswitchwhenR2isverylarge(Why?).b.E-enolatesDiastereoselec68EffectofR1EffectofR169EffectofR3EffectofR370EffectofR2EffectofR271Metood2PreformedBoronEnolatesMetood2PreformedBoronEnol72高等有機(jī)合成ppt課件73a.Z-enolatePreparationandReactionsa.Z-enolatePreparationandR74b.E-enolatePreparationandReactionsb.E-enolatePreparationandR75-Originallydifficulttocontrolbut:-Originallydifficulttocont76c.Examplesofmorerecentmethodstocontrolboronenolategeometryc.Examplesofmorerecentmet77高等有機(jī)合成ppt課件78AldolCondensationwithChiralEnolatesAldolCondensationwithChiral79高等有機(jī)合成ppt課件80TienolatepromotedEvansaldol(non-Evanssynaldol)TienolatepromotedEvansald81Chelatedandnon-chelatedTienolatesChelatedandnon-chelatedTi82Metood3Acid-CatalysedDirectedAldolReactions該方法是在酸性條件下反應(yīng)；但立體選擇性較差。Metood3Acid-CatalysedDirec833)有機(jī)小分子催化醇醛縮合反應(yīng)（SmallOrganicMoleculesCatalystedAldolReactions)3)有機(jī)小分子催化醇醛縮合反應(yīng)（SmallOrgani84高等有機(jī)合成ppt課件85高等有機(jī)合成ppt課件86高等有機(jī)合成ppt課件87高等有機(jī)合成ppt課件88高等有機(jī)合成ppt課件89NovelSmallOrganicMoleculesforaHighlyEnantioselectiveDirectAldolReactionJ.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,ChinaNovelSmallOrganicMolecules90高等有機(jī)合成ppt課件91高等有機(jī)合成ppt課件92高等有機(jī)合成ppt課件932.MichaelAdditionReactionApplications:Synthesisof1,5-dicarbonylcompoundsGeneralScheme2.MichaelAdditionReactionA94Development:AsymmetryMichaelAdditionReaction手性金屬配位化合物催化Development:AsymmetryMich95MacmillanGroup’sWorkSmallOrganicMoleculecatalyzedasymmetricMichaelreactionsMacmillanGroup’sWorkSmall96高等有機(jī)合成ppt課件97高等有機(jī)合成ppt課件98TheFirstEnantioselectiveOrganocatalyticMukaiyama-MichaelReaction:TheFirstEnantioselectiveOrg99S.P.Brown,N.C.Goodwin,andD.W.C.MacMillan*,

J.Am.Chem.Soc.2003,125(5),1192-1194S.P.Brown,N.C.Good1003.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(yīng)

活潑H組份醛、酮、活潑亞甲基化合物、酚類(lèi)化合物、雜環(huán)、炔等。3.MannichReactionGeneralSc101Example2Example1Example2Example1102Development: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.

Development:AsymmetryMann103(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.SmallOrganicMoleculecatalyzedasymmetricMannichreactionsSmallOrganicMoleculecatal104高等有機(jī)合成ppt課件105高等有機(jī)合成ppt課件106TheDirectandEnantioselective,One-Pot,Three-Component,Cross-MannichReactionofAldehydesAngew.Chem.Int.Ed.2003,42,3677–3680Y.Hayashi,W.Tsuboi,I.Ashimine,T.Urushima,Dr.M.ShojiDepartmentofIndustrialChemistry,FacultyofEngineeringTokyoUniversityofScience,KagurazakaTheDirectandEnantioselectiv107Three-componentMannichreactionwithvariousacceptoraldehydesN-methyl-2-pyrrolidinone(NMP)Three-componentMannichreacti108Three-componentMannichreactionwithvariousdonoraldehydes.Three-componentMannichreacti1094.ClaisenCondensationGeneralSchemeMechanism4.ClaisenCondensationGenera110

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一種酯的自身縮合Scopeofapplicat111DirectedClaisencondensationDirectedClaisencondensatio1125.DickmannCondensation5.DickmannCondensation113高等有機(jī)合成ppt課件114高等有機(jī)合成ppt課件115Chapter3FormationofCarbon-CarbonDouleBondsChapter31161.-Eleminationreactions（-消去反應(yīng)）I.TheSyntheticMethodsofAlklenes1.-Eleminationreactions（-1172.Pyrolyticsyneliminations（順式熱消去反應(yīng)）Applications:SynthesisofterminalalkenesfromprimaryacetatesDisadvantages:Highreactiontemperature2.Pyrolyticsyneliminations（118CopereactionChugavereaction反應(yīng)條件比對(duì)應(yīng)的酯熱消去溫和。CopereactionChugavereaction反1193.Wittigandrelatedreactions（Wittig及有關(guān)反應(yīng)）WittigReactionG.Wittigreceivedthe1979NobelPrizeinChemistryfor"manysignificantcontributionstoOrganicChemistry"whichincludednotonlytheWittigreaction,butalsoPhLipreparedbymetal-halogenexchange,benzyne,andtheWittigrearrangement.3.Wittigandrelatedreaction120GeneralSchemeMildreactionconditions;

