高等有机合成全套课件.ppt

1、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%,Robinso

2、n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

3、，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 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

4、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,Mec

5、hanism,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

6、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

7、： 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 Reactio

8、n 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

9、 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 pro

10、duct) 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

11、 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

12、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 E

13、vans 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

14、. 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

15、, 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: Syn

16、thesis 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.

17、 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

18、,(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.

19、 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.

20、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.

21、 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 Man

22、nich 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,

23、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 Claise

24、n 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 temper

25、ature,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 meta

26、l- 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,Activit

27、y 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

28、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;

29、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,

30、 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.,Pre

31、paration 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),M

32、asamune, 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-

33、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 volat

34、ile 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.,S

35、tabilized 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

36、 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 alkyla

37、tion 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

38、. 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.,-

39、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 Rea

40、ction,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 t

41、ri- 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,

42、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.,Jahnge

43、n, 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

44、., 1983, 16, 55,Mechanism,Less substituted alkene,Example 1,Example 2,11. Fragmentation Reactions (裂解反应）,X = leaving group, e.g.: -OSO2C6H4CH3-p, -OSO2CH3,100% stereospecific,Example,12. Olefin Inversion Reactions (烯烃构型转换反应）,Deoxygenation of epoxides (with retention of geometry),Other examples,13. S

45、rereospecific 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 Aust. J. Chem. 1964, 17, 1392. Eastwood Tetrahedron Lett. 1970, 5223.,Burgstahler, Boger Tetrahedron 1976, 32, 30

46、9.,14. 3,3-Sigmatropic Rearrangements,Claisen and Cope Rearrangement,Examples,Evans J. Am. Chem. Soc. 1975, 97, 4765.,Burgstahler J. Am. Chem. Soc. 1961, 83, 198.,Carnduff J. Chem. Soc., Chem. Commun. 1967, 606.,Thio-Claisen Rearrangement,An advantage of the thio-Claisen rearrangement is that the pr

47、ecursor can be deprotonated and alkylated.,Corey J. Am. Chem. Soc. 1970, 92, 5522. Yamamoto J. Am. Chem. Soc. 1973, 95, 2693 and 4446.,Block J. Am. Chem. Soc. 1985, 107, 6731.,The Carroll Reaction,Carroll J. Chem. Soc. 1940, 704, 1266. Hartung J. Chem. Soc. 1941, 507. Cope J. Am. Chem. Soc. 1943, 65

48、, 1992. Tanabe J. Am. Chem. Soc. 1980, 102, 862.,15. 2,3-Sigmatropic Rearrangements,Review: Comprehensive Org. Syn., Vol. 6, pp 834, 873908. Org. React. 1994, 46, 105209.,- Analogous to 3,3-sigmatropic rearrangement except it enlists a localized charge (anion) in place of a double bond.,Examples,Jul

49、ia Tetrahedron Lett. 1974, 2077.,Lythgoe J. Chem. Soc., Chem. Commun. 1972, 757.,Evans Tetrahedron Lett. 1973, 4691.,Amino-Claisen Rearrangement,- This reaction occurs best when nitrogen is converted to the ammonium salt.,Gilbert Tetrahedron Lett. 1984, 25, 2303. Stille J. Org. Chem. 1991, 56, 5578.

50、,Nakai Chem. Lett. 1990, 2069.,Sato J. Am. Chem. Soc. 1990, 112, 1999.,II. Olefin Synthesis Exemplified with Juvenile Hormone,(保幼激素的合成）,Juvenile Hormone （HJ),1. Trost Synthesis: J. Am. Chem. Soc. 1967, 89, 5292. 2. Syntex Synthesis: J. Am. Chem. Soc. 1968, 90, 6224. 3. Corey Synthesis: J. Am. Chem.

51、Soc. 1968, 90, 5618. 4. Johnson Synthesis: J. Am. Chem. Soc. 1968, 90, 6225. 5. Corey Synthesis: J. Am. Chem. Soc. 1970, 92, 6635, 6636, 6637. 6. Johnson Synthesis: J. Am. Chem. Soc. 1970, 92, 4463. 7. StotterKondo Synthesis: J. Am. Chem. Soc. 1973, 95, 4444. J. Chem. Soc., Chem. Commun. 1972, 1311.

52、 8. Still Synthesis: Tetrahedron Lett. 1979, 593. 9. Other Syntheses:,(1). Trost Synthesis,WadsworthHornerEmmons Reaction,Stereoselectivity - not much difference between Me and H (second atom steric effect) - both isomers obtained from the Wadsworth HornerEmmons reaction (Modern improvements now ava

53、ilable),Retrosynthetic Analysis - repeating subunits recognized - repeating reactions utilized,J. Am. Chem. Soc. 1967, 89, 5292.,(2). Syntex Synthesis,J. Am. Chem. Soc. 1968, 90, 6224.,Robinson Annulation Alkylation Diastereoselectivity Directed Epoxidation Reaction Fragmentation Reaction,Selective

54、Reduction - saturated vs. a,b-unsaturated carbonyl - ring strain associated with 5-membered ring carbonyl released on reduction - attack from least hindered face,THP Protecting Group - if R group contains chiral centers, diastereomers result - removed by mild acid,Thermodynamic Enolate - severe 1,3-

55、diaxial interaction in chair-like T.S. axial alkylation - no steric incumberance to axial alkylation on least hindered face of twist boat T.S.,LiAlH(OtBu)3 Reduction - large reagent, usually equatorial H delivery - 1,2-interaction (torsional strain) relatively invariant to Nu size - 1,3-steric inter

56、action highly dependent on Nu size - due to absence of axial C(3)H, large reagent now gives axial delivery,Epoxidation - in Et2O, coordination of peracid to solvent gives delivery from the least hindered a-face - in CH2Cl2, H-bonding of OH to peracid provides delivery to the less accessibleb-face -

57、Teranishi J. Am. Chem. Soc. 1979, 101, 159.,Fragmentation Reaction - utilized to control C=C bond stereochemistry - trans periplanar orientation of breaking bonds - dictates Z olefin geometry in product,3. Corey Synthesis,Dissolving Metal Reductions Cyclic Precursors to Trisubstituted Olefins Oxidat

58、ive Cleavage of Enol Ethers LiAlH4 Reduction of Propargyl Alcohols Cuprate Coupling Reactions Allylic Alcohol Oxidation,J. Am. Chem. Soc. 1968, 90, 5618.,Stereospecific Synthesis of Trisubstituted Olefins,MnO2 Oxidation - mild oxidation of allylic alcohols - direct, mild method for oxidation to a me

59、thyl ester,Epoxidation - selective - in polar solvent the molecule folds up such that the terminal C=C is more accessible,4. Johnson Synthesis:,Trimethyl pyridine,J. Am. Chem. Soc. 1968, 90, 6225.,5. Corey Synthesis: J. Am. Chem. Soc. 1970, 92, 6635, 6636.,1,5-H Shift,Diimide Reduction,- less substituted C=C reduced more rapidly - generated in-situ,6. Johnson Synthesis: J. Am. Chem. Soc. 1970, 92, 4463.,Olefinic Ketal Claisen Reaction - selectivity dependent on 1,3-interaction in chair-like T.S. - sec