高等有机合成高等有机合成AdvancedOrganicSynthesis绪绪论论一、有机合成的历史回顾一、有机合成的历史回顾二、有机合成化学的发展趋势二、有机合成化学的发展趋势三、学习内容和方法三、学习内容和方法四、重要参考书及期刊四、重要参考书及期刊五、课程安排五、课程安排一、有机合成的历史回顾一、有机合成的历史回顾1.尿素的合成尿素的合成（1828年，德国化学家年，德国化学家Wohler）有机化学的开始有机化学的开始2.颠茄酮的合成颠茄酮的合成1)1902年，德国化学家年，德国化学家Willstatter(1915年获年获Noble化学奖）化学奖）21steps,overallyield0.7%2）1917年，英国化学家年，英国化学家Robinson(1947年获年获Noble化学奖）化学奖）3steps,overallyield90%Robinson为什么能是发现这条合成路线？为什么能是发现这条合成路线？MannichReaction(1912)3.维生素维生素B12的合成的合成（Woodward,1977年）年）在在Woodward及及Eschenmoser领导下领导下,经过两个经过两个实验室，实验室，100多位科学家的共同努力，于多位科学家的共同努力，于1977年完成年完成了维生素了维生素B12的全合成工作。的全合成工作。将有机合成作为一种艺术展现在世人面前。将有机合成作为一种艺术展现在世人面前。因在因在1945-1954年人工合成了奎宁、类固醇、年人工合成了奎宁、类固醇、马钱子碱、羊毛甾醇、麦角碱等近马钱子碱、羊毛甾醇、麦角碱等近20种复杂天然种复杂天然产物而产物而1965年获年获Noble化学奖化学奖4.E.J.Corey,(1990年获年获Noble化学奖化学奖)如果说 W oodward 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 C orey 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 20世 纪 70年代以来整个有机合成领域的蓬勃发展。逆合成分析逆合成分析(Retrosyntheticanalysis)Woodward(1981)红霉素的全合成Y.Kishi(1987)海葵毒素的全合成S.L.Schreiberet al(1993)FK-1012的全合成K.C.Nicolaou&S.L.Schreiber（1994）紫杉醇（Taxol)的全合成5.K.C.Nicolaou&S.L.SchreiberK.C.Nicolaou,et al.Theartandscienceoftotalsynthesisatthedawnoftwenty-firstcentury,Angew. Chem. Int. Ed. Engl.,2002,39,44S.L.Schreiber,et al.Target-orientedanddiversity-orientedorganicsynthesisindrugdiscovery,Science,2000,287,1964高立体选择性高立体选择性（HighStereoselectivity)原子经济性反应原子经济性反应（AtomEconomicalReaction)绿色化学绿色化学（GreenChemistry)二、有机合成化学的发展趋势二、有机合成化学的发展趋势1.新试剂、新反应、新方法的发现永无止境新试剂、新反应、新方法的发现永无止境Epibatidine的研究的研究Y(OTf)3-catalyzednovelMannichreactionofN-alkoxy-carbonylpyrroles,formaldehydeandprimaryaminehydrochloridesC.X.Zhuan,J.C.Dong,T.M.Cheng,R.T.Li*,Tetrahedron Letters,2001,43(3),461-463Aldol缩合反应的研究缩合反应的研究2.与生命科学和材料科学的联系越来越紧密与生命科学和材料科学的联系越来越紧密三、学习内容和方法三、学习内容和方法 内容内容1.对重要的基础有机反应要能够熟练运用对重要的基础有机反应要能够熟练运用新新化合物的合成化合物的合成比葫芦画瓢比葫芦画瓢逆合成分析逆合成分析2.跟踪文献，尽可能将最新的试剂、反应和方法应用于跟踪文献，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。自己的研究工作中。3.学习别人的思路，创造性地借鉴和运用学习别人的思路，创造性地借鉴和运用 方法方法四、重要参考书及期刊四、重要参考书及期刊参考书参考书1.F.A.Carey著，王积涛译，高等有机化学，B.反应与合成，高等教育出版社，1986。2.岳保珍，李润涛，有机合成基础，北京医科大学出版社，2000。3.吴毓林，姚祝军，现代有机合成化学，科学出版社，2001。4.W.Carruthers著，李润涛等译，有机合成的一些新方法，河南大学出版社，1991。5.黄宪，王彦广，陈振初，新编有机合成化学，化学工业出版社，2003。6.王咏梅等，高等有机化学习题解答，南开大学出版社，2002。7.DaleL.Boger,ModernOrganicSynthesis,TheScrippsResearchInstitute,TsriPress,1999.8.ComprehensiveOrganicSynthesis,Vol.1-9期刊期刊1.Angew.Chem.Int.Ed.2.J.Am.Chem.Soc.3.J.Org.Chem.4.Org.Letters5.Chem.Commun.6.Tetrahedron7.TetrahedronLetters.8.TetrahedronAsymm.9.Synthesis10.Synlett11.Synth.Commun.12.Eur.J.Chem.13.Eur.J.Org.Chem.14.Heterocyclics15.J.HeterocyclicChem.16.J.Med.Chem.17.Bioorg.Med.Chem.18.Bioorg.Med.Chem.Lett.19.Eur.J.Med.Chem.20.J.Comb.Chem.五、课程安排五、课程安排1.进度安排进度安排2.3.2.讲授原则讲授原则4.复习老反应，补充新反应，复习老反应，补充新反应，5.重点讲进展，强调学思路。重点讲进展，强调学思路。3.考试考试4.1）写综述一篇写综述一篇（近（近5年的进展）（年的进展）（40%）5.2）笔试（笔试（60%）Chapter2FormationofCarbon-CarbonSingleBonds一、一、GeneralPrinciples烷化反应：烷化反应：E=烷化剂烷化剂缩合反应：缩合反应：E=醛、酮、酯等醛、酮、酯等Michael加成：加成：E=Mannich反应反应二、二、影响反应的主要因素影响反应的主要因素a.反应底物反应底物（Substrate)-NO2-CORSO2R-CN-CO2R-Ph,SORA和和B至少要有一个是至少要有一个是EWGA和和B应该能使其应该能使其 -碳上的碳上的H活化的基团，通常为吸电子活化的基团，通常为吸电子基（基（ElectronwithdrawgroupEWG）。）。b.碱碱（Base）常用的碱：常用的碱：Ph3C-(Me2CH)2N-EtO-OH-R3N碱的选择取决于底物的反应活性理想的碱：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.溶剂溶剂（Solvent)SolventO-alkylationC-alkylation反应速度反应速度常用的非质子极性溶剂（polaraproticsolvent):DMFDMSOHMPAd.亲电试剂亲电试剂（Electrophilicreagent)所有能与负碳离子发生反应的碳正离子或分子。所有能与负碳离子发生反应的碳正离子或分子。例：例：RX,R-SO3H,RCO2Et,RCOR这四种影响因素之间是相互联系，相互影响的。在分析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。一个具体反应时，应该综合分析考虑这四种影响因素。三、烷基化反应三、烷基化反应(Alkylation)1.O-alkylation&C-alkylationExample1Example2Degree of substitution of alkylating agent:Example32.区域选择性区域选择性（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很大. .热力学控制条件下主要生成取代基较多的烯醇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动力学控制条件下主要生成取代基较少的烯醇; ;Example1Example23.立体选择性立体选择性（Steroselectivity)烯醇化合物的立体选择性形成烯醇化合物的立体选择性形成,将为不对将为不对称合成提供平台称合成提供平台.Example1Example2Example3Example44.二羰基化合物的二羰基化合物的 -烷基化反应烷基化反应( -Alkylationof1,3-dicarbonylcompounds)J. Am. Chem. Soc.,1974,90,1082;1963,85,3237;1965,87,82.Example1Example2Example3继承与发展继承与发展5.芳基卤化物与烯醇盐的反应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。关键是要有形成苯炔的条件。6.酮和酯的烷基化反应酮和酯的烷基化反应(Alkylationsofketonesandesters)避免避免Aldol缩合反应发生的方法：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。烷化剂要待酮完全转化为烯醇式后再加入。常用的碱：常用的碱：NaNH2,KNH2,NaH,Ph3CNa等；有副产物。等；有副产物。LDA,LTMP,LHMDS等效果很好。等效果很好。Example1Example2不对称酮的选择性烷基化反应不对称酮的选择性烷基化反应(Selectivealkylationofasymmetricketones)在一个在一个-位引入一个活化基位引入一个活化基(略）略）如：如：DieckmannReaction;Claisencondensation制成结构专属性的烯醇负离子制成结构专属性的烯醇负离子在取代基较多的在取代基较多的 -位烷基化位烷基化(烯醇硅醚法烯醇硅醚法)碱性条件碱性条件酸性条件酸性条件在取代基较少的在取代基较少的 -位烷基化位烷基化(烯胺法烯胺法,StorkEnamineSynthesis)u通常，用活泼的卤代烷，可以高产率生成通常，用活泼的卤代烷，可以高产率生成C-烷基化产物；烷基化产物；但对于一般的卤代烃，但对于一般的卤代烃，C-烷基化产物收率较底。若用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。烷基化产物。u对于不对称酮，主要在取代基较少的对于不对称酮，主要在取代基较少的 -位发生烷基化。位发生烷基化。Example1Example27.对映选择性烷基化反应（对映选择性烷基化反应（Enantioselectivealkylations)u利用手性胺利用手性胺u利用二甲基肼利用二甲基肼扩展：扩展：二甲基腙锂化合物的另一应用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，而有机铜化合物在合物在C-C键的形成中很有用。键的形成中很有用。u利用利用SAMP和和RAMP若用RAMP，则得到另一种对映异构体。u羧酸的羧酸的 -不对称烷基化不对称烷基化Example8.极性翻转（极性翻转（Umpolung)俞俞凌凌翀，刘志昌，极性转换及其在有机合成中的应翀，刘志昌，极性转换及其在有机合成中的应用，科学出用，科学出版社，版社，1991Example1安息香缩合安息香缩合Example2醛氰醇法醛氰醇法Example31,3二噻烷法二噻烷法不易发生不易发生Michael加成反应。加成反应。Example4乙基乙硫甲基亚砜法乙基乙硫甲基亚砜法1,4二酮二酮四、缩合反应四、缩合反应(Condensation)1.AldolReaction2.MichaelAddition3.MannichReaction4.ClaisenCondensation5.DieckmannCondrnsation6.DarzensReaction7.Reformatslyreaction1.AldolReaction(condensation)1)经典经典Aldol反应的两大缺点反应的两大缺点不同醛、酮之间的反应常得到混合产物；不同醛、酮之间的反应常得到混合产物；立体选择性差立体选择性差2)定向醇醛缩合反应定向醇醛缩合反应（DirectedAldolcondensation)Metood1PreformedLithiumEnolatesZ-enolatesgivepredominantlysyn(orthreo)aldolproducts(thermodynamicenolates).E-enolatesgivepredominantlyanti(orerythro)aldolproducts(kineticenolates).Example1-StericsizeofR1affectsdiastereoselectivityOriginofDiastereoselectivitya.Z-enolatesDiastereoselectivityforZ-enolate(givingsynaldolproduct)ismaximizedwhenR1andR3arestericallydemanding(R1/R3interactionismaximized).Diastereoselectivityalsoincreasesasmetalischangedtoboron.ThisisattritubtedtoatighterT.S.(BObondshorter,soR1/R3stericinteractionsaremagnifiedinT.S.forantiproduct). WhenR2isverylargetheR3/R2gaucheinteractionR1/R31,3-diaxialinteraction(Why?).b.E-enolatesDiastereoselectivityincreasesasR1andR3becomestericallylarge,andaswitchtotheboronenolatewillincreaseselectivity.DiastereoselectivitymayswitchwhenR2isverylarge(Why?).uEffectofR1uEffectofR3uEffectofR2Metood2PreformedBoronEnolatesa.Z-enolatePreparationandReactionsb.E-enolatePreparationandReactions-Originallydifficulttocontrolbut:c.ExamplesofmorerecentmethodstocontrolboronenolategeometryAldolCondensationwithChiralEnolatesTienolatepromotedEvansaldol(non-Evanssynaldol)Chelatedandnon-chelatedTienolatesMetood3Acid-CatalysedDirectedAldolReactions该方法是该方法是在酸性条件在酸性条件下反应；但下反应；但立体选择性立体选择性较差。较差。