高等有机合成 全套ppt课件.ppt

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B12 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B12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. LettersChem. Commun.TetrahedronTetrahedron Letters.Tetrahedron Asymm.SynthesisSynlett,11. Synth. Commun.12. Eur. J. Chem.13. Eur. J. Org. Chem.14. Heterocyclics15. 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),-NO2 -COR SO2R -CN -CO2R -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： Ph3C- (Me2CH)2N- EtO- OH- R3N 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- alkylationC-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-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：NaNH2, KNH2, NaH, Ph3CNa 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 ReactionMichael AdditionMannich ReactionClaisen CondensationDieckmann CondrnsationDarzens ReactionReformatsly 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 R1 affects diastereoselectivity,Origin of Diastereoselectivity,a. Z-enolates,Diastereoselectivity for Z-enolate (giving syn 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 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?).,Effect of R1,Effect of R3,Effect of R2,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 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, 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. ShojiDepartment of Industrial Chemistry, Faculty of EngineeringTokyo 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,WadsworthHornerEmmons 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, iPr2NEt, Et3N),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 (Me3SiOH/ Me3SiOSiMe3) is simpler to remove than Ph3PO. 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 predominantlythe 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 Cp2TiMe2: 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, 4833Kocienski, P. J. et al., J. Chem. Soc. Perkin I, 1978, 829.,- Example:,- RambergBacklund reaction,Org. React. 1977, 25, 1.,Base,- SO2,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 R4 and the larger of the groups R1 and R2 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,