1. 1. 刑其毅主编 基础有机化学 2. 曾昭琼主编 有机化学实验 3. 宁永成主编 有机化合物结构鉴定与有机波 谱学 4. 谢如刚主编 现代有机合成化学 5. 吴毓林主编 现代有机合成化学 阅读书目

2. Asymmetric Organic Synthesis Quan-Zhong Liu Open Laboratory of Asymmetric Synthesis, China West Normal University

3. 1. 有机不对称合成 : 从理论到实践 1). 手性是自然界的基本属性 手性 : chirality 2). 手性药物 手性药物的销售情况 年份 199920002001 备注 销售额 96312301472 手性药物 52%

4. 2. 手性的命名及相关术语 1). Fisher 规则 2). Cahan-Ingold-Prelog 规则

5. 2). 相关术语 D- or L- d- or l- 立体异构体、对映（异构）体、非对映（异构）体 对映（异构）体过量、对映选择性 对映选择性：一个化学反映中产生的某一个对映体多于其相应的异构体的程度 光学活性、光学异构体和光学纯度 外消旋、内消旋和外消旋化 racemization Re, Si

6. 顺式 / 反式（ syn/anti) 、苏式 / 赤式 (threo/erythro form) 苏式赤式

7. 3. 对映体组成的测定 比旋光度的测定 [a] 测定的旋光度 L 样品池的光路长度 dm C 浓度 g/mL 光学纯度或 ee 值 =100% * [  ] 测定 /[  ] 绝对 核磁共振

8. 手性位移试剂 HPLC 绝对构型的测定

9. 4. Asymmetric Organic Synthesis Chiral Resolution: Kinetic Resolution:

10. Dynamic Kinetic Resolution: Chiral induction:

11. Catalytic Asymmetric Synthesis:

13. Asymmetric Alkylation

14. 1. Asymmetric Alkylation

15. 1.1 Asymmetric Alkylation of tert-Butyl Glycinate Schiff Base 1) Cinchona derived phase transferred catalysts

17. 金鸡纳生物碱的结构 : 反应机理 : 2) BINOL derived quternary ammonium catalyst

18. 合成方法 :

19. 参考文献 : J. Am. Chem. Soc. 1989, 111, 2323-2355. J. Am. Chem. Soc. 1997, 119, 12414-12415. Org. Process Res. Dev., 2008, 12, 679–697 J. Am. Chem. Soc., 2005, 127,5073–5083

20. 1.2 Asymmetric Alkylation of enolate

24. 2. Coupling Reactions The Stille reaction (or Stille Coupling) is a chemical reaction coupling an organotin compound with an sp 2 -hybridized organic halide catalyzed by palladium. The reaction is widely used in organic synthesis. X is typically a halide, such as Cl, Br and I. Additionally, X can be a pseudohalide such as a triflate, CF 3 SO 3 - The Stille reaction was discovered in 1977 by John Kenneth Stille and David Milstein, a post-doctorate in his laboratory. Stille reactions were used in 50% of all cross-coupling reactions published in 1992. The reaction continues to be exploited industrially, especially for pharmaceuticals. 2.1 Stille reaction

25. 2.1.1 Mechanism Reaction condition: inert atmosphere, dehydrated and degassed solvent, trimethylstannyls are more reactive than tributylstannyl but more poisonous

26. Rate of ligand transfer (transmetalation) from tin: alkynyl > alkenyl > aryl > allyl = benzyl > α-alkoxyalkyl > alkyl The low reactivity of alkyl stannanes is a serious drawback but can be remedied by the use of strongly polar solvents such as, DMF or dioxane.

30. 2.2.2 Application

32. 2. 2 Suzuki Coupling Reactions Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457-2483. Suzuki, A. J. Organometallic Chem. 1999, 576, 147–168. The Suzuki reaction is the organic reaction of an aryl- or vinyl-boronic acid with an aryl- or vinyl-halide catalyzed by a palladium(0) complex. It is widely used to synthesize poly-olefins, styrenes, and substituted biphenyls, and has been extended to incorporate alkyl bromides

33. The scheme above shows the first published Suzuki Coupling, which is the palladium-catalysed cross coupling between organoboronic acid and halides. Recent catalyst and methods developments have broadened the possible applications enormously, so that the scope of the reaction partners is not restricted to aryls, but includes alkyls, alkenyls and alkynyls. Potassium trifluoroborates and organoboranes or boronate esters may be used in place of boronic acids. Some pseudohalides (for example triflates) may also be used as coupling partners. 2. 2.1 Mechanism

34. 2. 2.2 Substrate scope

36. 2. 2.3 Organoboranes

37. 2. 2.3 Application

39. 2. 3 Heck Reaction The Heck reaction (also called the Mizoroki-Heck reaction) is the chemical reaction of an unsaturated halide (or triflate) with an alkene and a strong base and palladium catalyst to form a substituted alkene. It is named after the American chemist Richard F. Heck. The reaction is performed in the presence of an organopalladium catalyst. The halide or triflate is an aryl, benzyl, or vinyl compound and the alkene contains at least one proton and is often electron-deficient such as acrylate ester or an acrylonitrile.The catalyst can be tetrakis(triphenylphosphine)palladium(0), palladium chloride or palladium(II) acetate. The ligand is triphenylphosphine or BINAP. The base is triethylamine, potassium carbonate or sodium acetate