3)有机小分子催化醇醛缩合反应有机小分子催化醇醛缩合反应（SmallOrganicMoleculesCatalystedAldolReactions)NovelSmallOrganicMoleculesforaHighlyEnantioselectiveDirectAldolReactionJ.AM.CHEM.SOC.2003,125,5262-5263ZhuoTang,FanJiang,Luo-TingYu,XinCui,Liu-ZhuGong,*,Ai-QiaoMi,Yao-ZhongJiang,andYun-DongWu*Key Laboratory for Asymmetric Synthesis and Chirotechnology of Sichuan Province, Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu, 610041, China, College of Chemical Engineering,Sichuan UniVersity, Chengdu, 610065, China, and State Key Laboratory of Molecular Dynamics and Stable Structures, College of Chemistry and Molecular Engineering, Peking UniVersity, Beijing, 100871, China2.MichaelAdditionReactionApplications:Synthesisof1,5-dicarbonylcompoundsGeneralSchemeDevelopment:AsymmetryMichaelAdditionReaction手性金属配位化合物催化手性金属配位化合物催化MacmillanGroupsWorkSmallOrganicMoleculecatalyzedasymmetricMichaelreactionsTheFirstEnantioselectiveOrganocatalyticMukaiyama-MichaelReaction:S.P. Brown,N.C.Goodwin,andD.W. C.MacMillan*,J. Am. Chem. Soc.2003,125(5),1192-11943.MannichReactionGeneralScheme 胺组份胺组份 氨、伯胺、仲胺氨、伯胺、仲胺 醛组份醛组份 HCHO, HCHO, PhCHOPhCHO, RCHO , RCHO 可分别发生三、双、单可分别发生三、双、单 Mannich 反应反应 活泼活泼 H 组份组份醛、醛、 酮、酮、 活泼亚甲基化合物、酚类化合物、杂环、炔等。活泼亚甲基化合物、酚类化合物、杂环、炔等。Example2Example1Development:AsymmetryMannichReaction Lewis acid-catalyzed asymmetric Mannich reactions(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. (a)Notz,W.;Sakthivel,K.;Bui,T.;Zhong,G.;Barbas,C.F.,IIITetrahedron Lett.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.Tetrahedron 1999,55,8857;(d)List,B.J.Am.Chem.Soc.2000,122,9336;(e)Cordova,A.;Notz,W.;Zhong,G.;Betancort,J.M.;Barbas,C.F.,IIIJ.Am.Chem.Soc.2002,124,1842;(f)Cordova,A.;Watanabe,S.-i.;Tanaka,F.;Notz,W.;Barbas,C.F.,IIIJ.Am.Chem.Soc.2002,124,1866.SmallOrganicMoleculecatalyzedasymmetricMannichreactionsTheDirectandEnantioselective,One-Pot,Three-Component,Cross-MannichReactionofAldehydesAngew.Chem.Int.Ed.2003,42,36773680Y.Hayashi,W.Tsuboi,I.Ashimine,T.Urushima,Dr.M.ShojiDepartmentofIndustrialChemistry,FacultyofEngineeringTokyoUniversityofScience,KagurazakaThree-componentMannichreactionwithvariousacceptoraldehydesN-methyl-2-pyrrolidinone(NMP)Three-componentMannichreactionwithvariousdonoraldehydes.4.ClaisenCondensationGeneralSchemeMechanism 一种酯的自身缩合一种酯的自身缩合Scopeofapplication 一种含一种含 -H的酯与一种不含的酯与一种不含 -H的酯之间的缩合的酯之间的缩合ExamplesDirectedClaisencondensation5.DickmannCondensationChapter3FormationofCarbon-CarbonDouleBonds1. -Eleminationreactions（ -消去反应消去反应）I.TheSyntheticMethodsofAlklenes2.Pyrolyticsyneliminations（顺式热消去反应顺式热消去反应）Applications:SynthesisofterminalalkenesfromprimaryacetatesDisadvantages:HighreactiontemperatureCopereactionChugavereaction反应条件比对应的酯热消去温和。反应条件比对应的酯热消去温和。3.Wittigandrelatedreactions（Wittig及及有关反应）有关反应）WittigReactionG.Wittigreceivedthe1979NobelPrizeinChemistryformanysignificantcontributionstoOrganicChemistrywhichincludednotonlytheWittigreaction,butalsoPhLipreparedbymetal-halogenexchange,benzyne,andtheWittigrearrangement.GeneralSchemeMildreactionconditions;Thepositionofthedoublebondisunambiguous.FeaturesRepresentativeExamplesExample1Example2Example3Example4Mechanism2+2cycloaddition.InfluenceofsolventontheselectivityActivityandstereoselectivityofYild Schlsser modification: allows the preparation of trans vs. cis olefins.Schlsser Angew. Chem., Int. Ed. Eng. 1966, 5, 126.StabilizedYlides-Stabilizedylidesaresolid;stabletostorage,notparticularlysensitivetomoisture,andcanevenbepurifiedbychromatography.-Becausetheyarestabilized,theyaremuchlessreactivethanalkylylides.Theyreactwellwithaldehydes,butonlyslowlywithketones.-Thefirststep,involvingtheadditiontothealdehyde,isslowandreversiblewithstabilizedylides.InfluenceofsolventontheselectivityWadsworthHornerEmmonsReactionHornerChem.Ber.1958,91,61;1959,92,2499.Wadsworth,EmmonsJ.Am.Chem.Soc.1961,83,1733.Reviews:Org.React.1977,25,73253.ComprehensiveOrg.Syn.,Vol.1,761.PreparationofPhosphonateEstersArbuzovJ.Russ.Phys.Chem.Soc.1906,38,687.-ArbuzovRearragement-Thesameapproachtothepreparationof-ketophosphonatesisnotsuccessful:-ButcanusevariationonClaisenconditions:ModificationsandScope-LiCl/tertiaryamines(DBU,iPr2NEt,Et3N)Masamune,RoushTetrahedronLett.1984,25,2183. Can substitute for conventional conditions and is especially good for base sensitive substrates.-HinderedphosphonatesandhinderedaldehydesincreaseE-selectivity(trans).-StillGennarimodificationselectiveforZ-alkenes(cis):-AdditionalZ-selectivestabilizedphosphonates.SelecteddiarylphosphonatesprovideHighZ-selectivityaswell. Peterson ReactionReviews:Org.React.1990,38,1.PetersonreactionoffersanalternativetoWittigprocedure.TheyaremorereactiveandstericallylessdemandingthanaWittigreagentandthevolatilebyproduct(Me3SiOH/Me3SiOSiMe3)issimplertoremovethanPh3PO.Itdoes,however,requireasecondsteptopromoteeliminationofthe -hydroxysilane.-Theeliminationisstereospecific:acid-promotedbeingantiandbase-promotedbeingsyn.Hudrlik,PetersonJ.Am.Chem.Soc.1975,97,1464.StabilizedPetersonReagents-ThestabilizedPetersonreagentsgivepredominantlythemoststabletransolefins(E)-Additionalexamples:4. The Tebbe Reaction and Related Titanium-stabilized Methylenations (Tebbe反应及与有关稳定化钛试剂的亚甲基化反应）反应及与有关稳定化钛试剂的亚甲基化反应）-Toleratesketalandalkenederivatives.ScopedefinedbyEvansandGrubbsJ.Am.Chem.Soc.1980,102,3270.ExtendedtotertiaryamidesbyPineJ.Org.Chem.1985,50,1212.ForananalogoususeofCp2TiMe2:PetasisJ.Am.Chem.Soc.1990,112,6392.5. Sulphoxide-sulphenate rearragement: Synthesis of allyl alcohols(亚砜亚砜-次磺酸酯重排：烯丙醇类化合物的合成次磺酸酯重排：烯丙醇类化合物的合成)Combinedwithalkylationofsulphoxidesthereactionprovidesaversatilesynthesisofdi-andtri-substitutedallylicalcoholsEvansandAndrews,Acc.Chem.Res.,1974,7,147 -alkylationofallylicalcohlosExample1Example26. Alkenes from sulphones(由砜制备烯烃）由砜制备烯烃）-JuliaOlefinationReview:ComprehensiveOrg.Syn.,Vol.1,792.-Example:JuliaTetrahedronLett.1973,4833.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:-RambergBacklundreactionOrg.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.,1995,117,1437.7.Decarboxylationof -lactones( -内酯的脱羧反应）内酯的脱羧反应）ReformatskyReactionNote:NostilbenewasformedSynthesisoftri-ortetrasubsitutedalkenesExample1FehrC.etal.TetrahedronLett.,1992,33,2465MolbierW.R.etal.J.Org.Chem.,1995,60,5378Example2Example3MulzerJ.,etal.,J.Chem.Soc.Chem.Commun.,1979,528.Stereoselectivesynthesisoftri-andtetra-substitutedalkenes(三、四取代烯烃的立体选择性合成）三、四取代烯烃的立体选择性合成）Thefirststepishighlystereoselective.TheR4andthelargerofthegroupsR1andR2areantitoeachother.EarlyMethodCornforth,J.W.etal.,J.Chem.Soc.,1959,112DevelopmentMethod1Corey,E.J.etal.,J.Am.Chem.Soc.,1967,89,4246.Example(54%;97%E)Method2Example:R=Et,Yield72%Zweifel,G.etal.,J.Am.Chem.Soc.,1967,89,2754.Zweifel,G.etal.,J.Am.Chem.Soc.,1967,89,5085.9.Oxidativedecarboxylationofcarboxylicacids(羧酸的氧化脱羧反应）羧酸的氧化脱羧反应）Sheldon,R.A.,etal.,OrganicReactions,1972,19,279.Jahngen,B.G.E.,J.Org.Chem.,1974,39,1650.与与Dieal-Alder反应结合，反应结合，是制备环状烯烃是制备环状烯烃的好方法。的好方法。Example1TanzawaT.etal.TetrahedronLett.,1992,33,6783Example2Example310.Alkenesfromarylsulphonylhydrazones(由芳基磺酰腙制备烯烃）由芳基磺酰腙制备烯烃）KolonkoK.,et al.J.Org.Chem.,1978,43,1404;AdlingtonR.M.,et al.Acc.Chem.Res.,1983,16,55MechanismLesssubstitutedalkeneExample1Example211.FragmentationReactions(裂解反应）裂解反应）X=leavinggroup,e.g.:-OSO2C6H4CH3-p,-OSO2CH3100% stereospecificExample12.OlefinInversionReactions(烯烃构型转换反应）烯烃构型转换反应）Deoxygenationofepoxides(withretentionofgeometry)Otherexamples13.Srereospecificsynthesisofalkenesfrom1,2-diols(由由1,2-二醇立体选择性地合成二醇立体选择性地合成烯烃）烯烃）CoreyWinterOlefinSynthesisCoreyJ.Am.Chem.Soc.1963,85,2677.CoreyJ.Am.Chem.Soc.1965,87,934.EastwoodAust.J.Chem.1964,17,1392.EastwoodTetrahedronLett.1970,5223.Burgstahler,BogerTetrahedron1976,32,309.14. 