Thepositionofthedoublebondisunambiguous.FeaturesGeneralSchemeMildreactio121RepresentativeExamplesExample1Example2RepresentativeExamplesExam122Example3Example4Example3Example4123Mechanism[2+2]cycloaddition.Mechanism[2+2]cycloadditi124InfluenceofsolventontheselectivityActivityandstereoselectivityofYildInfluenceofsolventonthe125Schl?ssermodification:allowsthepreparationoftransvs.cisolefins.Schl?sserAngew.Chem.,Int.Ed.Eng.1966,5,126.Schl?ssermodification:allo126StabilizedYlides-Stabilizedylidesaresolid;stabletostorage,notparticularlysensitivetomoisture,andcanevenbepurifiedbychromatography.-Becausetheyarestabilized,theyaremuchlessreactivethanalkylylides.Theyreactwellwithaldehydes,butonlyslowlywithketones.-Thefirststep,involvingtheadditiontothealdehyde,isslowandreversiblewithstabilizedylides.StabilizedYlides-Stabilize127高等有機(jī)合成ppt課件128InfluenceofsolventontheselectivityInfluenceofsolventonthe129

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.Wadsworth–Horner–EmmonsReact130PreparationofPhosphonateEstersArbuzovJ.Russ.Phys.Chem.Soc.1906,38,687.-ArbuzovRearragement-Thesameapproachtothepreparationof

-ketophosphonatesisnotsuccessful:PreparationofPhosphonateEs131-ButcanusevariationonClaisenconditions:-ButcanusevariationonCla132ModificationsandScope-LiCl/tertiaryamines(DBU,iPr2NEt,Et3N)Masamune,RoushTetrahedronLett.1984,25,2183.Cansubstituteforconventionalconditionsandisespeciallygoodforbasesensitivesubstrates.ModificationsandScope-LiC133-HinderedphosphonatesandhinderedaldehydesincreaseE-selectivity(trans).-Still–GennarimodificationselectiveforZ-alkenes(cis):-Hinderedphosphonatesandhin134-AdditionalZ-selectivestabilizedphosphonates.SelecteddiarylphosphonatesprovideHighZ-selectivityaswell.-AdditionalZ-selectivestabi135PetersonReactionReviews:Org.React.1990,38,1.PetersonreactionoffersanalternativetoWittigprocedure.TheyaremorereactiveandstericallylessdemandingthanaWittigreagentandthevolatilebyproduct(Me3SiOH/Me3SiOSiMe3)issimplertoremovethanPh3PO.Itdoes,however,requireasecondsteptopromoteeliminationofthe

-hydroxysilane.PetersonReactionReviews:Org136-Theeliminationisstereospecific:acid-promotedbeingantiandbase-promotedbeingsyn.Hudrlik,PetersonJ.Am.Chem.Soc.1975,97,1464.-Theeliminationisstereospe137StabilizedPetersonReagents-ThestabilizedPetersonreagentsgivepredominantlythemoststabletransolefins(E)StabilizedPetersonReagents138-Additionalexamples:-Additionalexamples:1394.TheTebbeReactionandRelatedTitanium-stabilizedMethylenations(Tebbe反應(yīng)及與有關(guān)穩(wěn)定化鈦試劑的亞甲基化反應(yīng)）4.TheTebbeReactionandRela140-Toleratesketalandalkenederivatives.

