浙江大学有机化学有机合成路线设计原理讲解

策略2. Disconnection on TMs without FG （无官能团时的切断策略）
—— adding FG （添加官能团）
+-
Br NaC
H
H+
Br
H
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O AlCl3
+ O
Cl
13
Br
Br
NH2
Br
Br
1. NaNO2, HCl Br
Br
2. EtOH
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1. Retrosynthetic analysis (逆合成分析)
In this procedure the target molecule is transformed progressively into simpler structures by disconnecting selected carbon-carbon bonds. These disconnections rest on transforms, which are the reverse of plausible synthetic constructions. Each simpler structure, so generated, becomes the starting point for further disconnections, leading to a branched set of interrelated intermediates. A retrosynthetic transform is depicted by the => symbol, as shown in next slide. Once a complete analysis has been conducted, the desired synthesis may be carried out by application of the reactions
CHO CHO
1.O3 2.Zn/AcOH
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CO2Me CHO
OMe Me
OMe Me
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OMe Li, liq. NH3 EtOH
Me Birch还原
OMe 1. O3, MeOH 2. Me2S
Me
CO2Me CHO
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4. Rearrangment
O
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MeO
HCl MeOH
MeO Li, liq. NH3
EtOH
30
（2）, -unsaturated carboxylic acid
Ar CO2H
Ar CHO + (CH3CO)2O
Perkin
Reaction
Ac2O, AcONa
O
CHO
150oC
O CH CHCO2H
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Symbol
CHO CHO
1.O3 2.Zn/AcOH
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策略1 Functional Group transforms （官能团转换）
NH2
H2 Pd/C
CN
Br
wenku.baidu.com
NaCN
OH
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OH
10
O PCC
OH
1. B2H6 2. H2O2
NaOH
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OO
R
R'
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O C+ R O
- R'
O
R OEt O
R'
34
O
CO2Et
1. NaOEt 2. H3O+
CO2Et CO2Et
1.KMnO4 2. EtOH,H+
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（5）1,4-bicarbonyl （1,4-二羰基化合物）
O R
R' O
OH R
CO2Et R'
28
4. Disconnection on Bifunctional groups （双官能团化合物）
（1）, -unsaturated compounds
O
O
R
R
R1 R2
Aldol
condesation
O +
R1 R2
O
O
O
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O
OR
OR
HCl MeOH
Li, liq. NH3 EtOH
O
O
CH3 CH OEt
R + NaX
O
O
O
O
CH3
1. NaOH, H2O
CH
OEt 2. H3O+
CH3
CH OH -CO2
R
R
O CH3CCH2R
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O
O
1. EtONa
CH3
CH2 OEt 2. RX
O
O
1. EtONa
CH3
CH OEt 2. R2X
R
OO
CH3 C OEt R R'
Introduction to Organic Synthesis 有机合成简介
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合成化学家在旧的自然界旁又建起了一个新 的自然界。
—— R. B. Woodward
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E. J. Corey Retrosynthetic analysis The Noble Prize in 1990
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（3）-Hydroxyester
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CO2Et OH
COCl
+ BrCH2CO2Et O
O +
-
CH2MgBr
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（4）1,3-bicarbonyl （1,3-二羰基化合物）
OO
R
OEt
O C+ R O
- OEt
O
R OEt O
OEt
Claisen缩合
H3C C C CH3
OH CH3 （iii）
O CH3
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OH
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OH
O
Claisen重排
O-Na+ + Br
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习题尝试逆合成分析并合成以下目标化合物）
O
O
OH
O
O
MeO
OH OH
OH
CO2H O2N
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O
O R
EtO2C +
R' O
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（6）1,5-bicarbonyl
CH2(CO2Et)2 + CH3COCH CH2
KOH EtOH
CH3COCH2CH2CH(CO2Et)2
——迈克尔（Michael）加成反应
O
O
R
R'
O
O
R
R'
CO2Et
O
O
R'
+
R
CO2Et
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underlying the transforms.
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Disconnection rest on transforms
Synthon
Equivalent
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Synthon （合成子) Equivalent （等价物）
O C+ R
OH C+ R R+
O C R Cl O
RH
O C R OR
RX
R-
R
C-
O CR
RMgX
R
C-Na+ R
CMgX
SS R Li
Polar Inversion 极性反转
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Polar Inversion 极性反转
O
O
C- + +
SS H
Br
SS Li
CHO
SS
NBS
O
aq. acetone
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O
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O CO2Et
O
O
CO2Et
OO OEt
+ Br
OO OEt
O+
38
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O
OO
+
O
O
39
Me + CH2
O
O CHCCH3
EtONa Michael加成
Me OO
NaOH 羟醛缩合
54%
Me 草酸
O
OH
86%
Me O
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（7）1,6-bicarbonyl
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CH2(CO2Et)2
1. EtONa, EtOH 2. n-C5H11Br
CH3(CH2)4CH(CO2Et)2
1. EtONa, EtOH 2. CH3I
80%
CH3(CH2)4C(CO2Et)2 CH3
1. OH2. H3O+,
CH3(CH2)4CHCO2H CH3
+
O
-O
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+ HO OH HO
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嚬哪醇重排：
CH3 CH3 H3C C C CH3
OH OH
CH 3 H3C C C CH3
OH CH3 （ii）
H
CH3 CH3
H2O
CH3 CH3
H3C C C CH2
H3C C C CH3
OH OH2
OH
（i）
CH 3
CH 3
H
H3C C C CH3
80%
99%
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3.2 Application of Ethyl Acetoacetate （乙酰乙酸乙酯）
OO OC2H5
酮式
pKa ＝ 11
H OO
OC2H5
烯醇式
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O
O
EtONa
CH3
CH2 OEt
O
O
CH3 CH OEt Na+ R X
O
O
CH3 CH OEt
R1 OH R2
R1 OH + -R2
R1 O
R2MgBr
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HO
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O +
CH2MgX
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HO HO
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H2 Pd/C
O
C4H9-n
1. Et2O 2. H3O+
+ n-C4H9
CMgX
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3.4 Disconnection on Cyclohexene （环己烯） a) D-A 反应
NH2
NH2
NH2 CN
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CN +
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策略3. Disconnection on TMs with mono FG
3.1Application of Malonic ester （丙二酸二酯，活泼亚甲基）
O R
CO2Et R
- CO2Et CO2Et
OH
CO2Et
1. NaOH, H2O
EtONa
R+
2. H3O+, -CO2
C-CO2Et CO2Et
RBr
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CH2(CO2Et)2
1. EtONa 2. RX
RCH(CO2Et)2 1. OH2. H3O+,
1. EtONa 2. R'X
RR'C(CO2Et)2
1. OH2. H3O+,
RCH2CO2H RR'CHCO2H
+ Diels-Alder Reacton
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CO2Et
CO2Et
CO2Et +
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b) Birch还原
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Na, liq. NH3
EtOH
OR
OR
Li, liq. NH3 EtOH
CO2R
CO2R
Li, liq. NH3 EtOH
Birch还原
OO
1. NaOH, H2O
2. H3O+
CH3 C OH R R'
-CO2
OR CH3CCH
R'
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O Ph
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O CO2Et Ph
O CO2Et + Cl Ph
O O + Br OEt
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3.3 Application of Epoxy compounds （环氧化物）