3,3-Sigmatropic RearrangementsClaisenandCopeRearrangementExamplesEvansJ.Am.Chem.Soc.1975,97,4765.BurgstahlerJ.Am.Chem.Soc.1961,83,198.CarnduffJ.Chem.Soc.,Chem.Commun.1967,606.Thio-ClaisenRearrangement-Anadvantageofthethio-Claisenrearrangementisthattheprecursorcanbedeprotonatedandalkylated.CoreyJ.Am.Chem.Soc.1970,92,5522.YamamotoJ.Am.Chem.Soc.1973,95,2693and4446.BlockJ.Am.Chem.Soc.1985,107,6731.TheCarrollReactionCarrollJ.Chem.Soc.1940,704,1266.HartungJ.Chem.Soc.1941,507.CopeJ.Am.Chem.Soc.1943,65,1992.TanabeJ.Am.Chem.Soc.1980,102,862.15. 2,3-Sigmatropic RearrangementsReview:ComprehensiveOrg.Syn.,Vol.6,pp834,873908.Org.React.1994,46,105209.-Analogousto3,3-sigmatropicrearrangementexceptitenlistsalocalizedcharge(anion)inplaceofadoublebond.ExamplesJuliaTetrahedronLett.1974,2077.LythgoeJ.Chem.Soc.,Chem.Commun.1972,757.EvansTetrahedronLett.1973,4691.Amino-ClaisenRearrangement-Thisreactionoccursbestwhennitrogenisconvertedtotheammoniumsalt.GilbertTetrahedronLett.1984,25,2303.StilleJ.Org.Chem.1991,56,5578.NakaiChem.Lett.1990,2069.SatoJ.Am.Chem.Soc.1990,112,1999.II.OlefinSynthesisExemplifiedwithJuvenileHormone(保幼激素的合成）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.StotterKondoSynthesis:J.Am.Chem.Soc.1973,95,4444.J.Chem.Soc.,Chem.Commun.1972,1311.8.StillSynthesis:TetrahedronLett.1979,593.9.OtherSyntheses:(1).TrostSynthesisWadsworthHornerEmmonsReactionStereoselectivity-notmuchdifferencebetweenMeandH(secondatomstericeffect)-bothisomersobtainedfromtheWadsworthHornerEmmonsreaction(Modernimprovementsnowavailable)Retrosynthetic Analysis-repeatingsubunitsrecognized-repeatingreactionsutilizedJ.Am.Chem.Soc.1967,89,5292.(2).SyntexSynthesisJ.Am.Chem.Soc.1968,90,6224.RobinsonAnnulationAlkylationDiastereoselectivityDirectedEpoxidationReactionFragmentationReactionSelectiveReduction-saturatedvs.a,b-unsaturatedcarbonyl-ringstrainassociatedwith5-memberedringcarbonylreleasedonreduction-attackfromleasthinderedfaceTHPProtectingGroup-ifRgroupcontainschiralcenters,diastereomersresult-removedbymildacidThermodynamicEnolate-severe1,3-diaxialinteractioninchair-likeT.S.axialalkylation-nostericincumberancetoaxialalkylationonleasthinderedfaceoftwistboatT.S.LiAlH(OtBu)3Reduction-largereagent,usuallyequatorialHdelivery-1,2-interaction(torsionalstrain)relativelyinvarianttoNusize-1,3-stericinteractionhighlydependentonNusize-duetoabsenceofaxialC(3)H,largereagentnowgivesaxialdeliveryEpoxidation-inEt2O,coordinationofperacidtosolventgivesdeliveryfromtheleasthindereda-face-inCH2Cl2,H-bondingofOHtoperacidprovidesdeliverytothelessaccessibleb-face-TeranishiJ.Am.Chem.Soc.1979,101,159.FragmentationReaction-utilizedtocontrolC=Cbondstereochemistry-transperiplanarorientationofbreakingbonds-dictatesZolefingeometryinproduct3.CoreySynthesisDissolvingMetalReductionsCyclicPrecursorstoTrisubstitutedOlefinsOxidativeCleavageofEnolEthersLiAlH4ReductionofPropargylAlcoholsCuprateCouplingReactionsAllylicAlcoholOxidationJ.Am.Chem.Soc.1968,90,5618.StereospecificSynthesisofTrisubstitutedOlefinsMnO2Oxidation-mildoxidationofallylicalcohols-direct,mildmethodforoxidationtoamethylesterEpoxidation-selective-inpolarsolventthemoleculefoldsupsuchthattheterminalC=Cismoreaccessible4.JohnsonSynthesis:TrimethylpyridineJ.Am.Chem.Soc.1968,90,6225.5.CoreySynthesis:J.Am.Chem.Soc.1970,92,6635,6636.1,5-HShiftDiimideReduction-lesssubstitutedC=Creducedmorerapidly-generatedin-situ6.JohnsonSynthesis:J.Am.Chem.Soc.1970,92,4463.OlefinicKetalClaisenReaction-selectivitydependenton1,3-interactioninchair-likeT.S.-secondClaisenmoreselectiveduetolargerRgroupvs.CO2Me7.StotterKondoSynthesis:J.Am.Chem.Soc.1973,95,4444.J.Chem.Soc.,Chem.Commun.1972,1311.8.StillSynthesis:TetrahedronLett.1979,593.2,3-SigmatropicRearrangementChapter4ConversionofFunctionalGroups1.AdditionofCarbon-CarbonDoubleBonds2.HalogenationofAlcoholsGeneralMethodsOrg. Lett., 2002,4(4),553-555TCT/DMFMethodDevelopment2,4,6-trichloro1,3,5triazineTCTTable1.ConversionofAliphaticAlcoholsintotheCorrespondingAlkylHalidesa Forcompleteconversionofthealcohol.b Thecorrespondingchlorideisformedalso.Table2.ConversionofDiolsandUnsaturatedand -aminoAlcoholsintotheCorrespondingAlkylHalidesa Forcompleteconversionofthealcohol.b Thecorrespondingchlorideisformedalso.MechanismMe3SiCl该方法对苄醇、伯醇、烯丙醇、该方法对苄醇、伯醇、烯丙醇、叔醇，室温下反应迅速，收率高。叔醇，室温下反应迅速，收率高。J.Org.Chem.1995,60,26383.FormationofAminesGeneralMethods与氮烯有关的重排反应与氮烯有关的重排反应 SynthesisprimaryamineGabrielSynthesisHarshhydrolysisconditionsImprovementSynthesis,1990,8,735;1995,7,756Synlett,1996,2,179;Synth.Commun.,1999,29,2685SynthesisofArylaminesfromaminationofArylHalidesDevelopmentEarlyPalladium-CatalyzedAmination该该反应仅限于仲胺与电中性的卤代苯。反应仅限于仲胺与电中性的卤代苯。要求等当量的有机钯催化剂。要求等当量的有机钯催化剂。J. Am. Chem. Soc.,1994,116,5969-5970P.Patt,Hartiget. al. 发现发现Pd可循环使用可循环使用从从1985到到1994近近10年没有关于年没有关于Pd催化胺化反应的报道。催化胺化反应的报道。存在的问题：存在的问题：1）要将胺变成锡胺化物；）要将胺变成锡胺化物；2）不适应于伯胺；）不适应于伯胺；3）反应速度较慢；）反应速度较慢；4）催化剂用量较大。）催化剂用量较大。InitialTin-freeAminationofArXHartwigandBuchwald,Angew. Chem. Int. Edu.,1995,34,1348-1350;Tetrahedron Lett.1995,36,3609RoomTemperatureCatalyticAminationofArylIodidesJ. Org. Chem. 1997,62, 6066-6068JohnP.WolfeandStephenL.Buchwald*Department of Chemistry, Massachusetts Institute ofTechnology, Cambridge, Massachusetts 02139Table2.RoomTemperatureCatalyticAminationofArylIodidesTable2.ContinuedAHighlyActiveCatalystforPalladium-CatalyzedCross-CouplingReactions:Room-TemperatureSuzukiCouplingsandAminationofUnactivatedArylChloridesDavidW.Old,JohnP.Wolfe,andStephenL.Buchwald*J. Am. Chem. Soc. 1998,120, 9722-9723AminationReactionsofArylHalideswithNitrogen-ContainingReagentsMediatedbyPalladium/ImidazoliumSaltSystemsGabrielaA.Grasa,MihaiS.Viciu,JinkunHuang,andStevenP.Nolan*Department of Chemistry, University of New Orleans, New Orleans, Louisiana 70148J. Org. Chem. 2001,66, 7729-7737ImesHClImes:1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylideneIpr:1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene)ImidazoliumChlorideLigandsTable2.AminationofArylChlorideswithVariousAminesTable2ContinuedTable3.AminationInvolvingArylBromidesandIdodideswithVariousAminesMostinterestinginthesestudiesinvolvinganarylbearingbothchloroandiodo(orbromo)substituentsistheobservationthatbromoandiodofunctionalitiescanbeconvertedatroomtemperature(entries3and4)andtheremainingchlorofunctionalitycansubsequentlybeconvertedatmoreelevatedtemperatures.Thiscouldprovetobeasignificantadvantageinprocesschemistry.Table4.InfluenceofPalladium(0)/ImidazoliumSaltRatioonAminationReactionsTable5.AminationofChlopyridinesandBromopyridineswithVariousAminesGeneralcatalyticcycleforaminationreaction.Table6.AminationofArylChlorideswithBenzophenoneImineTable7.AminationofArylBromideswithBenzophenoneImineTable9.EffectoftheImidazoliumChloridesandBasesonN-ArylSubstitutionofIndolewithBromobenzeneTable10.AminationofArylBromideswithVariousIndolesThestandardaminationconditionsdidnotaffectthearylationofindoles.Table10ContinuedSynthesisofLinezolidIntermediateLinezolidismemberofanewclassofantibiotics.AnImprovedMethodforthePalladium-CatalyzedAminationofArylIodidesMayssamH.AliandStephenL.Buchwald*Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139J. Org. Chem. 