高等有机合成-全套课件.ppt

单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,高等有机合成,Advanced Organic Synthesis,绪 论,一、有机合成的历史回顾,二、有机合成化学的发展趋势,三、学习内容和方法,四、重要参考书及期刊,五、课程安排,一、有机合成的历史回顾,1.,尿素的合成（,1828,年，德国化学家,Wohler,）,有机化学的开始,2.,颠茄酮的合成,1)1902,年，德国化学家,Willstatter,(1915,年获,Noble,化学奖）,21 steps,overall yield 0.7%,2,）,1917,年，英国化学家,Robinson,(,1947,年获,Noble,化学奖）,3 steps,overall yield 90%,Robinson,为什么能是发现这条合成路线？,Mannich,Reaction(1912),3.,维生素,B,12,的合成（,Woodward,1977,年）,在,Woodward,及,Eschenmoser,领导下,经过两个实验室，,100,多位科学家的共同努力，于,1977,年完成了维生素,B,12,的全合成工作。,将有机合成作为一种艺术展现在世人面前。,因在,1945-1954,年人工合成了奎宁、类固醇、马钱子碱、羊毛甾醇、麦角碱等近,20,种复杂天然产物而,1965,年获,Noble,化学奖,E.J.Corey,(1990,年获,Noble,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,(,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 twenty-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（,High,Stereoselectivity,),原子经济性反应（,Atom Economical Reaction),绿色化学（,Green Chemistry),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,Epibatidine,的研究,Y(OTf),3,-catalyzed novel,Mannich,reaction of N-,alkoxy,-,carbonylpyrroles,formaldehyde and primary amine,hydrochlorides,C.X.,Zhuan,J.C.Dong,T.M.Cheng,R.T.Li*,Tetrahedron Letters,2001,43(3),461-463,Aldol,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,三、学习内容和方法,内容,1.,对重要的基础有机反应要能够熟练运用,新,化合物的合成,比葫芦画瓢,逆合成分析,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。,3.,学习别人的思路，创造性地借鉴和运用,方法,四、重要参考书及期刊,参考书,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,。,岳保珍，李润涛，有机合成基础，北京医科大学出版社，,2000,。,吴毓林，姚祝军，现代有机合成化学，科学出版社，,2001,。,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,。,黄宪，王彦广，陈振初，新编有机合成化学，化学工业出版社，,2003,。,王咏梅等，高等有机化学习题解答，南开大学出版社，,2002,。,Dale L.,Boger,Modern Organic Synthesis,The Scripps Research Institute,Tsri,Press,1999.,Comprehensive Organic Synthesis,Vol.1-9,期刊,Angew,.Chem.Int.Ed.,J.Am.Chem.Soc.,J.Org.Chem.,Org.Letters,Chem.,Commun,.,Tetrahedron,Tetrahedron Letters.,Tetrahedron,Asymm,.,Synthesis,Synlett,11.,Synth,.,Commun,.,12.,Eur,.J.Chem.,13.,Eur,.J.Org.Chem.,14.,Heterocyclics,15.J.Heterocyclic Chem.,16.J.Med.Chem.,Bioorg,.Med.Chem.,Bioorg,.Med.Chem.,Lett,.,Eur,.J.Med.Chem.,20.J.Comb.Chem.,五、课程安排,进度安排,2.,讲授原则,复习老反应，补充新反应，,重点讲进展，强调学思路。,考试,1,）,写综述一篇（近,5,年的进展）（,40%,）,2,）笔试（,60%,）,Chapter 2,Formation of Carbon-Carbon Single Bonds,一、,General Principles,烷化反应：,E=,烷化剂,缩合反应：,E=,醛、酮、酯等,Michael,加成：,E=,Mannich,反应,二、,影响反应的主要因素,a.,反应底物（,Substrate),-NO,2,-COR SO,2,R -CN -CO,2,R -Ph,SOR,A,和,B,至少要有一个是,EWG,A,和,B,应该能使其,-,碳上的,H,活化的基团，通常为吸电子基（,Electron withdraw group EWG,）。,b.,碱（,Base,）,常用的碱：,Ph,3,C,-,(Me,2,CH),2,N,-,EtO,-,OH,-,R,3,N,碱的选择取决于底物的反应活性,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（,Solvent),Solvent,O-,alkylation,C-,alkylation,反应速度,常用的非质子极性溶剂（,polar,aprotic,solvent):,DMF DMSO HMPA,d.,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。,例：,RX,R-SO,3,H,RCO,2,Et,RCOR,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。,三、烷基化反应,(,Alkylation,),1.O-,alkylation,&C-,alkylation,Example 1,Example 2,Degree of substitution of,alkylating,agent:,Example 3,2.,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很大,.,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,;,Example 1,Example 2,3.,立体选择性（,Steroselectivity,),烯醇化合物的立体选择性形成,将为不对,称合成提供平台,.,Example 1,Example 2,Example 3,Example 4,4.,二羰基化合物的,-,烷基化反应,(,-,Alkylation,of,1,3-,dicarbonyl,compounds,),J.Am.Chem.Soc.,1974,90,1082;,1963,85,3237;,1965,87,82.,Example 1,Example 2,Example 3,继承与发展,5.,芳基卤化物与烯醇盐的反应,(Reactions of aromatic halide with,enolates,),Example,Mechanism,关键是要有形成苯炔的条件。