ScopedefinedbyEvansandGrubbsJ.Am.Chem.Soc.1980,102,3270.ExtendedtotertiaryamidesbyPineJ.Org.Chem.1985,50,1212.ForananalogoususeofCp2TiMe2:PetasisJ.Am.Chem.Soc.1990,112,6392.-Toleratesketalandalkened1415.Sulphoxide-sulphenaterearragement:Synthesisofallylalcohols(亞砜-次磺酸酯重排：烯丙醇類(lèi)化合物的合成)Combinedwithalkylationofsulphoxidesthereactionprovidesaversatilesynthesisofdi-andtri-substitutedallylicalcoholsEvansandAndrews,Acc.Chem.Res.,1974,7,1475.Sulphoxide-sulphenaterearr142-alkylationofallylicalcohlosExample1Example2-alkylationofallylicalcohl1436.Alkenesfromsulphones(由砜制備烯烴）-JuliaOlefinationReview:ComprehensiveOrg.Syn.,Vol.1,792.-Example:JuliaTetrahedronLett.1973,4833.6.Alkenesfromsulphones(由砜制144Juliadevelopedamorerecent,single-stepvariantthatavoidsthereductiveeliminationJuliaBull.Soc.Chim.,Fr.1993,130,336.Julia,M.etal.,TetrahedronLett.,1973,4833Kocienski,P.J.etal.,J.Chem.Soc.PerkinI,1978,829.-Example:Juliadevelopedamorerec145-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.-Ramberg–BacklundreactionOrg1467.Decarboxylationof-lactones(-內(nèi)酯的脫羧反應(yīng)）ReformatskyReactionNote:NostilbenewasformedSynthesisoftri-ortetrasubsitutedalkenesExample17.Decarboxylationof-lacton147FehrC.etal.TetrahedronLett.,1992,33,2465MolbierW.R.etal.J.Org.Chem.,1995,60,5378Example2Example3FehrC.etal.TetrahedronLet148MulzerJ.,etal.,J.Chem.Soc.Chem.Commun.,1979,52MulzerJ.,etal.,J.Chem.So1498.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.,1959,1128.Stereoselectivesynthesis150DevelopmentMethod1Corey,E.J.etal.,J.Am.Chem.Soc.,1967,89,4246.DevelopmentMethod1Corey,E.151Example(54%;97%E)Example(54%;97%E)152Method2Example:R=Et,Yield72%Zweifel,G.etal.,J.Am.Chem.Soc.,1967,89,2754.Method2Example:R=Et,Yie153Zweifel,G.etal.,J.Am.Chem.Soc.,1967,89,5085.Zweifel,G.etal.,J.Am.Che1549.Oxidativedecarboxylationofcarboxylicacids(羧酸的氧化脫羧反應(yīng)）Sheldon,R.A.,etal.,OrganicReactions,1972,19,279.Jahngen,B.G.E.,J.Org.Chem.,1974,39,1650.與Dieal-Alder反應(yīng)結(jié)合，是制備環(huán)狀烯烴的好方法。Example19.Oxidativedecarboxylation155TanzawaT.etal.TetrahedronLett.,1992,33,6783Example2Example3TanzawaT.etal.Tetrahedron15610.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.,1983,16,55Mechanism10.Alkenesfromarylsulphony157LesssubstitutedalkeneExample1Example2LesssubstitutedalkeneExample15811.FragmentationReactions(裂解反應(yīng)）X=leavinggroup,e.g.:-OSO2C6H4CH3-p,-OSO2CH3100%stereospecificExample11.FragmentationReactions(159高等有機(jī)合成ppt課件160高等有機(jī)合成ppt課件16112.OlefinInversionReactions(烯烴構(gòu)型轉(zhuǎn)換反應(yīng)）Deoxygenationofepoxides(withretentionofgeometry)12.OlefinInversionReactions162OtherexamplesOtherexamples16313.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.1965,87,934.13.Srereospecificsynthesis164EastwoodAust.J.Chem.1964,17,1392.EastwoodTetrahedronLett.1970,5223.Burgstahler,BogerTetrahedron1976,32,309.EastwoodAust.J.Chem.1964,16514.[3,3]-SigmatropicRearrangementsClaisenandCopeRearrangement14.[3,3]-SigmatropicRearrang166ExamplesEvansJ.Am.Chem.Soc.1975,97,4765.BurgstahlerJ.Am.Chem.Soc.1961,83,198.ExamplesEvansJ.Am.Chem.So167CarnduffJ.Chem.Soc.,Chem.Commun.1967,606.CarnduffJ.Chem.Soc.,Chem.168Thio-ClaisenRearrangementAnadvantageofthethio-Claisenrearrangementisthattheprecursorcanbedeprotonatedandalkylated.CoreyJ.Am.Chem.Soc.1970,92,5522.YamamotoJ.Am.Chem.Soc.1973,95,2693and4446.BlockJ.Am.Chem.Soc.1985,107,6731.Thio-ClaisenRearrangementAn169TheCarrollReactionCarrollJ.Chem.Soc.1940,704,1266.HartungJ.Chem.Soc.1941,507.CopeJ.Am.Chem.Soc.1943,65,1992.TanabeJ.Am.Chem.Soc.1980,102,862.TheCarrollReactionCarrollJ.17015.