高等有机合成

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1、高等有机合成高等有机合成Advanced Organic Synthesis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）NH4OCNH2NNH2O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）2

2、1 steps,overall yield 0.7%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）3 steps,overall yield 90%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？R1NHR2+HCHO+R3R4OR3R4OR1NR2Mannich Reaction(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19

3、77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Woodward 一生奋斗的成就是将有机合成作为一种艺术展现在世人面前，那么Corey 则是将有机合成从艺术转变成为科学的一个关键人物。他的逆合成分析是现代有机合成化学

4、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 (Retrosynthetic analysis)Woodward(1981)红霉素的全合成 Y.Kishi(1987)海葵毒素的全合成 S.L.Schreiber et 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.Schreiber K.C.Nicolaou,et al.The art and science of total synthesis at the dawn of t

5、wenty-first century,Angew.Chem.Int.Ed.Engl.,2002,39,44 S.L.Schreiber,et al.Target-oriented and diversity-oriented organic synthesis in drug discovery,Science,2000,287,1 964高立体选择性高立体选择性（High Stereoselectivity)原子经济性反应原子经济性反应（Atom Economical Reaction)绿色化学绿色化学（Green Chemistry)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

6、.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HNNClEpibatidineisolated from skins of the Ecuadoran poison frog Epipedobates tricolorDaly,John W.etal.J.Am.Chem.Soc.(1992),114(9),3475-8ED50:0.005 mg/kg s.c.1.5 mg/kg i.p.Daly,John W.et al.Ki:(+)0.045nM;(-)0.058 nM,in mice,hot plate testnAChRCorey,E.J.et al.USA.

7、J.Org.Chem.(1993),58(21),5600-2.First patent:US 845042(1993)First total synthesis of(+)and(-)-EPGeneral Introduction of Epibatidine Epibatidine 的研究的研究NRR+NRRRRNBocSO2TolHNBocSO2Tol+NRR+NRRRRNRR+NRRY(OTf)3 Y(OTf)3-catalyzed novel Mannich reaction of N-alkoxy-carbonylpyrroles,formaldehyde and primary

8、amine hydrochlorides C.X.Zhuan,J.C.Dong,T.M.Cheng,R.T.Li*,Tetrahedron Letters,2001,43(3),461-463NR+RCHO+RNH2HCl.Y(OTf)3(10%mmole)NNRRNRCHNHRRAB Aldol 缩合反应的研究缩合反应的研究RCHO +RCH2CHOOH-经经典典的的方方法法TiCL4定定向向 Aldol 缩缩合合L-Proline有有机机小小分分子子催催化化RCHCHCHOOHR2.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Combinatorial Chem

9、istry组组合合化化学学药药物物化化学学Medicinal Chemistry材材料料科科学学Material Sciences三、学习内容和方法三、学习内容和方法 内容内容有有机机合合成成反反应应的的学学习习反反应应的的应应用用 （有有机机化化合合物物合合成成路路线线设设计计）分分子子骨骨架架的的形形成成官官能能团团之之间间的的转转换换C C-C C单单键键的的形形成成C C-C C双双键键的的形形成成氧氧化化反反应应还还原原反反应应取取代代反反应应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化合物的合成新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

10、.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

11、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.Dale L.Boger,Modern Organic Synthesis,The Scripps Research Institute,Tsri Press,1999.8.Comprehensive Organic Synthesis,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.Tetrahedron Letters.

12、8.Tetrahedron Asymm.9.Synthesis10.Synlett11.Synth.Commun.12.Eur.J.Chem.13.Eur.J.Org.Chem.14.Heterocyclics15.J.Heterocyclic Chem.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.讲授原则讲授原则 复习老反应，补充新反应，复习老反应，补充新反应，重点讲进展，强调学思路。重点讲进展，强调学思路

13、。3.考试考试 1）写综述一篇写综述一篇（近（近5年的进展）（年的进展）（40%）2）笔试（笔试（60%）Chapter 2 Formation of Carbon-Carbon Single Bonds一、一、General Principles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EWGCHABHBaseCHAB-E+CHABE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 -COR SO2R -CN -CO2R -Ph,SOR A和和B至

14、少要有一个是至少要有一个是 EWGCH2AB A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（Electron withdraw group EWG）。）。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（polar aprotic solvent):DM

15、F DMSO HMPAPOMe2NNMe2NMe2d.亲电试剂亲电试剂（Electrophilic reagent)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。ROTsRClRBrRI反应速度Hard alkylating agentSolft alkylating agent三、烷基化反应三、烷基化反应(Alky