,6.,酮和酯的烷基化反应,(,Alkylations,of,ketones,and esters),避免,Aldol,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。,常用的碱：,NaNH,2,KNH,2,NaH,Ph,3,CNa,等；有副产物。,LDA,LTMP,LHMDS,等效果很好。,Example 1,Example 2,不对称酮的选择性烷基化反应,(Selective,alkylation,of asymmetric,ketones,),在一个,-,位引入一个活化基,(,略）,如：,Dieckmann,Reaction;,Claisen,condensation,制成结构专属性的烯醇负离子,在取代基较多的,-,位烷基化,(,烯醇硅醚法,),碱性条件,酸性条件,在取代基较少的,-,位烷基化,(,烯胺法,Stork,Enamine,Synthesis),通常，用活泼的卤代烷，可以高产率生成,C-,烷基化产物；,但对于一般的卤代烃，,C-,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,C-,烷基化产物。,对于不对称酮，主要在取代基较少的,-,位发生烷基化。,Example 1,Example 2,7.,对映选择性烷基化反应（,Enantioselective,alkylations,),利用手性胺,利用二甲基肼,扩展：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，而有机铜化合物在,C-C,键的形成中很有用。,利用,SAMP,和,RAMP,若,用,RAMP,，,则得到另一,种对映异构,体。,羧酸的,-,不对称烷基化,Example,8.,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 用，科学出版社，,1991,Example 1,安息香缩合,Example 2,醛氰醇法,Example 3 1,3,二噻烷法,不易发生,Michael,加成反应。,Example 4,乙基乙硫甲基亚砜法,1,4,二酮,四、缩合反应,(Condensation),Aldol,Reaction,Michael Addition,Mannich,Reaction,Claisen,Condensation,Dieckmann,Condrnsation,Darzens,Reaction,Reformatsly,reaction,Aldol,Reaction(condensation),1),经典,Aldol,反应的两大缺点,不同醛、酮之间的反应常得到混合产物；,立体选择性差,2),定向醇醛缩合反应（,Directed,Aldol,condensation),Metood,1 Preformed Lithium,Enolates,Z-,enolates,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 R,1,affects,diastereoselectivity,Origin of,Diastereoselectivity,a.Z-,enolates,Diastereoselectivity,for Z-,enolate,(giving,syn,aldol,product)is maximized when R,1,and R,3,are,sterically,demanding(R,1,/R,3,interaction is maximized).,Diastereoselectivity,also increases as metal is changed to boron.This is,attritubted,to a tighter T.S.(BO bond shorter,so R,1,/R,3,steric,interactions are magnified in T.S.for anti product).,When R,2,is very large the R,3,/R,2,gauche interaction R,1,/R,3,1,3-diaxial interaction(Why?).,b.E-,enolates,Diastereoselectivity,increases as R,1,and R,3,become,sterically,large,and a switch to the boron,enolate,will increase selectivity.,Diastereoselectivity,may switch when R,2,is very large(Why?).,Effect of R,1,Effect of R,3,Effect of R,2,Metood,2 Preformed Boron,Enolates,a.Z-,enolate,Preparation and Reactions,b.E-,enolate,Preparation and Reactions,-Originally difficult to control but:,c.Examples of more recent methods to control boron,enolate,geometry,Aldol,Condensation with,Chiral,Enolates,Ti,enolate,promoted Evans,aldol,(non-Evans,syn,aldol,),Chelated,and non-,chelated,Ti,enolates,Metood,3 Acid-,Catalysed,Directed,Aldol,Reactions,该方法是,在酸性条件,下反应；但,立体选择性,较差。