[2,3]-SigmatropicRearrangementsReview:ComprehensiveOrg.Syn.,Vol.6,pp834,873–908.Org.React.1994,46,105–209.-Analogousto[3,3]-sigmatropicrearrangementexceptitenlistsalocalizedcharge(anion)inplaceofadoublebond.ExamplesJuliaTetrahedronLett.1974,2077.15.[2,3]-SigmatropicRearran171LythgoeJ.Chem.Soc.,Chem.Commun.1972,757.EvansTetrahedronLett.1973,4691.LythgoeJ.Chem.Soc.,Chem.C172Amino-ClaisenRearrangement-Thisreactionoccursbestwhennitrogenisconvertedtotheammoniumsalt.GilbertTetrahedronLett.1984,25,2303.StilleJ.Org.Chem.1991,56,5578.NakaiChem.Lett.1990,2069.Amino-ClaisenRearrangement-173SatoJ.Am.Chem.Soc.1990,112,1999.SatoJ.Am.Chem.Soc.1990,1174II.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:II.OlefinSynthesisExemplifi175(1).TrostSynthesisWadsworth–Horner–EmmonsReaction(1).TrostSynthesisWadsworth–176Stereoselectivity-notmuchdifferencebetweenMeandH(secondatomstericeffect)-bothisomersobtainedfromtheWadsworth–Horner–Emmonsreaction(Modernimprovementsnowavailable)RetrosyntheticAnalysis-repeatingsubunitsrecognized-repeatingreactionsutilizedJ.Am.Chem.Soc.1967,89,5292.StereoselectivityRetrosyntheti177(2).SyntexSynthesis(2).SyntexSynthesis178J.Am.Chem.Soc.1968,90,6224.RobinsonAnnulationAlkylationDiastereoselectivityDirectedEpoxidationReactionFragmentationReactionSelectiveReduction-saturatedvs.a,b-unsaturatedcarbonyl-ringstrainassociatedwith5-memberedringcarbonylreleasedonreduction-attackfromleasthinderedfaceTHPProtectingGroup-ifRgroupcontainschiralcenters,diastereomersresult-removedbymildacidJ.Am.Chem.Soc.1968,90,62179ThermodynamicEnolate-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,largereagentnowgivesaxialdeliveryThermodynamicEnolateLiAlH(OtB180Epoxidation-inEt2O,coordinationofperacidtosolventgivesdeliveryfromtheleasthindereda-face-inCH2Cl2,H-bondingofOHtoperacidprovidesdeliverytothelessaccessibleb-face-TeranishiJ.Am.Chem.Soc.1979,101,159.FragmentationReaction-utilizedtocontrolC=Cbondstereochemistry-transperiplanarorientationofbreakingbonds-dictatesZolefingeometryinproductEpoxidationFragmentationReac1813.CoreySynthesis3.CoreySynthesis182DissolvingMetalReductionsCyclicPrecursorstoTrisubstitutedOlefinsOxidativeCleavageofEnolEthersLiAlH4ReductionofPropargylAlcoholsCuprateCouplingReactionsAllylicAlcoholOxidationJ.Am.Chem.Soc.1968,90,5618.StereospecificSynthesisofTrisubstitutedOlefinsDissolvingMetalReductionsJ.183MnO2Oxidation-mildoxidationofallylicalcohols-direct,mildmethodforoxidationtoamethylesterEpoxidation-selective-inpolarsolventthemoleculefoldsupsuchthattheterminalC=CismoreaccessibleMnO2OxidationEpoxidation1844.JohnsonSynthesis:Trimethylpyridine4.JohnsonSynthesis:Trimethyl185J.Am.Chem.Soc.1968,90,6225.J.Am.Chem.Soc.1968,90,621865.CoreySynthesis:J.Am.Chem.Soc.1970,92,6635,6636.5.CoreySynthesis:1871,5-HShiftDiimideReduction-lesssubstitutedC=Creducedmorerapidly-generatedin-situ1,5-HShiftDiimideReduction-1886.JohnsonSynthesis:J.Am.Chem.Soc.1970,92,4463.6.JohnsonSynthesis:189OlefinicKetalClaisenReaction-selectivitydependenton1,3-interactioninchair-likeT.S.-secondClaisenmoreselectiveduetolargerRgroupvs.CO2MeOlefinicKetalClaisenReactio1907.Stotter–Ko