高等有机合成.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),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,3,1,3diaxial 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.;UenoM.;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).,-StillGennari 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:,-RambergBacklund 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,4and 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 alJ.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,Example 2,Example 3,10.Alkenes from arylsulphonylhydrazones (,由芳基磺酰腙制备烯烃）,Kolonko K.,et al.,J.Org.Chem.,1978,43,1404;,Adlington R.M.,et al.,Acc.Chem.Res.,1983,16,55,Mechanism,Less substituted alkene,Example 1,Example 2,11.Fragmentation Reactions(裂解反应）,X=leaving group,e.g.:-OSO,2,C6H,4,CH,3,-,p,-OSO,2,CH,3,100%stereospecific,Example,12.Olefin Inversion Reactions(,烯烃构型转换反应）,Deoxygenation,of,epoxides,(with retention of geometry),Other examples,13.Srereospecific synthesis of alkenes from 1,2-diols,(由1,2-二醇立体选择性地合成,烯烃）,CoreyWinter Olefin Synthesis,Corey J.Am.Chem.Soc.,1963,85,2677.,Corey J.Am.Chem.Soc.,1965,87,934.,Eastwood