2001,66, 2560-2565Table2.AminationofArylIodideswithNaOt-BuasBaseTable2.ContinuedTable3.AminationofArylIodideswithCs2CO3asBaseCs2CO3Pd-CatalyzedIntermolecularAmidationofArylHalides:TheDiscoverythatXantphosCanBeTrans-ChelatinginaPalladiumComplexJingjunYinandStephenL.Buchwald*Contribution from the Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139J.AM.CHEM.SOC.2002,124,6043-6048CuI,K3PO4Table1.Cu-CatalyzedAminationofArylBromidesTable1.ContinuedTable2.Copper-CatalyzedAminationofortho-SubstitutedAndHeteroarylBromidesTable3.IntramolecularCopper-CatalyzedAminationofArylHalidesTable4.Solvent-FreeCu-CatalyzedAminationofArylBromidesSolvent-freeAminoacid-mediatedGoldbergreactionsbetweenamidesandaryliodidesWeiDeng,Ye-FengWang,YanZou,LeiLiu*,andQing-XiangGuo*DepartmentofChemistry,UniversityofScienceandTechnologyofChina,Hefei230026,ChinaTetrahedronLetters45(2004)23112315Table1.YieldsofthecouplingreactionbetweencaprolactamandiodobenzeneunderdifferentconditionsaIsolatedyield.b5mol%.c20mol%.Table3.YieldsoftheCuI-catalyzedcouplingreactionsbetweeniodobenzeneandvariousamides(baseK3PO4,solventdioxane,temperature100oC,reactiontime24h)Table4.YieldsoftheCuI-catalyzedcouplingreactionsbetweenvariousarylhalidesandamides(ligandglycine,baseK3PO4,solventdioxane,temperature100oC,reactiontime24h)MechanismPalladium-CatalyzedAminationofArylBromidesUsingTemperature-ControlledMicrowaveHeatingYiqiangWan,MathiasAlterman,AndersHallbergSynthesis,2002,11,1597-1600MatsLarhedandAndersHallbergDDT, 6 (8), 406 - 416, 2001Microwave-assistedHigh-speedchemistry:ANewTechniqueinDrugDiscoveryFigure2.Examplesofpalladium(Pd)-catalyzedHeckarylationsdemonstratingretainedregioselectivitiesunderMicrowaveinducedflash-heatingconditions.Microwave-assistedintramolecularandtwo-componentreactionsFigure4.Examplesoffastmicrowave-assistedorganicreactionsonpolymericsupports.Microwave-assistedmulti-componentreactionsThedrugdiscoveryprocessandtheforeseenimpactofmicrowavechemistryonautomatedmedicinal/combinatorialchemistryChapter5ApplicationofOrganometallicReagentsinOrganicSynthesisSc,Y,La(镧系）镧系）17种种(s,p,d.f1-14)5.1基本原理基本原理5.1.1 5.1.1 非过渡金属试剂的特性非过渡金属试剂的特性 电负性电负性 反应活性反应活性主族主族Li-RNa-RK-RRb-RAg-RAu-R;Zn-RCd-RHg-R主副族主副族比较比较Li-RCu-R;Be-RZn-R;Mg-RZn-R同一周期同一周期Li-RBe-RB-R;Na-RMg-RAl-R; 反应性反应性 特性总结特性总结a.含有含有C-M键键b.C-M键中键中C为电负性的为电负性的c.C-M键中键中的的C原子常被亲核试剂进攻原子常被亲核试剂进攻 金属有机试剂中常见的金属部分金属有机试剂中常见的金属部分Na,K,Li,Mg,Zn,Cu,Fe,Pd,Ni,Ti5.1.2 5.1.2 金属试剂的制备通法金属试剂的制备通法1) 1) 卤代烃与金属反应卤代烃与金属反应2）有机金属化合物与卤代烃的交换）有机金属化合物与卤代烃的交换3）有机金属化合物与金属盐的交换）有机金属化合物与金属盐的交换4)烃的金属化烃的金属化5.1.3 5.1.3 结构与反应性结构与反应性5.2有机镁试剂（有机镁试剂（Grignardreagents）通常表示为：通常表示为：RMgX，以乙醚溶液使用以乙醚溶液使用实际存在方式：实际存在方式：5.2.1 5.2.1 制备制备 通常用乙醚作溶剂，但制备芳基和烯基类通常用乙醚作溶剂，但制备芳基和烯基类G-试剂试剂 时，要用时，要用THF作溶剂，以便提高温度，使反应进行完作溶剂，以便提高温度，使反应进行完全。全。5.2.2 5.2.2 特殊的反应性特殊的反应性5.2.3 5.2.3 在合成上的应用在合成上的应用 烷烃的制备烷烃的制备碳链碳链非异构非异构化产物化产物 醇的制备醇的制备选择性差选择性差 醛的制备醛的制备增加一个碳原子增加一个碳原子 酮的制备酮的制备a.b.c.5.3有机锂试剂（有机锂试剂（Organolithiumreagents）活性：活性：RNaRLiRMgX 5.3.1 5.3.1 制备制备-configurationallystable-retentionofconfiguration5.3.2反应反应能克服位阻的影响能克服位阻的影响与与 , -不饱和酮主要发生不饱和酮主要发生1,2-加成加成 与羧酸、与羧酸、CO2反应生成酮反应生成酮5.4 5.4 有机锌试剂（有机锌试剂（Organozinereagents） Reformatsky反应及扩展反应及扩展“一锅煮一锅煮”制备制备 , -不饱和羰基化合物，不饱和羰基化合物，Zn催化催化将将三步的三步的Wittig反应压缩为反应压缩为“一锅一锅”法完成。法完成。沈延昌沈延昌, , 金属有机化合物的化学反应，金属有机化合物的化学反应，化学工业出版社，化学工业出版社，2000.7. P 60-782000.7. P 60-78 Lombardos试剂试剂（Zn+CH2Cl2+TiCl4）ADirectCatalyticAsymmetricMannich-typeReactiontosyn-AminoAlcoholsBarryM.Trost*andLamontR.TerrellDepartment of Chemistry, Stanford UniVersity, Stanford, California 94305-5080J.Am.Chem.Soc.2003,125,338-339Scheme1.GenerationofDinuclearZincCatalystsTable1.AdditionstoGlyoxalateIminesTable2.AdditionstoAldiminesMultipleComponentReactions:AnEfficientNickel-CatalyzedReformatsky-TypeReactionandItsApplicationintheParallelSynthesisof -AminoCarbonylLibrariesJamesC.Adrian,Jr.*,andMarcL.SnapperChemistry Department, Union College, Schenectady, New York 12308, and Department of Chemistry,Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467J. Org. Chem. 2003,68,2143-2150TABLE1.ComparisonofCatalyticActivity(a)Sibille,S.;dIncam,E.;Leport,L.;Massebiau,M.-C.;PerichonJ.Tetrahedron Lett. 1987,28,55-58.(b)Mcharek,S.;Sibille,S.;Nedelec,J.-Y.;PerichonJ.J. Organomet. Chem. 1991,401,211-215.(c)Conan,A.;Sibille,S.;PerichonJ.J. Org, Chem. 1991,56,2018-2024.TABLE2.EffectofCatalystLoadingSCHEME3.ProposedCatalyticCycleTABLE3.3CCNickel-CatalyzedReformatskyReactionAffordingCompoundswiththe -AminoCarbonylCoreStructureTable3.ContinuedSynthesis,2004,5,683-6915.5 5.5 有机镉试剂（有机镉试剂（Organocadmiumreagents）制备制备 反应活性远低于反应活性远低于RMgX和和RLi 反应反应5.6 5.6 有机铜化合物（有机铜化合物（Organocoppercompounds）RCuR2CuLi5.6.1制备制备5.6.2反应反应 与与 , -不不饱饱和和羰羰基基化化合合物物反反应应均为均为1,4-加成产物加成产物 与卤化物反应与卤化物反应 与环氧化物反应与环氧化物反应从位阻较小的一侧，取代基较少的碳原子上进攻。从位阻较小的一侧，取代基较少的碳原子上进攻。5.7 5.7 有机钯化合物有机钯化合物（Organopalladiumcompounds） 络合物络合物Wacker反应反应 3-烯丙络合物烯丙络合物制备制备反应反应 Pd络合物的氧化加成反应络合物的氧化加成反应（HeckReaction)HeckReaction(Review)1.Heck,R.F.;Nolley,J.P.,Jr.J. Am. Chem. Soc.1968,90,5518;2.Heck,R.F.Acc. Chem. Res.1979,12,146;3.R.F.Heck,Organic Reactions,1982,27,345;4.A.de.MeijereandF.E.Meyer,Angew. Chem. Int. Ed. Engl.,1994,33,2379;5.W.CabriandI.Candiani,Acc. Chem. Res.,1995,28,2;6.G.T.Grisp,Chem. Soc. Rev.,1998,27,4277.Amatore,C.;Jutand,A.Acc. Chem. Res.2000,33,341.OxidativeHeck-TypeReactionInvolvingCleavageofaCarbon-PhosphorusBondofArylphosphonicAcidsAtsushi Inoue, Hiroshi Shinokubo,* and Koichiro Oshima*Department of Material Chemistry, Graduate School of Engineering, Kyoto UniVersity, Kyoto 606-8501, JapanJ.AM.CHEM.SOC.2003,125,1484-1485Table2.OxidativeHeck-TypeReactionofArylphosphonicAcidsDirectCouplingofBenzenewithOlefinCatalyzedbyPd(OAc)2CombinedwithHeteropolyoxometalateunderDioxygenTakahiroYokota,MasayukiTani,SatoshiSakaguchi,andYasutakaIshiiDepartment of Applied Chemistry, Faculty of Engineering, Kansai UniVersity, Suita, Osaka 564-8680, JapanJ.AM.CHEM.SOC.2003,125,1476-1477 偶联反应偶联反应催化剂：催化剂：Pd(PPh3)4SuzukiReactionSuzukiReaction1.N.MiyauraandA.Suzuki.Chem. Rev.1995,95,24572.A.Suzuki,Puer Appl. Chem.,1994,66,213;3.N.MiyauraandA.Suzuki,Org.Syn.,Coll.Vol.VIII,1993,532;4.B.E.Huff,T.M.Koenigetal.,Org. Syn.,1996,75,53;5.F.E.Goodson,T.L.WallowandB.M.Novak,Org. Syn.1996,75,61;6.F.S.Ruel,M.P.BraunandC.R.Johnson,Org. Syn.,1996,75,697.Miyaura,N.Top. Curr. Chem. 2002,219,11-59.8.Suzuki,A.InMetal-Catalyzed Cross-Coupling Reactions;Diederich,F.,Stang,P.J.,Eds.;Wiley-VCH:NewYork,1998;Chapter2.9.J.Hassan,.M.Sevignon;C.Gozzi;E.Schulz;andM.LemaireChem.Rev.2002,102,1359-1469BoronicAcids:NewCouplingPartnersinRoom-TemperatureSuzukiReactionsofAlkylBromides.CrystallographicCharacterizationofanOxidative-AdditionAdductGeneratedunderRemarkablyMildConditionsJanH.Kirchhoff,MatthewR.Netherton,IvoryD.Hills,1andGregoryC.Fu*Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139J.Am.Chem.Soc.2002,124,13662-13663Table1.SuzukiCross-Couplingofn-OctBrwithPhB(OH)2(5%Pd(OAc)2,10%ligand,rt):EffectofAdditive,Solvent,andLigandTable2.Pd/P(t-Bu)2Me-CatalyzedSuzukiCross-CouplingsofAlkylBromideswithBoronicAcidsMechanismDi-2-pyridylmethylamine-BasedPalladiumComplexesasNewCatalystsforHeck,Suzuki,andSonogashiraReactionsinOrganicandAqueousSolventsTable1.HeckCouplingReactionsCatalyzedby4Table2.SuzukiCouplingReactionsCatalyzedbyComplex4bTable3.SonogashiraCouplingReactionsCatalyzedby4bThePalladium-CatalyzedAdditionofOrganoboronicAcidstoAlkynes*ChangHoOh,*HyungHoonJung,KiSeongKim,andNakjoongKimAngew. Chem. Int. Ed.2003,42,805-808Table1:Pd-catalyzedhydroalkylationofalkynes1withorganoboronicacids2SuzukiCross-CouplingsofUnactivatedSecondaryAlkylBromidesandIodidesJianrong (Steve) Zhou and Gregory C. Fu*Contribution from the Department of Chemistry,Massachusetts Institute of Technology,J.AM.CHEM.SOC.2004,126,1340-1341BPInthiscommunication,wereportthefirstmethodforachievingSuzukicross-couplingsofunactivatedsecondaryalkylhalidesTransition-Metal-FreeSuzuki-TypeCouplingReactionsNicholasE.Leadbeater*andMariaMarcoAngew. Chem. Int. Ed.2003,42,1407 CO插入反应插入反应5.8 5.8 有机镍化合物有机镍化合物 3-烯丙基镍络合物的制备烯丙基镍络合物的制备 3-烯丙基镍络合物偶联反应烯丙基镍络合物偶联反应RR收率收率4-羟基环己基羟基环己基CH388%C6H5CH398%1,5-cyclo-octadiene 镍络合物催化格氏试剂的反应镍络合物催化格氏试剂的反应E.Wenkert,et.al.,J. Chem. Soc., Chem. Commun.,617(1984)G.Consiglio,et.al.,J. Chem. Soc., Chem. Commun.,112(1983)5.9有机钛试剂有机钛试剂5.9.1 5.9.1 两类重要钛试剂两类重要钛试剂试剂试剂B(TebbesReagent)F.N.Tebbe,G.W.ParshallandG.S.Reddy,J. Amer. Chem. Soc.,100,3611(1978)Cp2Ti=CH25.9.2试剂试剂A的反应的反应与与格格氏氏试试剂剂相相比比的两个优点：的两个优点：1）当当与与醛醛、酮酮羰羰基基反反应应时时，酯酯基基、氰氰基基、环环氧氧基基、卤原子不受影响；卤原子不受影响；2）与与醛醛加加成成时时有有高立体选择性。高立体选择性。5.9.3 5.9.3 试剂试剂B(Tebbes试剂试剂)的反应的反应Tebbe试剂与试剂与Wittig试剂相比的优点：试剂相比的优点：1）对位阻较大的羰）对位阻较大的羰基仍能反应；基仍能反应；2）可与酯反应生成）可与酯反应生成醚，与酰胺反应生醚，与酰胺反应生成烯胺，与酰卤或成烯胺，与酰卤或酸酐反应生成甲基酸酐反应生成甲基酮。酮。J.Am.Chem.Soc.102,3271(1980)J.Am.Chem.Soc.105,1664(1983)RelatedBooks1.Rod.Bates,OrganicSynthesisUsingTransitionMetals,SheffieldAcademicPress,20002.陆熙炎，杜灿屏，金属有机化合物的化学反应，化学工业出版社，20003.黄耀曾，钱长涛等，金属有机化合物在有机合成中的应用，上海科学技术出版社，1990Chapter6Diels-AlderReactionandDevelopmentDiscoveryWieland(Ber.1906,39,1492)describedthe1:1dimerizationofconjugateddienesinwhatwasprobablythefirstreportofaDielsAlderreaction.Albrecht(Thiele)Reaction:Ann.1906,348,31.StaudingerStructure:DieKetene,Stuttgart1912,59.DielsandAlderAnn.1928,460,98.Infact,vonEulerhadcorrectly,buttentatively,identifiedthe2:1adductofisoprenewithp-benzoquinonebeforeDielsandAlderswork.vonEuler,JosephsonBer.1920,53,822.Diastereoselectivitya.cisPrinciple:Geometryofdienophileanddienearemaintainedinthe4+2cycloadduct.e.g.b.AldersEndoRule:StereoselectiveEndoproductandendotransitionstatepredominateeventhoughexoproductsareusuallymorestable;endoisthekineticproduct.Result:BothcisruleandendoruleDielsAlderreactionveryuseful,diastereoselectivec.FactorsinfluencingendoselectivityoftheDielsAlderreactionEndotransitionstateisfavoredbystabilizingsecondaryorbitalinteractions.EndoselectivityoftenincreaseswiththeuseofLewisacidcatalysis.Endoselectivityoftenincreaseswithincreaseinpressureofreaction.Endoselectivityalsoincreaseswithdecreasesintemperatureatwhichthereactionisconducted.J. AM. CHEM. SOC.2002,124(1),11EnantioselectiveRare-EarthCatalyzedQuinoneDiels-AlderReactionsDavidA.Evans*andJimmyWuDepartment of Chemistry and Chemical Biology, HarVard UniVersity, Cambridge, Massachusetts 02138J. AM. CHEM. SOC. 2003, 125, 10162-10163Hydroxyapatite-BoundCationicRutheniumComplexesasNovelHeterogeneousLewisAcidCatalystsforDiels-AlderandAldolReactionsKohsukeMori,TakayoshiHara,TomooMizugaki,KohkiEbitani,andKiyotomiKaneda*Department of Chemical Science and Engineering, Graduate School of Engineering Science, Osaka UniVersity, 1-3 Machikaneyama, Toyonaka, Osaka 560-8531, JapanJ. AM. CHEM. SOC.2003,125,11460-11461Figure1.Proposedstructuresof(A)RuHAP,(B)cationicRuHAP-(I)and(II)(I,X=SbF6;II,X=OTf),and(C)Ru-enolateintermediate(X=OTf).Table1.RuHAP-(I)-CatalyzedDiels-AlderReactionTable2.RuHAP-(II)-CatalyzedAldolReactionUsingNitrilesSmallOrganicMolecularEnantioselectiveCatalystsTandemDiels-AlderCycloadditionsinOrganicSynthesisJeffreyD.WinklerDepartmentofChemistry,TheUniversityofPennsylvania,Philadelphia,Pennsylvania19104Chem.Rev.1996,96,167-176Reactions of Bicyclic Bis-DienesVisnick,M.;Battiste,M.J. Chem. Soc., Chem. Commun. 1985,1621.AcetylenicBis-DienophilesGoldberg,D.;Hansen,J.;Giguere,R.Tetrahedron Lett. 1993,8003.Nahm,S.;Weinreb,S.Tetrahedron Lett. 1981,3815.ExocyclicBis-DienesHosomi,A.;Masunari,T.;Tominaga,Y.;Yanagi,T.;Hojo,M.Tetrahedron Lett. 1990,6201.MaskedBis-DienesBluestone,H.;Bimber,R.;Berkey,R.;MandelZ.J. Org. Chem. 1961,26,346.Swarbrick,T.;Marko,I.Kennard,L.Tetrahedron Lett. 1991,2549.Marko,I.;Seres,P.;Swarbrick,T.;Staton,I.;Adams,H.Tetrahedron Lett. 1992,5649.Reddy,G.;Bhatt,M.Tetrahedron Lett. 1980,3627. Chapter7OxidationReactions氧化反应的概念氧化反应的概念碳原子周围电子云密度的降低，即碳原子氧碳原子周围电子云密度的降低，即碳原子氧化数化数(氧化态，氧化值氧化态，氧化值)升高的反应。升高的反应。广义的概念广义的概念狭义的概念狭义的概念加氧反应和加氧反应和/或脱氢反应。或脱氢反应。氧化反应的分类氧化反应的分类1. 1. 碳原子上的氢被吸电子的基团或原子取代碳原子上的氢被吸电子的基团或原子取代2. 2. 碳碳相联接转变成与吸电子基团或原子相联接碳碳相联接转变成与吸电子基团或原子相联接3. 3. 脱氢脱氢4. 4. 功能团的氧化功能团的氧化选择性高选择性高反应条件温和反应条件温和环境友好环境友好原料便宜易得原料便宜易得理想的氧化反应理想的氧化反应Epoxidationreactions:-Oxidation of Carbon-Carbon Double BondsComprehensive Org. Syn.,Vol.1,819;Vol.7,357,390.PeracidOxidation1.PeracidReactivity:ThelowerthepKa,thegreaterthereactivity(i.e.,thebettertheleavinggroup)2.Mechanism:过氧酸对双键发生亲电进攻，形成环氧化合物。3.Stereochemistry:a.Stereochemistryofolefinismaintained:diastereospecific.b.Reactionrateisinsensitivetosolventpolarityconcertedmechanismwithoutintermediacyofionicintermediates.c.Lesshinderedfaceofolefinisepoxidized.4.Chemoselectivity:-Electrophilicreagent:mostnucleophilicC=Creactsfastest.-Examples:5.Diastereoselectivity EndocyclicOlefins ExocyclicOlefinsHenbest,J. Chem. Soc., Chem. Commun.,1967,1085.-Theeffectivesizeofthereagentincreaseswithincreasingsolventpolarity,i.e.thesolvationshellofthereagentincreasesinsize-Smallreagentpreference:axialattackand1,3-diaxialinteractionsvarywithsizeofthereagent.-Largereagentpreference:equatorialattackand1,2-interactions(torsionalstrain)arerelativelyinvariantwiththesizeofthereagent.Carlson,J. Org. Chem.,1967,32,1363. AllylicAlcohols(endocyclic)HenbestJ. Chem. Soc.,1957,1958;Proc.Chem. Soc,1963,159.-Metal-catalyzedepoxidationsofallylicalcoholsSharpless Aldrichimica Acta 1979, 12, 63. AllylicAlcohols(exocyclic)VedejsandDent.,J.Am.Chem. Soc.,1989,111,6861. AcyclicAllylicAlcoholsGeneralizations:EclipsedConformationsinm-CPBAEpoxidationBisectedConformationsinMetal-CatalyzedEpoxidationExamples:(continued)(continued) HomoallylicAlcohols(高烯丙系高烯丙系)-Alternativechairhastwoaxialsubstituents.-Intermolecularoxygendeliveryoccursthroughmoststablechair-liketransitionstate.-H-Eclipsedconformation.-Epoxidationfromleasthinderedface;-Notadirectedepoxidation!-DiadtereoselectivitystillgoodandthroughH-eclipsedconformation.