,3),有机小分子催化醇醛缩合反应,（,Small Organic Molecules,Catalysted,Aldol,Reactions),Novel Small Organic Molecules for a Highly,Enantioselective,Direct,Aldol,Reaction,J.AM.CHEM.SOC.2003,125,5262-5263,Zhuo,Tang,Fan,Jiang,Luo,-Ting Yu,Xin,Cui,Liu-Zhu Gong,*,Ai-,Qiao,Mi,Yao-Zhong,Jiang,and,Yun,-Dong Wu*,Key Laboratory for Asymmetric Synthesis and,Chirotechnology,of Sichuan Pro,v,ince,Chengdu,Institute of Organic Chemistry,Chinese Academy of Sciences,Chengdu,610041,China,College of Chemical Engineering,Sichuan,Uni,V,ersity,Chengdu,610065,China,and State Key Laboratory of Molecular Dynamics and Stable Structures,College of Chemistry and Molecular Engineering,Peking,Uni,V,ersity,Beijing,100871,China,2.Michael Addition Reaction,Applications:Synthesis of 1,5-dicarbonyl compounds,General Scheme,Development:Asymmetry Michael Addition Reaction,手性金属配位化合物催化,Macmillan Groups Work,Small Organic Molecule catalyzed asymmetric Michael reactions,The First,Enantioselective,Organocatalytic,Mukaiyama,-,Michael Reaction:,S.P.Brown,N.C.Goodwin,and D.W.C.,MacMillan,*,J.Am.Chem.Soc,.2003,125(5),1192-1194,3.,Mannich,Reaction,General Scheme,胺组份 氨、伯胺、仲胺,醛组份,HCHO,PhCHO,RCHO,可分别发生三、双、单,Mannich,反应,活泼,H,组份,醛、酮、活泼亚甲基化合物、酚类化合物、杂环、炔等。,Example 2,Example 1,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),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.,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),Cordova,A.;,Notz,W.;,Zhong,G.;,Betancort,J.M.;,Barbas,C.F.,III,J,.,Am,.,Chem,.,Soc,.2002,124,1842;,(f),Cordova,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,reactions,The Direct and,Enantioselective,One-Pot,Three-Component,Cross-,Mannich,Reaction of,Aldehydes,Angew,.Chem.Int.Ed.2003,42,3677 3680,Y.Hayashi,W.,Tsuboi,I.,Ashimine,T.,Urushima,Dr,.M.Shoji,Department of Industrial Chemistry,Faculty of Engineering,Tokyo University of Science,Kagurazaka,Three-component,Mannich,reaction with various acceptor,aldehydes,N-methyl-2-pyrrolidinone(NMP),Three-component,Mannich,reaction with various donor,aldehydes,.,4.,Claisen,Condensation,General Scheme,Mechanism,一种酯的自身缩合,Scope of application,一种含,-H,的酯与一种不含,-H,的酯之间的缩合,Examples,Directed,Claisen,condensation,5.,Dickmann,Condensation,Chapter 3,Formation of Carbon-Carbon,Doule,Bonds,1.,-,Elemination,reactions,（,-,消去反应,）,I.The Synthetic Methods of,Alklenes,2.,Pyrolytic,syn,eliminations,（,顺式热消去反应,）,Applications:,Synthesis of terminal alkenes from primary acetates,Disadvantages:,High reaction temperature,Cope reaction,Chugave,reaction,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）,Wittig,Reaction,G.,Wittig,received the 1979 Nobel Prize in Chemistry for many significant contributions to Organic Chemistry which included not only the,Wittig,reaction,but also,PhLi,prepared by metal-halogen exchange,benzyne,and the,Wittig,rearrangement.,General Scheme,Mild reaction conditions;,The,position of the double bond is unambiguous.,Features,Representative Examples,Example 1,Example 2,Example 3,Example 4,Mechanism,2+2,cycloaddition,.,Influence of solvent on the selectivity,Activity and,stereoselectivity,of,Yild,Schlsser,modification: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 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 can 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 selectivity,W,adsworth,H,orner,E,mmons Reaction,Horner 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,Esters,Arbuzov,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,iPr,2,NEt,Et,3,N),Masamune,Roush Tetrahedron,Lett,.,1984,25,2183.,Can substitute for conventional