阅读书目
1.刑其毅主编
2.曾昭琼主编
3.宁永成主编
谱学
4.谢如刚主编
5.吴毓林主编
基础有机化学
有机化学实验
有机化合物结构鉴定与有机波
现代有机合成化学
现代有机合成化学
Asymmetric Organic Synthesis
Quan-Zhong Liu
Open Laboratory of Asymmetric Synthesis, China West Normal University
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
1999
2000
2001
备注
销售额
963
1230
1472
手性药物
52%
2. 手性的命名及相关术语
1). Fisher 规则
2). Cahan-Ingold-Prelog 规则
2). 相关术语
D- or Ld- 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
顺式/反式（syn/anti)、苏式/赤式(threo/erythro form)
苏式
赤式
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% * [a]测定/[a]绝对
核磁共振
手性位移试剂
HPLC
绝对构型的测定
4. Asymmetric Organic Synthesis
Chiral Resolution:
Kinetic Resolution:
Dynamic Kinetic Resolution:
Chiral induction:
Catalytic Asymmetric Synthesis:
Asymmetric Alkylation
1. Asymmetric Alkylation
1.1 Asymmetric Alkylation of tert-Butyl Glycinate Schiff Base
1) Cinchona derived phase transferred catalysts
金鸡纳生物碱的结构:
反应机理:
2) BINOL derived quternary ammonium catalyst
合成方法:
合成方法:
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
1.2 Asymmetric Alkylation of enolate
2. Coupling Reactions
2.1 Stille reaction
The Stille reaction (or Stille Coupling) is a chemical reaction
coupling an organotin compound with an sp2-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, CF3SO3The 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.
Reaction condition: inert atmosphere, dehydrated and degassed solvent ,
trimethylstannyls are more reactive than tributylstannyl but more poisonous
2.1.1 Mechanism
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.
2.2.2 Application
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
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
2. 2.2 Substrate scope
2. 2.3 Organoboranes
2. 2.3 Application
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
2. 3.1 Mechanism
2. 3.2 Application
2. 4 Kumada reaction
2. 5 Sonogashira reaction
3 Aldol reaction
3.1 Z-enolates and E-enolates
3.2 Aldol reaction of Z-enolates
3.3 Removal of Oxazolidinones
Transamination
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.
3. 5 Catalytic asymmetric aldol reaction
3.6 Organocatalytic direct aldol reaction
Amino acids and anologies
Angew. Chem. Int. Ed. 1971, 10, 496-497.
1. J. Am. Chem. Soc. 2000, 122, 2395
2. J. Am. Chem. Soc. 2001, 123, 5260
J. Am. Chem. Soc. 2005, 127, 9285
Org. Lett. 2005, 7, 4543.
Tetrahedron 2006, 62, 346.
Chiral diamines
1
2
Babars C. F., Angew. Chem. Int. Ed. 2004, 43, 2420
Babars C. F., J. Am. Chem. Soc. 2006, 128, 734
Yamamoto, H.; Tetrahedron 2002, 58, 8167.
Chen, J. J. Am. Chem. Soc. 2007, 129, 3074
Chen, J. Org. Lett. 2008, 10, 653.
Liu, Q. Org. Biomol. Chem. 2007, 5, 2913
Liu, Q. Tetrahedron Lett. 2008, 49, 7434
4. Asymmetric transformations catalyzed by chiral amines
4.1 Mannich Reactions
Lu, Y. Org. Biomol. Chem. 2007, 5, 1018
Lu, Y. Chem. Commun. 2007, 4143
Babars III, C. F. J. Am. Chem. Soc. 2007, 129, 288
Cordova, A. Tetrahedron Asymmetry, 2007, 18, 1033
Babars III, C. F. Adv. Synth. Catal. 2008, 350, 791.
Tsogoeva, S. B. Angew. Chem. Int. Ed. 2008, 47, 6624
4.2 Michael reactions
Alexakis, A. Chem. Commun. 2007, 3123
Connon, S. J. Org. Lett. 2007, 9, 599.
Cordova, A. Adv. Synth. Catal. 2006, 348, 418.
Tsogoeva, S. B. Chem. Commun. 2006, 145
Jacobsen, E. N. J. Am. Chem. Soc. 2006, 128, 7170
Feng, X. Adv. Synth. Catal. 2008, 350, 2001
Ma, J.-A. Org. Lett. 2007, 9, 923
Feng, X. Adv. Synth. Catal. 2007, 349, 2156
Chen, Y.-C. Synlett. 2008, 49, 3881
Lu, Y. Chem. Commun. 2008, 6315
4.3 Amination
Chen, Y.-C. Org. Lett. 2007, 9, 3671
4. 4 Primary amine-induced iminium activation
Chen, Y.-C. Org. Biomol. Chem. 2007, 5, 816
Melchiorre, P. Org. Lett. 2007, 9, 1403
Chin, J. Org. Lett. 2006, 8, 5239
Chen, Y.-C. Org. Lett. 2007, 9, 413
Chen, Y.-C. Angew. Chem. Int. Ed. 2007, 46, 389
Deng, J. Org. Biomol. Chem. 2008, 6, 349
Liang, X. Chem. Commun. 2008, 3302
Melchiorre, P. Adv. Synth. Catal. 2008, 350, 3302
Deng, L. Angew. Chem. Int. Ed. 2008, 47, 7710
Melchiorre, P. Eur. J. Org. Chem. 2007, 5492
Ishihara, K. Adv. Synth. Catal. 2006, 348, 2457
Ishihara, K. Org. Lett. 2006, 8, 2229
Deng, L. J. Am. Chem. Soc. 2008, 130, 2422
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
List, B. J. J. Am. Chem. Soc. 2008, 130, 6070
Deng, L. J. Am. Chem. Soc. 2008, 130, 8134
Zhong, G. Org. Lett. 2008, 10, 2437