(continued)Schreibe,Tetrahedron Lett.1990,31,31Hanessian,J. Am Chem Soc,1990,112,5276. OtherDirectedEpoxidations-StudiessuggestaxialNHCBZdeliverssynepoxidewhileequatorialdoesnot.MohamadiTetrahedronLett.1989,30,1309.6.ScopeandLimitationsa.Olefingeometryismaintained.b.Reactionisdiastereospecific:thestereochemistryofthereactantandproductbearadefiniterelationshiptooneanother.c.Reactioncanbebufferedtopreventepoxideopening.d.Athighertemperatures,afreeradicalscavengermaybeusedtoavoidperaciddecomposition.e.CommonSideReactions:Baeyer-VilligerReactionsofKetones(andaldehydes)Oxidationofamines-Nitrogenmustbeprotected(e.g.asamide)oranotherreagentselected.ImineoxidationSulfuroxidation7.EpoxidationofElectron-DeficientOlefinsa. , -unsaturatedesters:canchooseastrongperacidorvigorousreactionconditions.b. , -unsaturatedketone:Baeyer-VilligercompeteswithepoxidationEmmons,J. Am.Chem.Soc.,1955,77,89.MacPeek,J. Am. Chem. Soc.1959,81,680.Solution:differentconditions(reagents)areneede.AdditionalMethodsforEpoxidationofOlefins1.H2O2,NaOH-Thefollowingreactionisdiastereoselective(notdiastereospecific)Thereactionoccursviaareversibleprocess:Similarly:tBuOOH/TritonBPayneJ. Org. Chem.,1961,26,651.Ph3COOH/R4NOHCoreyJ. Am. Chem. Soc.1988,110,649.tBuOOH/nBuLiCegg Tetrahedron,1988,29,48889.2.Peroxyimidate-Thisreagentpermitstheuseofneutralreactionconditions.Unlikem-CPBA,thereagentbehavesasalargereagentandthusaproachesfromtheequatorialfaceofanexocyclicdoublebond.-AnalogousReagent:3.SulfurYlides-Thisistheresultofkineticcontrol:reactiongivesthethermodynamicallylessstableepoxideproduct.Corey,Chaykovsky,J. Am. Chem. Soc.,1965,87,1353.Initialreactionisreversibleandisnotcapableofgeneratingtheaxialdeliveryproductbecauseofthedestabilizing1,3-interactionsinthetransitionstaterequiredforepoxideclosure.SummaryofExocyclicEpoxideFormation4.DimethylDioxirane(DMDO)MurrayJ.Am. Chem Soc,1986,108,2470.Acc.Chem. Res.,1989,22,205Amildneutralreagent5.SummaryofOtherMethodsofEpoxideFormationa.CyclizationofHalohydrinsb.Cyclizationof1,2-diolsc.EpoxidesfromCarbonylcompoundsGeneralizedbyDarzenthroughyears19041937.Asymmetricvariants/EvansChiralOxazolidinoneLantosJ. Am. Chem. Soc.,1986,108,4595.CatalyticAsymmetricEpoxidation1.SharplessCatalyticAsymmetricEpoxidation(AEReaction)Keyreference:Asymmetric Synthesis:Vol.5,MorrisonJ.D.Ed.Chapter7and8Reviews:Katsuki,MartinOrg. React.,1996,48,1.Comprehensive Org. Syn.,Vol.7,389436.SharplessJ. Am.Chem. Soc.,1980,102,5974;1981,103,6237;1984,106,6430;1987,109,1279,5765;1991,113,106,113;1987,109,1279(1)Theenantiofacialselectivityofthereactionisgeneralanddependableforassignments.(2).Selectivityiscatalystdepent:Ti(OiPr)495%e.e.Zr(OiPr)410%e.e.Al(OtBu)35%e.e.Hf(OiPr)43%e.e.MoO2(acac)215%e.e.Nb(OEt)35%e.e.VO(OiPr)317%e.e.Ta(OiPr)539%e.e.Sn(OiPr)4NR(3).SharplessAsymmetricEpoxidiation-MatchofTi/Tartratesuchthatasinglecomplexdominatesthechemistry.-Ligandaccelerationofreaction.-Stericandstereoelectronicfeacturesofreactioncontrolenantioselectivitythe best known and practical asymmetric reactionScopeEpoxidationwithTitanium-TartrateCatalysts(continued)(continued)(4).KineticResolution:Sharpless,J. Am.Chem.Soc.,1981,103,6237Pure Appl. Chem.,1983,55,589.- Sharpless epoxidation product is different from the directed oxidation of allylic alcohols by peracids (m-CPBA)(5).PayneRearrangementPayneJ.Org. Chem.,1962,27,3819.Base-catalyzed(NaOH,aq.)migrationof , -epoxyalcohol.Ingeneral,themoresubstitutedepoxideisfavoredasthereactionproduct.However,stericfactorsandrelativealcoholacidities(123)areadditionalfactorswhichdeterminetheultimatecompositionoftheequilibriummixture.Themorereactiveepoxidecanbetrappedbystrongnucleophiles(e.g.,PhSH).2.JacobsenEpoxidation-UnactivatedalkenesJacobsensJ. Am.Chem.,1991,113,7063.Example:Boger,BoyceSynlett1997,515.3.ChiralDioxiranesShi,J.Am. Chem Soc,1996,118,9806J. Am.Chem. Soc.,1997,119,11224.J. Org. Chem.,1997,62,2328.-Examplesoftransandtrisubstitutedolefins-pH10(K2CO3,KHCO3)sppressesBaeyer-VilligerreactionofKetoneprecursor.-C2symmetricChiralKetoneYangJ.Am.Chem.Soc.1996,118,11311;1998,120,5943.(过过硫酸氢钾制剂）硫酸氢钾制剂）PolymerSupportedPolyAminoAcidsItsunoJ.Org.Chem.1990,55,6047.VegaAngew.Chem.,Int.Ed.Eng.1980,19,929.Baeyer-VilligerandRelatedReactionsRef:Comprehensive Org. Syn.,Vol.7,671-688.Org. React.,1957,9,73;1993,43,251.Baeyer,VilligerBer.,1899,32,3625;1900,33,858.Baeyer,1905NobelPrizeinChemistryMechanism:Peracid nucleophilic addition reactiona.Alkylgroupthatmigratesdosesowithretentionofconfigurationb.Themoreelectron-rich(mostsubstituted)alkylgroumigrationinpreference(ingeneral).t-alkyls-alkylbenzylphenyln-alkylmethylMehtylketonesinvariablyprovideacetate.-Examples:BenzylicHydroperoxideRearrangement-AlternativetoBaeyer-VilligerreactionBoger,ColemanJ. Org.Chem.,1986,51,5436.J. am.Chem.Soc.,1987,109,2717.Tetrahedron Lett.,1987,28,1027.Boger, Yohannes J. Org. Chem. 1987, 52, 5283.Urea-H2O2asafealternativetoH2O2BeckmannRearrangementandRelatedreaction - An analogous reaarangement reaction can be utilized to prepare lactam and amide1.BeckmannRearrangement-Preparedfromtheoxime.-Awiderangeofleavinggroupsandcatalystshavebeenutilized.Beckmann,Ber,1886,89,988.a.Groupantitooximeleavinggroupmigrates.b.Thealkylgroupmigrateswithretentionofconfiguration.2.CurtiusrearrangementCurtius Ber.,1890,23,3023.-(PhO)2P(O)N3(DPPA),direcyconversionofcarboxylicacidstoacylazides-Rgroupmigrateswithretentionofconfiguration.3.HofmannRearrangementHofmann,Ber.1881,14,2725-Reagentemployedincludebasichypohalides:Pb(OAc)4,PhI(O2CCF3),PhIO-Rgroupmigrateswithretentionofconfiguration.4.SchmidtReactionA.ConversionofKetonestoAmides-MoststudiesofSchmidtvariants,similartoBeckmannrearrangement.-AsymmetricVariantutilizeschiralalkylazidedonorswhichprovideproductsinhighdiastereoselectivity.-Bicycleketoneslightlyfavormigrationoflesssubstitutedgroup,oppositeofbeckmann.-Reactivity:dialkylketonealkyl,arylketonediarylKetoneCarboxylicacidoralcoholB.ConversionofCarboxylicAcidstoAmines-AcidcatalystusuallyH2SO4,PPA,TFA-TFAA,orsomeLewisacid.-GoodresultswhenR=alkyl,hinderedalkyloraryl.-AdvantageinprocesslengthoverHofmannandCurtisrearrangements,butmoredrasticconditions.C.ConversionofAldehydestoNitriles-AcidcatalystusuallyH2SO4,canbeLewisacid.-Schmidtreactionistheusualbyproductundertheseconditionstoprovideformamide.-Morecommonmethodistoconversionaldehydetooximewithhydroxylamine,followedbydehydration-Aromaticaldehydesaregoodsubstrates.5.LossenRearrangementOlefinOsmylation(Dihydroxylation)First use: Criegee Justus Liebigs Ann. Chem. 1936, 522, 75.Milas J. Am. Chem. Soc. 1936, 58, 1302.MechanismScopeComprehensiveOrg.Syn.,Vol.7,pp437448.Chem.Rev.1980,80,187.OsO4isanelectrophilicreagent,anditbehavesasalargereagent.Strained,unhinderedolefinsreactfasterthanunstrained,stericallyhinderedolefins.Electron-richolefinsreactfasterthanelectron-deficientolefins.Diastereospecific,withattackontheC=Cfromtheleasthinderedface.-AlternativereagentstoOsO4:-butOsO4isexpensive,volatile,andtoxic-variousimprovements:KMnO4:Synthesis1987,85.YieldsrarelyashighasOsO4butlesshazardousandlessexpensiveespeciallyforlargescaleRuO4orRuO22H2O/RuCl3H2O+cooxidantMorevigorousthanOsO4andolefincleavageisobservedDiastereoselectivitya. Endocyclic Olefinsb. Acyclic Systems-Alsoobservedwithallylicethers-HigherdiastereoselectivityofZvs.Eisomerimplieseclipsedconformationimportant.c. Exocyclic OlefinsVedejsJ.Am.Chem.Soc.1989,111,6861d.H-BondingandDirectedDihydroxylationDiolStereochemistryComparisionm-CPBAOsO4ViaBromohydrin-Epoxidationonmosthinderedfaceofolefin(togvedifferentepoxidefromm-CPBA).