40. 2. 3.1 Mechanism

42. 2. 3.2 Application

43. 2. 4 Kumada reaction 2. 5 Sonogashira reaction

45. 3 Aldol reaction

46. 3.1 Z-enolates and E-enolates

48. 3.2 Aldol reaction of Z-enolates

52. 3.3 Removal of Oxazolidinones

57. Transamination

58. 3.4 Diastereoselective Anti-Aldol Reactions of β-Ketoimides The C2 stereocenter is the dominant control element in these aldol reactions; "matched" vs. "mismatched" effects of the remote auxiliary are negligible.

62. 3. 5 Catalytic asymmetric aldol reaction

73. 3.6 Organocatalytic direct aldol reaction Angew. Chem. Int. Ed. 1971, 10, 496-497. Amino acids and anologies

75. 1.J. Am. Chem. Soc. 2000, 122, 2395 2.J. Am. Chem. Soc. 2001, 123, 5260

77. J. Am. Chem. Soc. 2005, 127, 9285 Tetrahedron 2006, 62, 346. Org. Lett. 2005, 7, 4543.

78. Chiral diamines Babars C. F., Angew. Chem. Int. Ed. 2004, 43, 2420 Babars C. F., J. Am. Chem. Soc. 2006, 128, 734 12

79. Yamamoto, H.; Tetrahedron 2002, 58, 8167. Chen, J. J. Am. Chem. Soc. 2007, 129, 3074

80. Chen, J. Org. Lett. 2008, 10, 653.

81. Liu, Q. Org. Biomol. Chem. 2007, 5, 2913 Liu, Q. Tetrahedron Lett. 2008, 49, 7434

83. 4. Asymmetric transformations catalyzed by chiral amines 4.1 Mannich Reactions Lu, Y. Org. Biomol. Chem. 2007, 5, 1018

84. Lu, Y. Chem. Commun. 2007, 4143

85. Babars III, C. F. J. Am. Chem. Soc. 2007, 129, 288 Cordova, A. Tetrahedron Asymmetry, 2007, 18, 1033

86. Babars III, C. F. Adv. Synth. Catal. 2008, 350, 791. Tsogoeva, S. B. Angew. Chem. Int. Ed. 2008, 47, 6624

87. 4.2 Michael reactions Alexakis, A. Chem. Commun. 2007, 3123

88. Connon, S. J. Org. Lett. 2007, 9, 599. Cordova, A. Adv. Synth. Catal. 2006, 348, 418.

89. Tsogoeva, S. B. Chem. Commun. 2006, 145

90. Jacobsen, E. N. J. Am. Chem. Soc. 2006, 128, 7170

91. Feng, X. Adv. Synth. Catal. 2008, 350, 2001 Ma, J.-A. Org. Lett. 2007, 9, 923

92. Chen, Y.-C. Synlett. 2008, 49, 3881 Feng, X. Adv. Synth. Catal. 2007, 349, 2156

93. Lu, Y. Chem. Commun. 2008, 6315 4.3 Amination Chen, Y.-C. Org. Lett. 2007, 9, 3671

94. 4. 4 Primary amine-induced iminium activation Chen, Y.-C. Org. Biomol. Chem. 2007, 5, 816 Melchiorre, P. Org. Lett. 2007, 9, 1403

95. Chin, J. Org. Lett. 2006, 8, 5239 Chen, Y.-C. Org. Lett. 2007, 9, 413

96. Chen, Y.-C. Angew. Chem. Int. Ed. 2007, 46, 389 Deng, J. Org. Biomol. Chem. 2008, 6, 349

97. Liang, X. Chem. Commun. 2008, 3302 Melchiorre, P. Adv. Synth. Catal. 2008, 350, 3302

98. Deng, L. Angew. Chem. Int. Ed. 2008, 47, 7710 Melchiorre, P. Eur. J. Org. Chem. 2007, 5492

99. Ishihara, K. Adv. Synth. Catal. 2006, 348, 2457

100. Ishihara, K. Org. Lett. 2006, 8, 2229 Deng, L. J. Am. Chem. Soc. 2008, 130, 2422

101. MacMillan, D. W. C. J. Am. Chem. Soc. 2000, 122, 9874 List, B. J. Angew. Chem. Int. Ed. 2005, 44, 108, MacMillan, D. W. C. Acc. Chem. Rev. 2007, 40, 1327

102. List, B. J. J. Am. Chem. Soc. 2008, 130, 6070

103. Deng, L. J. Am. Chem. Soc. 2008, 130, 8134 Zhong, G. Org. Lett. 2008, 10, 2437