16、lation)OO1.O-alkylation&C-alkylationExample 1Example 2Degree of substitution of alkylating agent:Example 3OAcOAcOAcOOAcBr+MeCO2EtOK2CO3/TBABCH3CNr.t.OAcOAcOAcOOAcMeCO2EtOK2CO3/TBABCH3CNr.t.OAcOAcOAcOOAcMeEtO2CO+OAcOAcOAcOOAcOH+OAcOAcOAcOOAc62%R.T.Li et al.Synth.Commun.1997,27(8),1351-13572.区域选择性区域选择

17、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;Example 1Example 23.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.Example 1Example 2Example 3Example 44.二羰基化合物的二羰基

18、化合物的 -烷基化反应烷基化反应(-Alkylation of 1,3-dicarbonyl compounds)RROO2 equiv.BaseRROO1)RX2)H2ORROORJ.Am.Chem.Soc.,1974,90,1082;1963,85,3237;1965,87,82.MeMeOO1)2 KNH2/liq.NH32)n-BuBrMeOOC4H982%Example 1MeOOMeMeO烷烷基基化化难难易易次次序序：PhCH2-CH3-CH2-MeOEtOO1)1 equiv NaOH/THF/HMPA2)1 equiv.n-BuLiOEtOOBrOTHPOEtOOOTHPsev

19、erial steosOOO1)2 equiv.LDA2)C6H5SeBrOOOSeC6H51)H2O2,CH2Cl2,0oC2)-25oCOOOdiplodialide AExample 2C6H5SMeOOC6H5SCH2OO2 equiv NaH/THF/HMPAC6H5SOOC4H9-nn-C4H9BrH3O+Zn/AcOHCCl4/RefluxOC4H9-nOC4H9-nExample 3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(Reactions of aromatic halide with enolates)CO2EtCO2Et+C6H5Br过过

20、量量 NaNH2liq.NH3CO2EtCO2EtC6H5ExampleBrliq.NH3NaNH2CO2EtCO2EtCO2EtCO2EtCO2EtCO2EtH3O+CO2EtCO2EtMechanism关键是要有形成苯炔的条件。关键是要有形成苯炔的条件。NCOCH3BrKNH2/NH3NCOCH3MeO2CNCOCH3MeO2C6.酮和酯的烷基化反应酮和酯的烷基化反应(Alkylations of ketones and esters)XYCO2RRRORabOOORXRAldol CondensationOOH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

21、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。C6H5O1)NaNH2/C6H6,Reflux2)BrC6H5O88%Example 1Example 2CO2Me1)LDA/THF,-78 oC2)BrCO2Me1)LDA/THF,-78 oC2)BrCO2Me90%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(Selective alkylation of asymmetric ketones)RORab 在一个在一个-位引入

22、一个活化基位引入一个活化基(略）略）如：如：Dieckmann Reaction;Claisen condensation 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)OMe1)NaH/GDME2)Me3SiCl/Et3NOSiMe3MeOSiMe3Me+78%22%OSiMe3MeMeLi/GDME25 oCOLiMe+Me4SiC6H5CH2ClOLiMeOMeC6H5OMeC6H5+84%7%碱性条件碱性条件Me3SiOR1R2R3Lewis acidRXMe3SiOR1R2R3RX-OR1R2R3RLew

23、is acid:TiCl4,SnCl4,ZnCl2酸性条件酸性条件OSiMe3MeCH2Cl2/-23 oCOMeMe48%1)t-BuX/TiCl42)Na2CO3MeMe 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,Stork Enamine Synthesis)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

24、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。NNONHE+C-alkylationN-alkylationN+ClH3O+O96%ONHN1)LDA DME/-60oC2)MeI3)H3O+O98%Example 1Example 27.对映选择性烷基化反应（对映选择性烷基化反应（Enantioselective alkylations)u 利用手性胺利用手性胺HNC6H5OMeLDAHNC6H5OMeLiC2H5IHNC6H5OMeC2H5HOC2H5HHNC6H5OMeOC2H5H1)LDA/THF,-20oC2)EtI3)

25、H3O+yield 82%94%eeu 利用二甲基肼利用二甲基肼NNMe2Me1)LDA2)MeINNMe2MeMeNaIO4EtOH/H2OOMeMeyield 95%97%trans 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。LiCH2CH=NNMe2CuI(i-Pr)2STHF,-20 oCCH2CH=NNMe2CuLi2O1)2)H3O+OCHOCH2CH=NNMe2CuLi2Michael addition7