-transdiaxialringopening(togivesamehydrolysisproductasfromm-CPBAoxidation)PrevostNeighboringGroupParticipationtrans-diolWoodwardJ.Am.Chem.Soc.1958,80,209.Compt.rend.1933,196,1128.cis-diolAsymmetricDihydroxylationreactioncatalystbyOsO4andrelatedReagents1. Catalytic MethodsGoodorexcellentselectivityPoorselectivityCoreyJ. Am.Chem. Soc.,1987,109,6213.ShaplessCatalyticAsymmetricAminohydroxylation(AA)a.Sulfonamidevariant-a,-unsaturated esters:-a,-unsaturated amides:reaction works well without a ligand.b.Carbamatevariant-a,-unsaturated esters:-Styrenes:c.AmidevariantOxidationofAlcoholksChromium-basedOxidationReagentsCollinsreagents:CrO3-py2,alkalineoxidantJonesReagents:CrO3inaq.H2SO4/acetonePyridiniumChlorochromate(PCC)PyridiniumDichromate(PDC):Manganese-basedOxidationreagentsMnO2ActivatedMnO2KMnO4/H2SO4KMnO4/t-BuOH-5%NaH2PO4aq.bufferR4NMNO4Cu(MnO4)2-6H2OandBa(MnO4)2OtherOxidationReagentsNaOCl/NaClO2Ag2O/Ag2CO3m-CPBA/NaIO4Dess-MartinoxidationNitroxideOpenauerOxidation:Cl3CCHO,Al(OiPr)3Chapter8ReductionReactionsIntroductionandReview1. Conception and Classification 有机化合物中碳原子总的氧化态有机化合物中碳原子总的氧化态(oxidation state)(oxidation state)降低的反应降低的反应. .Reduction 有机分子增加氢或有机分子增加氢或/ /和减少氧的反应和减少氧的反应. .分类分类根据所采用根据所采用的方法分类的方法分类根据反应前后物质根据反应前后物质结构的变动分类结构的变动分类催化氢化催化氢化氢负离子还原氢负离子还原溶解金属还原溶解金属还原氢解反应氢解反应加氢反应加氢反应2. Catalytic hydrogenation 2.1Heterogenoushydrogenation（非均相催化氢化非均相催化氢化/多相催化）多相催化） 非均相催化非均相催化催化剂：催化剂：Pt,Pd,Raney-Ni，Pt,Pd:吸附在载体上，如：吸附在载体上，如：C,CaCO3特点：活性高，根据底物不同，可在常温，常压下反应；特点：活性高，根据底物不同，可在常温，常压下反应；也可在高温、高压下反应。也可在高温、高压下反应。缺点：很贵，缺点：很贵，含硫化合物会使其中毒失活含硫化合物会使其中毒失活不同功能团氢化难易程度不同功能团氢化难易程度FunctionalgroupHydrogenationproductsRCOClRCHORNO2RNH2RCH=CHR(Z-)RCHORCH2OHRCH=CHRRCH2CH2RRCORRCH(OH)RArCH2XArCH3RCH2NH2RCO2RRCH2OH+ROHRCONHRRCH2NHR易易难难2.2Homogenoushydrogenation(均相催化氢化均相催化氢化)催化剂：催化剂：Rh或或Ru的络合物的络合物常用：常用：（PPh3）3RhCl(TTC)（PPh3）3RuClH优点优点1)均相反应，溶解度好，收率明显提高，室温、常压反应；均相反应，溶解度好，收率明显提高，室温、常压反应；2）立体选择性高；）立体选择性高；3）有硫化物存在不会中毒失活；）有硫化物存在不会中毒失活；4）改变不同的配体，可得到不同性能的催化剂，前景广阔。改变不同的配体，可得到不同性能的催化剂，前景广阔。3. Metal hydride reductionMetal hydride亲核性氢负离子还原剂亲核性氢负离子还原剂LiAlH4NaBH4No.MetalhydrideSolvent1.LiAlH4Ether,THF,diglyme2.LiAlHOC(CH3)32THF,diglyme3.NaAlH2(OCH2CH2OCH3)2RED-AlBen,Tol,Xylene4.NaBH4W,ethanol,diglyme5.NaBH3(CN)W,methanol,DMSO6.LiBH4THF,diglyme7.AlH3Ether,THF8.AlHCH2CH(CH3)22DIBAL-HToluene,DMESolvents for metal hydride reductionsProducts of metal hydride reductionsa.Reductionproceedstothealdehydestageonly;b.veryslowreactionc.Reductonproceedstolactolstageonly;d.phenylestersgivealdehydes.e.Someamidesarereducedtoaldehydes;f.whereRisaliphatic;ifRisaromatic,Azoarenesareformed;g.X=halogenorOSO2R.Boron regents亲电性氢负离子还原剂亲电性氢负离子还原剂-易还原羧基易还原羧基-hydroborationBoranes金属氢化物与金属氢化物与LewisAcid配合后，还原活性变化配合后，还原活性变化-易还原双键易还原双键硼烷还原的功能团硼烷还原的功能团Selectivity:reagent,solventandreactionconditionAsymmetricreduction:chiralreducingagents4. Dissolvingmetalreduction（溶解金属还原溶解金属还原）Activemetals:Li,Na,K,Mg,Ca,Zn,Sn,FeProtondonor:water,ethanol,acid氢解氢解氢化还原氢化还原e.g.Reductionofcarbonylgroup,threetypesofproductConfoemationalAnalysis&StereochemistryofHydridereductionreactionofCarbonylGroups-Topic oneA.ConformationalEffectsofCarbonylGroupsonReactivityTheadditiontocyclohexanonesisfavorable1.ReversibleReactionsThermodynamicallymorefavorableforcyclohexanoneTorsionalstrainEffectofSP2hybridization2.IrreversibleReactionsOnecanselectivelyreduceacycliccarbonylinthepresenceofanacycliccarbonyl:underkineticorthermodynamicconditions.SyntheticconsiderationB.ReactionofCarbonylGroups-Eachreagentwilldisplaycompetitivereactionsamongthethreeprimarypathways.NatureofeachreagentandthenatureofXwilldeterminethecourse.C.ReversibleReductionReactions:Stereochemistry-Meerwein-Pondorff-VerleyReductionThereversereactionisOppenauerOxidationReversibleReductionMechanism:reversibleintramolecularhydridetransfer-Sinceitisfreelyreversible,oneobtainsthemoststablealcoholfromthereduction.Thereactionisdriventocompletionbyuseofexcessreagentandbydistillingofftheacetoneformedinthereaction.D.IrreversibleReductionReactions:Strereochemistry1.CyclicKetones-Differenceintherelativerates:1,2-interactonsslowtheequatorialadditionbyafactorof10.-LiAlH4=smallreagentFavoraxialhydridedelivery-1,3-interactionsaremoreremote(i.e.smaller),whencomparedtothe1,2-interactions(larger).-Thedestabilizing1,3-interactionsincreaseasthesizeofthereagentincreasesorwiththesizeofthe1,3-diaxialsubstituentswhilethe1,2-interactionsarenotnearlysosensitivetothesizeofreagentsorthesizeofthesubstituents.Examples:Effectofthesizeofthereagent:ComparisonofDiastereoselectivityofHydridereducingreagents.Origin of DiastereoselectivityThedirectionofattackisnotfromtheaxialorequatorialvector,butwitha109.5oapproachofthenucleophile.DunitzangleGoodoverlapandgoodapproachesbondAnglerequiredofSP3hybridization.Better - *overlapfornucleophilicaddition.Tetrahedron1974,30,1563.-CyclicKetones:Stericvs.Torsionalinteractions-Asthenucleophilegetslarger,thisstericinteractionwiththeC3-axialHgetsworse-equatorialapproachbecomesthepreferredlineofattack.-ForC2andC6-Hsubstituents,thistorsionalinteractionisworsethanthestericinteractionofNu-/C3andC5-Hs(forsmall,unhinderedNu-)-AllH-reductionhavetransitionstatesthatresemblerectantgeometry.-Diastereoselectivityisinfluencedby:a.Stericinteractions(1,3-diaxialinteractions);b.Torsionalstrain(1,2-interactions);c.Remoteelectroniceffects(electrostaticinteractions).-Incontrasttoearlytheoriesof“productdevelopmentcontrol”/latetransitionstatevs“stericapproachcontrol”/earlytransitionstate.Examples:-lockedtransdiaxialringfusion-preferentialaxialdeliveryofreagent.-equatorialOHismajorproduct-additionofNu-from -face(equatorialdelivery)suffersfromrepulsiveinteractionwithaxialMe.-vs-but2.AcyclicCarbonylGroupsReview:ComprehensiveOrg.Syn.,Vol.1,4975.-CramsRuleJ. Am. Chem. Soc.,1952,74,5828.Empiricalandnomechanisticinterpretationisimposedonmodel.J. Am. Chem. Soc.,1959,81,2748.(cheletion-controlledaddition)-PrelogHelv. Chim. Acta,1953,36,308.(1,3-inducton)-Felkin(orFelkin-Ahn)modelTetrahedron Lett.,1968,2199,2205Tetrahedron Lett.,1976,155,159.Nouv. J. Chim.,1977,1,61.a.CramsRule-EmpiricalModel-LargegroupLeclipsedwithRandnotthecarbonyl,Nu-approachfromsideofsmall(S)group.-Stereoselectivityobservedusuallymodest.b.Felkin-AhnModel-Largegroup(L)transantiperiplanartoformingbond.-Liseitherthelargestgroup(sterically)orthegroupwhosebondtothe -carbonprovidesthegreatest - *overlap(e.g.halide,alkoxygroup).-computationalstudiesofAhnconfirmedthisisthemoststabletransitionstateandextendeditto -chloroketones.Inthelattercase,thisminimizeddestabilizingelectrostaticinteractionsbetweenthehalogen(electronegativegroup)andtheincomingnucleophile.Felkin-AhnModelNucleophileprefersapproachthatminimizestorsionalStainandincorporatesBurgi-Dunitztrajectory.primaryInteractionisnowbetweentheNu-andthesmallormediumsubstituent.Johnson,J. Am. Chem. Soc.,1968,90,6225.c.ComparativeExamplesofDiastereoselection-Diastereoselectiondependsonthesizeoftheketonesubstituent-Diastereoselectivitydependsonsizeofnucleophiled.Chelation-controlledaddition螯合控制螯合控制羰基羰基 ， -位位羟基、氨基、烷氧基，金属离子，螯合成环羟基、氨基、烷氧基，金属离子，螯合成环-Review:Acc. Chem. Res.,1993,26,462.-Examplesof1,2-chelation-controlNicolao，J. Am. Chem. Soc1980,102,6611.Still,J. Am. Chem. Soc.,1980,102,2117,2120-Notethatnonchelation-controlledadditionexhibitrelativelymodeststereoselectivities,butchelation-controlledadditioncanexhibtverygoodstereocontrol.Twomodlespredictation螯合离子及溶剂的影响螯合离子及溶剂的影响Li+;THF -烷氧基取代基的影响烷氧基取代基的影响Still,Tetrahedron Lett.,1980,21,1031.Reetz,J. Chem. Soc., Chem. Commun.,1986,1600.