conditions and is especially good for base sensitive substrates.,-Hindered,phosphonates,and hindered,aldehydes,increase E-selectivity(trans).,-Still,Gennari,modification selective for Z-alkenes(,cis,):,-Additional Z-selective stabilized,phosphonates,.,Selected,diarylphosphonates,provide High Z-selectivity as well.,Peterson Reaction,Reviews:Org.React.1990,38,1.,Peterson reaction offers an alternative to,Wittig,procedure.They are more reactive and,sterically,less demanding than a,Wittig,reagent and the volatile byproduct(Me,3,SiOH/Me,3,SiOSiMe,3,)is simpler to remove than Ph,3,PO.It does,however,require a second step to promote elimination of the,-,hydroxysilane,.,-The elimination is,stereospecific,:,acid-promoted being anti and base-promoted being,syn,.,Hudrlik,Peterson J.Am.Chem.Soc.,1975,97,1464.,Stabilized Peterson Reagents,-The stabilized Peterson,reagents,give predominantly,the most stable trans olefins(E),-Additional examples:,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）,-Tolerates,ketal,and,alkene,derivatives.,Scope defined by Evans and Grubbs J.Am.Chem.Soc.1980,102,3270.,Extended to tertiary amides by Pine J.Org.Chem.1985,50,1212.,For an analogous use of Cp,2,TiMe,2,:,Petasis,J.Am.Chem.Soc.1990,112,6392.,5.,Sulphoxide-sulphenate,rearragement,:Synthesis of,allyl,alcohols,(,亚砜,-,次磺酸酯重排：烯丙醇类化合物的合成,),Combined with,alkylation,of,sulphoxides,the reaction provides a versatile synthesis of,di,-and tri-substituted,allylic,alcohols,Evans and Andrews,Acc.Chem.Res.,1974,7,147,-,alkylation,of,allylic,alcohlos,Example,1,Example 2,6.Alkenes from,sulphones,(,由砜制备烯烃）,-Julia,Olefination,Review:Comprehensive Org.,Syn,.,Vol.1,792.,-Example:,Julia Tetrahedron,Lett,.,1973,4833.,Julia developed a more recent,single-step variant,that avoids the reductive elimination,Julia Bull.Soc.Chim.,Fr.,1993,130,336.,Julia,M.et al.,Tetrahedron,Lett,.,1973,4833,Kocienski,P.J.et al.,J.Chem.Soc.,Perkin,I,1978,829.,-Example:,-,Ramberg,Backlund,reaction,Org.React.,1977,25,1.,Base,-SO,2,Nicolaou,K.C.et al.,J.Am Chem.Soc.,1992,114,7360.,Boockman,R.K.et al.,J.Am Chem.Soc.,1991,113,9682.,Alvarze,E.et al.,J.Am Chem.Soc.,1995,117,1437.,7.,Decarboxylation,of,-,lactones(,-,内酯的脱羧反应）,Reformatsky,Reaction,Note:No,stilbene,was formed,Synthesis of tri-or,tetrasubsituted,alkenes,Example 1,Fehr,C.et al.Tetrahedron,Lett,.,1992,33,2465,Molbier,W.R.et al.J.Org.Chem.,1995,60,5378,Example 2,Example 3,Mulzer,J.,et al.,J.Chem.Soc.Chem.,Commun,.,1979,52,8.,Stereoselective,synthesis of tri-and tetra-substituted alkenes,(,三、四取代烯烃的立体选择性合成）,The first step is highly,stereoselective,.,The R,4,and the larger of the groups R,1,and R,2,are,anti,to each other.,Early Method,Cornforth,J.W.et al.,J.Chem.Soc.,1959,112,Development,Method 1,Corey,E.J.et al.,J.Am.Chem.Soc.,1967,89,4246.,Example,(54%;97%E),Method 2,Example:R=Et,Yield 72%,Zweifel,G.et al.,J.Am.Chem.Soc.,1967,89,2754.,Zweifel,G.et al.,J.Am.Chem.Soc.,1967,89,5085.,9.Oxidative,decarboxylation,of carboxylic acids,(,羧酸的氧化脱羧反应）,Sheldon,R.A.,et al.,Organic Reactions,1972,19,279.,Jahngen,B.G.E.,J.Org.Chem.,1974,39,1650.,与,Dieal,-Alder,反应结合，是制备环状烯烃的好方法。,Example 1,Tanzawa,T.et al.Tetrahedron,Lett,.,1992,33,6783,Ex