高等有机合成cc单键的形成

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,2019/7/7,#,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,Condensation,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,