26、0%u 利用利用SAMP 和和 RAMPNNH2OMeNNH2OMe(S)-1-amino-2-(methoxymethyl)pyrrolidineSAMP(R)-1-amino-2-(methoxymethyl)pyrrolidineRAMPO+NNH2OMeNNOMe1)LDA2)C3H7I1)MeIyield 60%99.5%eeNNOMeMeC3H7H2)H3O+OMeC3H7H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HNOOHNOOC6H5NOOC6H5MeOLDA/THF-78 oCNOOC6H5MeOLiPhCH2BrNOOC6H5MeO

27、PhCH2PhCH2OLiPhCH2OHMeOPhCH2OCH2Ph75%,99:1H2/PdMeOPhCH2OHExample8.极性翻转（极性翻转（Umpolung)俞凌翀，刘志昌，极性转换及其在有机合成中的应俞凌翀，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，1991Example 1 安息香缩合安息香缩合C6H5CHOCN-C6H5CHOCNC6H5COHCNC6H5CHOC6H5COHCNCHOC6H5C6H5COCHOHC6H5-CN-Example 2 醛氰醇法醛氰醇法CH3CHOCN-CH3COHCNC6H5CHOSiMe3CNCH3COHCNH3OM

28、e3SiCl1)LDA2)BrCH3COSiMe3CNOHCH3CO85%Example 3 1,3 二噻烷法二噻烷法SHSH+RCHOHCl/CH3ClSSRHBuLiSSRLiRXSSRRH3O+/Hg 2+ORR不易发生不易发生Michael 加成反应。加成反应。Example 4 乙基乙硫甲基亚砜法乙基乙硫甲基亚砜法SSC2H5OC2H51)LDA2)RXSSC2H5OC2H5R1)RX2)H3O+RRO1)O2)H3O+ROOMicheal adition1,4 二酮二酮四、缩合反应四、缩合反应(Condensation)1.Aldol Reaction2.Michael Addit

29、ion3.Mannich Reaction4.Claisen Condensation5.Dieckmann Condrnsation6.Darzens Reaction7.Reformatsly reaction1.Aldol Reaction(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（Directed Aldol condensation)Metood 1 Preformed Lithium Enolates Z-eno

30、lates give predominantly syn(or threo)aldol products (thermodynamic enolates).E-enolates give predominantly anti(or erythro)aldol products(kinetic enolates).Example 1-Steric size of R1 affects diastereoselectivity Origin of Diastereoselectivitya.Z-enolates Diastereoselectivity for Z-enolate(giving s

31、yn aldol product)is maximized when R1 and R3 are sterically demanding(R1/R3 interaction is maximized).Diastereoselectivity also increases as metal is changed to boron.This is attritubted to a tighter T.S.(BO bond shorter,so R1/R3 steric interactions are magnified in T.S.for anti product).When R2 is

32、very large the R3/R2 gauche interaction R1/R3 1,3-diaxial interaction(Why?).b.E-enolates Diastereoselectivity increases as R1 and R3 become sterically large,and a switch to the boron enolate will increase selectivity.Diastereoselectivity may switch when R2 is very large(Why?).u Effect of R1u Effect

33、of R3u Effect of R2Metood 2 Preformed Boron Enolatesa.Z-enolate Preparation and Reactionsb.E-enolate Preparation and Reactions-Originally difficult to control but:c.Examples of more recent methods to control boron enolate geometryAldol Condensation with Chiral Enolates Ti enolate promoted Evans aldo

34、l(non-Evans syn aldol)Chelated and non-chelated Ti enolatesMetood 3 Acid-Catalysed Directed Aldol ReactionsR1R2OSiMe3R3TiCl4CH2Cl2R1R2R3OSiMe3OR4R5TiCl3ClCl-Me3SiClR1R2R3OTiCl3OR4R5H2OR1R2R3OHOR4R5 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（Small Organic Molecules Catal

35、ysted Aldol Reactions)OOOOOOAldolase Antibody 38C2Barbas,C.F.,III et al.J.Am.Chem.Soc.1997,119,8131L-ProlineHajos-Eder-Sauer-Wiechert reactionHajos,Z.G.et al.J.Org.Chem.1974,39,1615Eder,U.;Sauer;G.,Wiechert,R.Angew.Chem.Int.Ed.Engl.1971,10,496However,the proline-catalyzed direct intermolecular asymm