还原产物的立体控制还原产物的立体控制-1,3-Chelation-ContralledAdditions( -chelation-controlledaddition)Tetrahedron,1984,40,2233;TetrahedronLett.,1987,28,155;1986,27,3009.R3B/NaBH4,Et2BOCH3-NaBH4inTHF-MeOHDibal-H(98:2)AluminumHydrideReducingAgentslessreactive,moreselective-Examples:BorohydrideReducingAgentsHydrideReductionsofFunctionalGroupsReactionsofBorane(BH3) Characteristics of Hydride Reducing Agents NaCNBH3 LiBH4 Zn(BH4)2Review:NarasimhanAldrichim.Acta1998,31,19. NaBH4/CeCl3 (catalytic amount (0.1 equiv)LucheJ.Am.Chem.Soc.1981,103,5454;1978,100,2226.-Readilyenolizablecarbonylcanbereduced.cleanaddition,noenolizationImamotoJ.Am.Chem.Soc.1989,111,4392.Reagentcomparisionsfor1,2-vs.1,4-reduction NaBH4CoCl2Selectivereductionofnitriles.-Goodfor1,2-vs.1,4-reduction.GarnerOrg.Syn.1992,70,18.Asymmetric Reductions 烯烃双键的不对称催化氢化烯烃双键的不对称催化氢化SP2杂化碳杂化碳 羰基化合物的不对称还原羰基化合物的不对称还原 亚胺的亚胺的不对称还原不对称还原 不对称氢转移反应不对称氢转移反应手性二磷配体的设计策略手性二磷配体的设计策略:活跃的研究领域活跃的研究领域 碳碳双键的不对称催化氢化碳碳双键的不对称催化氢化用于催化不对称氢化反应的手性膦配体用于催化不对称氢化反应的手性膦配体1、烯酰胺的不对称氢化、烯酰胺的不对称氢化烯酰胺烯酰胺/Rhcomplex/H2 -氨基酸氨基酸潜潜(前前)手性手性Prochirality磷磷配体配体e.e% 构型构型R=PhR=H(R,R)-DIPAMP96(S)94(S)(S, S)-CHIRAPHOS99(R)91(R)(S, S)-NORPHOS95(S)90(R)(R, R)-DIOP85(R)73(R)(S, S)-BPPM91(R)98.5(R)(S)-BINAP100(R)98(R)(S,R)-BPPFA93(S)(S,S)-SKEWPHOS92(R)(S,S)-CYCPHOS88(R)(S,S)-Et-DuPHOS99(S)99.4(S)CatalyticMechanism螯合螯合吸氢吸氢Halpern,Brown,1980负氢转移负氢转移还原脱除还原脱除螺环瞵配体螺环瞵配体手性双氨基瞵配体手性双氨基瞵配体:2、手性、手性Rh-二茂铁基膦络合物催化的丙烯酸的不对称氢化二茂铁基膦络合物催化的丙烯酸的不对称氢化Hayashi,Ito,1987.“增强底物功能团与手性配体之间的亲和性相互作用可以提高立体选择性增强底物功能团与手性配体之间的亲和性相互作用可以提高立体选择性”“手性手性氨基氨基二茂铁二茂铁”烯烃烯烃配体配体溶剂溶剂时间时间(h)产物产物e.e.%构型构型2a1aTHF/MeOH(90/10)303a98.4(S)2a1aTHF/MeOH(80/20)203a97.6(S)2a1ai-PrOH203a97.0(S)2a1aMeOH53a95.8(S)2a1bTHF/MeOH(80/20)203a97.9(S)2a1cTHF/MeOH(80/20)303a98.1(S)2a1dTHF/MeOH(80/20)303a98.2(S)2b1aTHF/MeOH(80/20)403b97.4(S)2c1aTHF/MeOH(80/20)403c96.7(S)2d1aTHF/MeOH(80/20)653d97.3(S)E-4a1ai-PrOH1005a97.3(2S,3R)E-4b1aTHF/MeOH(80/20)1005b92.1(2S,3R)由由手性二茂铁基瞵手性二茂铁基瞵-铑配合物催化的三取代丙烯酸的不对称氢化铑配合物催化的三取代丙烯酸的不对称氢化Kang,1998Rh(COD)2BF3/(R,R)-FerroPHOS/H2/2atom,2030oC脱氢氨基酸，脱氢氨基酸，e.e.%99.9%空气稳定性空气稳定性3、钴络合物催化的、钴络合物催化的 ， -不饱和酯的不对称氢化不饱和酯的不对称氢化底物底物产率产率%e.e.(%)构型构型E-2a9794(R)-(+)Z-2a9594(S)-(-)E-2b9594(R)-(+)Z-2b9494(S)-(-)E-2c8496(S)-(-)Z-2c8690(R)-(+)E-2d9581(S)-(+)Z-2d9773(R)-(-) , -不饱和羧酸酯的对映选择性还原不饱和羧酸酯的对映选择性还原4、开链烯醇酯的不对称氢化、开链烯醇酯的不对称氢化中等程度的对映选择性中等程度的对映选择性二烯基二烯基酯酯(烯炔基酯烯炔基酯)5、应用实例、应用实例Noyori,1987.BINAP-Ru(II)二羧酸络合物二羧酸络合物生物碱的合成生物碱的合成:萘普生的合成萘普生的合成:Z-烯酰胺烯酰胺TakasagoCo.,1500t/year(S)-Cotronellal维生素维生素E,K侧链的合成侧链的合成: 羰基化合物的不对称还原羰基化合物的不对称还原催化氢化催化氢化/化学选择性化学选择性,金属氢化物还原金属氢化物还原1、用、用BINAL-H还原还原LiAlH4,NaBH4,BH3.THF的活性与选择性的改造的活性与选择性的改造手性配体修饰的金属氢化物手性配体修饰的金属氢化物活泼氢数目减至最少，获得高度的化学选择性活泼氢数目减至最少，获得高度的化学选择性手性配体的引入，手性配体的引入，提高对映面的选择性提高对映面的选择性1951，手性配体改造手性配体改造LAH1979,Noyori,手性联萘酚修饰手性联萘酚修饰BINAL-H手性手性LAH还原剂还原剂:R,温度的影响温度的影响产物的对映选择性可控产物的对映选择性可控!R,R/电性因素电性因素/立体空间因素立体空间因素优势构象优势构象非优势构象非优势构象n- 排斥排斥芳香酮的还原：芳香酮的还原：酮酮BINAL-H构型构型产物产物产率产率%e.e.%构型构型C6H5COCH3R6195RC6H5COC2H5S6298SC6H5CO-n-C3H7S78100SC6H5CO-n-C4H9S64100SC6H5COCH(CH3)2S6871SC6H5COC(CH3)3R8044R -TetraloneR9162R炔基酮炔基酮/烯基酮还原的立体选择性烯基酮还原的立体选择性光学活性的烯丙醇光学活性的烯丙醇/炔丙醇的制备炔丙醇的制备二二烷基酮的对映选择性不高烷基酮的对映选择性不高!苄基甲基酮苄基甲基酮(S)-1-苯基苯基-2-醇醇e.e.%13%2-辛酮辛酮(S)-2-辛醇辛醇e.e.%24%醛醛BINAL-H构型构型醇产物醇产物产率产率%e.e.%构型构型香茅醛香茅醛-1-dS9191/84S橙化醛橙化醛-1-dS9072SE,E-法尼醛法尼醛1-dR9188RZ,E-法尼醛法尼醛1-dR9382R苯甲醛苯甲醛-1-dR7582R2、过渡金属络合物催化的羰基氢化、过渡金属络合物催化的羰基氢化酮的不对称氢化酮的不对称氢化-制备手性醇制备手性醇BINAP-Ru(II)底物底物催化剂催化剂产物产物产率产率%threo:erythroaRuBr2-(R)-BINAP9799:1aRuBr2-(S)-BINAP969:91bRuBr2-(R)-BINAP9999:1cRuBr2-(R)-BINAP9299:1手性二醇手性二醇：1,2-,1,3-,1,4-二醇二醇/制备手性配体制备手性配体二酮的不对称氢化二酮的不对称氢化Chan,1997.BINAP-Ru(II)(OOCCH3)2BINAP-Ru(II)(OOCCH3)2/2CF3COOHBINAP-Ru(II)(OOCCH3)2/2HCl增加酸性增加酸性引入配位杂原子引入配位杂原子简单二烷基酮的还原一般选择性较低简单二烷基酮的还原一般选择性较低！Noyori,1995.RuCl2-(S)-BINAP(DMF)n,S,S-1,2-二苯基乙二胺二苯基乙二胺/KOH,isopropylalcohol开发稳定、高效的催化剂：开发稳定、高效的催化剂：Zhang,1998.-弱碱能加速简单酮的弱碱能加速简单酮的Rh催化氢化反应催化氢化反应反应反应酮酮Lutidine当当量量KBr当量当量时间时间hYield%e.e.%10.4_24979520.4_53949530.81.088959340.81.056997350.81.048967560.81.075668570.81.094998480.81.0106909290.81.0965194Rh-PennPhos体系催化简单酮的不对称氢化体系催化简单酮的不对称氢化3、硼杂噁唑烷催化体系、硼杂噁唑烷催化体系硼烷衍生物硼烷衍生物,硼杂噁唑烷硼杂噁唑烷:Chemzyme化学酶化学酶1981,Hirao;Itsuno;Corey,CBS催化剂催化剂(Corey-Bakshi-Shibata)CBS催化剂举例催化剂举例酮酮BH3当量当量(S)-1b当量当量产物构型产物构型(e.e.%)C6H5COCH32.01R(97)C6H5COCH31.00.1R(97)C6H5COCH31.20.025R(95)C6H5COC2H51.20.05R(86)C6H5COC2H51.00.05R(88)C6H5COC2H50.60.05R(90)t-BuCOCH30.60.05R(88)t-BuCOCH30.60.1R(92) -tetralone0.60.05R(89)C6H5COCH2Cl0.60.05S(97)CBS催化反应机理催化反应机理:前列腺素合成前列腺素合成,酮基的酮基的选择性还原选择性还原;C-15位的立体化学控制位的立体化学控制 -蒎烯衍生蒎烯衍生底物底物产物产物温度温度时间时间h产率产率%e.e.%05495922530493810519376253019690056655905290930529037Brown,H.C.,1961.(+)-(Ipc)2BCl,(Ipc)2BH,IpcBH2二二异松莰烯基硼烷异松莰烯基硼烷-仅对仅对Z-烯烃显示极好的选择性烯烃显示极好的选择性Masamune,S.1985.-反反-2,5-二甲基硼杂环戊烷二甲基硼杂环戊烷DMB-Z-/E-二取代烯烃、三取代烯烃二取代烯烃、三取代烯烃非硼杂噁唑烷类催化剂非硼杂噁唑烷类催化剂 -氨基醇类化合物氨基醇类化合物实现酮的对映选择性还原实现酮的对映选择性还原改良的改良的LAH硼杂噁唑烷硼杂噁唑烷手性配体配位的过渡金属催化手性配体配位的过渡金属催化 亚胺的亚胺的不对称还原不对称还原亚胺的亚胺的不对称还原制备手性仲胺与由酮制备醇同样重要不对称还原制备手性仲胺与由酮制备醇同样重要Burk,1993.Rh(COD)(DuPHOS)+CF3SO3-(2S,4S)-BPPM/BiI3/H2Buchwald,19921994二茂钛二茂钛催化剂：催化剂：活性高，空气稳定，活性高，空气稳定，高对映选择性高对映选择性 不对称氢转移反应不对称氢转移反应不对称氢转移还原：不对称氢转移还原：易于操作，不使用活性的金属氢化物或氢气易于操作，不使用活性的金属氢化物或氢气手性磷手性磷/手性氮配体手性氮配体Noyori,1997简单的氨基醇作为手性配体：简单的氨基醇作为手性配体：R1R2时间时间he.e.%MeMeEtn-Prn-Bun-C6H131.51.51.51.51.51.5949793929595RecentDevelopmentofAsymmetricReductionsAMetal-FreeTransferHydrogenation:OrganocatalyticConjugateReductionof , -UnsaturatedAldehydes*JungWoonYang,MariaT.HechavarriaFonseca,NicolaVignola,andBenjaminList*Angew.Chem.Int.Ed.2004,43,66606662Received: August 28, 2004Catalystscreeningfortheiminiumcatalyticconjugatereductionof , -unsaturatedaldehydes.Organocatalyticconjugatereductionof , -unsaturatedaldehydesContinueProposedmechanismofiminiumcatalysisInsummary,wehavedevelopedthe first metal-freecatalytic transfer hydrogenation.Thisnoveliminiumcatalyticconjugatereductionofa,b-unsaturatedaldehydesishighlyefficientandchemoselective.Itrequireslowcatalystloadingsandtoleratesvariousfunctionalgroupsthataresensitivetotheconditionsofstandardhydrogenationsandalternativeconjugatereductions.Metal-Free,OrganocatalyticAsymmetricTransferHydrogenationofUnsaturatedAldehydes*JungWoonYang,MariaT.HechavarriaFonseca,NicolaVignola,andBenjaminList*Angew.Chem.Int.Ed.2005,44,108110Received: October 26, 2004Organocatalyticasymmetrictransferhydrogenationof , -unsaturatedaldehydes.ContinueProposedmechanismoftheorganocatalyticasymmetrictransferhydrogenation.Attractivefeaturesofthisprocess1)Itshighyields,chemo-,andenantioselectivities;2)2)Itsenantioconvergence;3)3)itssimplicityandpracticability.Enantioselective Organocatalytic Hydride ReductionStephaneG.Ouellet,JamisonB.Tuttle,andDavidW.C.MacMillan*DiVision of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125J.AM.CHEM.SOC.2005,127,32-33Received October 10, 2004;EOHR:EnantioselectiveorganocatalytichydridereductionEffect of Catalyst and Solvent on EOHREffect of Dihydropyridine Component on EOHREffect of Aldehyde Substituents on EOHRContinueInsummary,wehavedevelopedthefirstorganocatalytichydridereduction,anoperationallysimplereactionthatallowstheenantioandchemoselectivetransferofhydrogenfromHantzschesterstogeometricallyimpureenals.