36、etric aldol reaction has not been described.Further,there are no asymmetric small-molecule aldol catalysts that use an enamine mechanism.Based on our own results and Shibasakis work on lanthanum-based small-molecule aldol catalysts,we realized the great potential of catalysts for the direct asymmetr

37、ic aldol reaction.OHNO2ODMSONO2OOHOHNO2ODMSONO2OOHOHODMSOOOHRR+L-proline30mol%68%(76%ee)+different amino acid30mol%+L-proline30mol%L-proline is bestyield:54-97%;%ee:60-96%OHNHOOHNHOOHOHNOOHNHOOHNOOHOHRHRCHONOOHOHRH2ONOOHOHOHRHOOHRHNHOOH+-H2O-+abcd+-+-+gef Proposed Enamine Mechanism of the Proline-ca

38、talyzed Asymmetric Aldol ReactionCarlos F.Barbas III et.al.J.Am.Chem.Soc.2000,122(10),2395-6Catalytic Asymmetric Synthesis of anti-1,2-DiolsOHHROODMSOOOHOH+L-Proline20-30mol%r.t.24-72hsyn:anti:15:1-20:1;yield:38-95%;%ee:67-99%Carlos F.Barbas III et.al.J.Am.Chem.Soc.2000,122(30),7386-7Proline-Catalyz

39、ed Asymmetric Aldol Reactions betweenHOOOOH+L-Proline10-20mol%3-7 dyield:A 22-35%,B 35-50%;%ee:36-73%RROR+20 vol%ABOOHRORABHOROL-ProlineL-ProlineNCO2-HR+ONCO2HRO-ProlineCompound B wasformed via Mannich CondensationKetones and a-Unsubstituted AldehydesBenjamin list et al.Org.Lett.2001,3(4),573-575CHC

40、l3RORArCHORORArOH+amino acidBarbas,C.F.etal.J.Am.Chem.Soc.2001,123(22),5260-5267HOXHOXOH+HOYYenantioselectivecatalystHOMeHOMeOHMeNHCO2HHR2OHOR1R2OH10mol%DMF,4oC anti:syn:3:1-24:1%ee:91:99HOR1+L-proline yield:75-88%MacMillan D.W.C.et al.J.Am.Chem.Soc.2002,124(24),6798-679910mol%DMF,4oC80%yield,4:1 an

41、ti:syn,99%eeThe First Direct and Enantioselective Cross-Aldol Reaction of AldehydesNovel Small Organic Molecules for a Highly Enantioselective Direct Aldol ReactionJ.AM.CHEM.SOC.2003,125,5262-5263Zhuo Tang,Fan Jiang,Luo-Ting Yu,Xin Cui,Liu-Zhu Gong,*,Ai-Qiao Mi,Yao-Zhong Jiang,and Yun-Dong Wu*Key La

42、boratory 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 Structur

43、es,College of Chemistry and Molecular Engineering,Peking UniVersity,Beijing,100871,China2.Michael Addition ReactionEWGCH2RRRREWG+:BRCHCRREWGGWECHREWG,EWG=-CHO,-CO-,-COR,-CN,-NO2,-SO2R et al.Applications:Synthesis of 1,5-dicarbonyl compounds General Scheme Development:Asymmetry Michael Addition React

44、ionO+CO2BnCO2Bn10 mol%Li-Al-(R)-BiNolTHF,r.t.,72 hOCH(CO2Bn)2H88%,99%eeArai T.et al.,Angew.Chem.Int.Ed.,1996,35,104 手性金属配位化合物催化手性金属配位化合物催化NHNOMeMeMePhR1O-ONRZONZRONZR1CHOCHORR1XRORCHOXANRXZOMeNO2-H2OTHF-H2ONRXZDiels-Alder Reaction1,3-Dipolar Cycloaddition+20mol%A-HCl23oCyiled:72-90%;%ee:83-96%endoex

45、oendo:exo:80:20-99:1%ee:90-99%yield:66-98%J.Am.Chem.Soc.2000,122(17),4243-4244J.Am.Chem.Soc.2000,122(40),9874-9875+20mol%A-HClO4-20oC20mol%A-TFAyiled:74-87%;%ee:89-97%J.Am.Chem.Soc.2001,123(18),4370-4371OMacmillan Groups Work Small Organic Molecule catalyzed asymmetric Michael reactionsNRXZO+20mol%A

46、-TFATHF-H2ONRXZ74-87%91-99%eeJ.Am.Chem.Soc.2001,123(18),4370-4371NHNOMeMeMePhANMeO+20mol%A-TFA85%56%eeMeNMeOMeCH2Cl2,-40oCNHNOMePhMeMeMeBONRO+20mol%B-TFAMeNMeORCH2Cl2-i-PrOHHX=TFASolvent:CH2Cl2-i-PrOHOptimal conditions:NMeO+20mol%B-HXMeNMeOMesolvent74-89%90%eeNMeO+RNROMe20mol%B-TFACH2Cl2-i-PrOH70-94

47、%89%eeZYZYJoel F.Austin and David W.C.MacMillan*,J.Am.Chem.Soc.2002,124(7),1172-1173The First Enantioselective Organocatalytic Mukaiyama-Michael Reaction:OR3SiOMeOMeOOOHOHMeOOHOR3SiOMeONHNOMeMeMeMePh+Lewis Acid(Mukalyama-Aldol)+AmineCatalystLewis acid catalysis:1,2-additionOrganocatalysis:1,4-additi

48、on(Mukalyama-Michael)CatalystROOOMeOTMSORO+AmineCatalystMeR=Me,Pr,i-Pr,Ph,CH2OBz,CO2MeYield:77-87%,%ee:84-99MeOOOROTMSOMeO+AmineCatalystRR=H,Me,Et,CO2MeYield:73-87%,%ee:90-98 S.P.Brown,N.C.Goodwin,and D.W.C.MacMillan*,J.Am.Chem.Soc.2003,125(5),1192-11943.Mannich Reaction General SchemeR2CHO+R3CH2CR4

49、OH+NHRR1NCHCHCR4RR1OR3R2 胺组份胺组份 氨、伯胺、仲胺氨、伯胺、仲胺 醛组份醛组份 HCHO,PhCHOHCHO,PhCHO,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。HHNHMeMeOHCHONMeOMeExample 2Example 1O+HCHO +HNMe2HCl.ONMe2OOEtOOMichael additionOCO2EtH3COAldol reactionCO2EtO1)OH2)H/-

50、CO2-+O Development:Asymmetry Mannich Reaction 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)I

51、shitani,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.2002,12

52、4,5640.(a)Notz,W.;Sakthivel,K.;Bui,T.;Zhong,G.;Barbas,C.F.,III Tetrahedron 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)Co rdova,A.;Notz,W.;Zhong,G.;Betanco

53、rt,J.M.;Barbas,C.F.,III J.Am.Chem.Soc.2002,124,1842;(f)Co rdova,A.;Watanabe,S.-i.;Tanaka,F.;Notz,W.;Barbas,C.F.,III J.Am.Chem.Soc.2002,124,1866.Small Organic Molecule catalyzed asymmetric Mannich reactionsThe Direct Catalytic AsymmetricThree-Component Mannich ReactionODMSOO+L-Proline35mol%r.t.HROODM

54、SO+L-Proline12-48hCHONH2OMe+12h50%NH-PMP94%ee35mol%p-anisidine(1.1eq.)ONH-PMPRR=NO2i-Pr-i-Bu-n-Bu-yield:35-90%;ee:73-96%ODMSOO+L-Proline35mol%r.t.CHONH2OMe+12h50%NH-PMPR1R2R2R1a.R1=H,R2=Me,99%ee;b.R1=H,R2=OMe,98%ee,yield 93%R1=Me,R2=H,94%ee;total yield 96%Benjamin List.J.Am.Chem.Soc.2000,122(38),933

55、6-7The Direct and Enantioselective,One-Pot,Three-Component,Cross-Mannich Reaction of AldehydesAngew.Chem.Int.Ed.2003,42,3677 3680Y.Hayashi,W.Tsuboi,I.Ashimine,T.Urushima,Dr.M.ShojiDepartment of Industrial Chemistry,Faculty of EngineeringTokyo University of Science,KagurazakaThree-component Mannich r

56、eaction with various acceptor aldehydesN-methyl-2-pyrrolidinone(NMP)Three-component Mannich reaction with various donor aldehydes.4.Claisen Condensation General Scheme2RCH2CO2EtB:RCH2CCHCO2EtRO MechanismRCHCOEtOB:HRCHCOEtO-+RCHCOHOEtRCHCOHOEtRCHCOEtO-EtO-RCH2CCHCO2EtRO 一种酯的自身缩合一种酯的自身缩合 Scope of appl

57、ication 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 ExamplesNCO2Et+NaHNCOCHCO2EtEtEtCH2CO2EtCO2EtCO2Et+PhCH2CO2EtEtONaEtOHCOCHCO2EtPhCO2Et-175oC-COCHPhCO2EtCO2Et Directed Claisen condensation LDARCHCO2EtRCOClRCHCO2EtCORRCH2CO2EtCO2MeCO2MeNLiCO2MeO5.Dickmann Condensation(CH2)nCO2EtCO2EtB:(CH2)n-1OCO2Et

58、分子内Claisen 缩合反应Chapter 3 Formation of Carbon-Carbon Doule Bonds1.-Elemination reactions（-消去反应消去反应）CCHXCC+HXX=-OH,-OCOR,卤素,-OSO2Ar,-N+R3,-S+R2 et al.RegioselectivitySaytzeff ruleHofmann ruleX=-OH,-OCOR,卤素,-OSO2Ar,X=-N+R3,-S+R2StereoselectivitySyn eliminationAnti eliminationHofmann eliminationsSaytzef

59、f eliminationsAnti eliminationI.The Synthetic Methods of Alklenes 2.Pyrolytic syn eliminations（顺式热消去反应（顺式热消去反应）CCHOCC+RCO2HRO300 500oCApplications:Synthesis of terminal alkenes from primary acetatesDisadvantages:High reaction temperatureCH3CH2CH2CH2OCOCH3500oCN2CH3CH2CH=CH2100%CCHOCC+HSCSRSRS100 200

60、oCOCope reactionCCHNR2CC+R2NOHO100 200oCChugave reaction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.Wittig and related reactions（Wittig 及有关反应）及有关反应）Wittig Reaction G.Wittig received the 1979 Nobel Prize in Chemistry for many significant contributions to Organic Chemistry which included not only the Wittig react

61、ion,but also PhLi prepared by metal-halogen exchange,benzyne,and the Wittig rearrangement.COR(H)R+CHRRX+CCRRRR(H)Ph3P General Scheme Mild reaction conditions;The position of the double bond is unambiguous.FeaturesOMeMgI1)2)H+HOMeCH2Ph3P=CH2-H2OCH3CH2+Representative Examples Example 1Example 2Example

62、 3Example 4 Mechanism 2+2 cycloaddition.-Ph3P-CH2CH3+EtCHO+DMF+LiC6H6+LiZ/E96/4 0/100PhCH=CHEtPh3PO Influence of solvent on the selectivity Activity and stereoselectivity of Yild Ph3P-CHR-R=alkyl，EDGR=R=EWGalkenyl or alkynylStereoselectivityZ-(major)Z/E (mixture)E-(major)Stabilityincrease Schlsser m

63、odification:allows the preparation of trans vs.cis olefins.Schlsser Angew.Chem.,Int.Ed.Eng.1966,5,126.An extension of this method An extension of this method can be used to prepare allylic alcohols.Instead ofbeing protonated,the -oxido ylide is allowed to react with formaldehyde.The -oxidoylide and

64、formaldehyde react to give,on warming,an allylic alcohol.Entry 12 is anexample of this reaction.The reaction is valuable for the stereoselective synthesis ofZ-allylic alcohols from aldehydes Stabilized Ylides-Stabilized ylides are solid;stable to storage,not particularly sensitive to moisture,and ca

65、n even be purified by chromatography.-Because they are stabilized,they are much less reactive than alkyl ylides.They react well with aldehydes,but only slowly with ketones.-The first step,involving the addition to the aldehyde,is slow and reversible with stabilized ylides.Influence of solvent on the

66、 selectivity WadsworthHornerEmmons ReactionHorner Chem.Ber.1958,91,61;1959,92,2499.Wadsworth,Emmons J.Am.Chem.Soc.1961,83,1733.Reviews:Org.React.1977,25,73253.Comprehensive Org.Syn.,Vol.1,761.Preparation of Phosphonate EstersArbuzov J.Russ.Phys.Chem.Soc.1906,38,687.-Arbuzov Rearragement-The same approach to the preparation of-ketophosphonates is not successful:-But can use variation on Claisen conditions:Modifications and Scope-LiCl/tertiary amines(DBU,iPr2NEt,Et3N)Masamune,Roush Tetrahedron Let