有机合成路线设计原理

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OMe CO2Me CHO
OMe
Me
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
-
+ HO
O
OH HO
CH3I + CH2 (CO2Et)2
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1. EtONa, EtOH CH2(CO2Et)2 1. EtONa, EtOH CH3(CH2)4CH(CO2Et)2 2. CH I 2. n-C5H11Br 3
80%
1. OH CH3(CH2)4C(CO2Et)2 2. H3O+, CH3
Birch还原
Li, liq. NH3 EtOH
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4. Disconnection on Bifunctional groups （1）, -unsaturated compounds
O R R1 R2 Aldol condesation R
O + R1
O R2
O O
O
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Application of Epoxy （环氧）compounds
R1 R1 R2 OH +
-
OH
R1 O
R2
R2MgBr
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O HO + CH2MgX
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HO H2 Pd/C O HO + C4H9-n 1. Et2 O 2. H3O+ n-C4H9 CMgX
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嚬哪醇重排：
CH3 CH3 H3C C C CH3 OH OH
H
CH3 CH3 H3C C C CH2 OH OH2 CH3 H3C C C CH3
H2O
CH3 CH3 H3C C C CH3 OH （i）
CH3 H3C C C CH3 （ii）
H H3C C O
CH3 C CH3 CH3
OH CH3
OH CH3 （iii）
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OH
OH
O
Claisen 重排
O -Na+ + Br
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5. Examples
O OH OH HC C-Na+ H2 SO 4 HgSO4
O
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O O + Cl
Zn-Hg HCl
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5
Synthon
O C+ OH C+ R+
Equivalent
O C O R RX H O C
R
R
Cl
R
OR
R
RR O R CC-
RMgX R C-Na+ R CMgX
S R
S Li
Polar Inversion
极性反转
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Polar Inversion
O O C+ +
Br S S Li
KOH EtOH CH3COCH2CH2CH(CO2Et)2
CH2(CO2Et)2 + CH3COCH CH2
——迈克尔（Michael）加成反应
O O R O R' R CO 2Et O O O R' R CO2Et + R'
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O
O CO 2Et O
O CO 2Et
O
O OEt O O OEt
n-C3H7
NH2
H2, R-Ni
NO 2
n-C3H7 n-C3H7COCl +
O
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Br Me Me
Br NH2 Me
Br NHAc
Me
NH2
Me
NHAc
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O O OH MeO OH CO2H O2N
O
O
OH OH
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+ CO2Et OH O
BrCH2CO2 Et
O COCl + -
CH2MgBr
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（4）1,3-bicarbonyl
O O R O OEt Claisen缩合 O O R O R' 2014-7-18
O R OEt O OEt OEt
C+ R O
O R OEt O R' R'
OH
CH3 MgI + OH +
O
COCl
O C+
+ CH3MgI
CO2Et
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O OMe
OH O + OMe MeOMa
+
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OH CO2Et Zn
CHO + BrCH2CO 2Et
CO2H
COCl
CO2Et
CO2Et
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n-C3H7
n-C3H7
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C+ R O
O CO 2Et 1. NaOEt 2. H3O+
CO2Et CO2 Et 1.KMnO 4 2. EtOH,H+
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（5）1,4-bicarbonyl
O R' R O R
OH
CO2Et R' O
O R
EtO2C + O
R'
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（6）1,5-bicarbonyl
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COH Ph Ph Ph OH +C Ph
Ph
CMgBr
O H Ph
合理的切割 合成子 等价试剂
Disconnection rest on transforms
Synthon
Equivalent
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C+ OH Ph Ph Ph OH -C Ph
不合理的切割
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Disconnection on Cyclohexene
+
Diels-Alder Reacton
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CO2 Et
CO2 Et +
CO2Et
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Na, liq. NH3 EtOH OR OR
Li, liq. NH3 EtOH CO2R CO2R
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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 underlying the transforms.
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O
OR
OR
HCl MeOH
Li, liq. NH3 EtOH
O
MeO HCl MeOH Li, liq. NH3 EtOH
MeO
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（2）, -unsaturated carboxylic acid
Ar Ar CHO + Perkin Reaction (CH3CO)2 O
54
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A synthesis of N-ethyl-2-aminomethylspiro[3.3]heptane from starting compounds having no more than three contiguous carbon atoms is required.
CO2H
O
Ac2O, AcONa 150oC CHO
O
CH CHCO2H
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（3）-Hydroxyester
O OH O CO 2Et OH R' + R (H) O CO 2Et R' R(H) O Br + Zn CO 2Et
R'
R (H)
Reformatsky 反应
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2. Disconnection on TMs without FG —— adding FG
TM： targeted molecule 目标分子
+ -
Br
NaC
H
H
+
Br
H
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O + AlCl3 Cl O
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NH2 Br Br Br Br
O OEt Na+ O OEt R X CH3
O CH R + NaX
O OEt
O CH3 CH R
O OEt 1. NaOH, H2O CH3 2. H3O+
O CH R
O OH -CO2
O CH3CCH2R
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O CH3 CH2
O
O 1. EtONa OEt 2. RX CH3 CH R
Br
+
O
+
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O
O
O
+ O O
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Me + CH2 O
O CHCCH3
Me EtONa Michael加成 OO NaOH 羟醛缩合 54%
Me 草酸 OH O 86%
Me
O
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（7）1,6-bicarbonyl
CHO CHO 1.O3 2.Zn/AcOH
IntrHale Waihona Puke Baiduduction to Organic Synthesis 有机合成初步
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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
20世纪 E. J. Corey Retro-synthetic analysis 逆合成分析 The Noble Prize in 1990 《The Logic of Chemical Synthesis》
S
S H
CHO
S
S
NBS aq. acetone
O
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Symbol
CHO CHO 1.O3 2.Zn/AcOH
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Functional Group transforms
NH2
CN
Br
H2 Pd/C
NaCN
OH
OH
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O PCC
OH 1. B2H6 2. H2O 2 NaOH
O 1. EtONa OEt 2. R X 2 CH3
O C R
O OEt R'
O 1. NaOH, H2O CH3 2. H3O+ C R
O OH R' -CO2
R CH3CCH R'
O
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O
O
O CO2Et
CO2Et
+ Cl
Ph
Ph
Ph
O
O
Br + OEt
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NH2
Br
1. NaNO2, HCl 2. EtOH
Br
NH2
NH2
CN
CN +
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3. Disconnection on TMs with mono FG Application of Malonic ester
O R R OH 1. NaOH, H2O 2. H3O+, -CO2 CO2Et CO2Et EtONa CO2Et CO2Et R+ C
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A synthesis of 2-acetyl-2-methylbicyclo[2.2.2]octane from cyclohexene and other starting compounds having no more than four contiguous carbon atoms is required.
-
CO2Et CO2Et
RBr
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CH2(CO2Et)2
1. EtONa 2. RX
RCH(CO2Et)2 1. EtONa 2. R'X RR'C(CO2Et)2
1. OH2. H3O+, 1. OH2. H3O+,
RCH2CO2H
RR'CHCO2H
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CH3(CH2) 4Br CH3(CH2) 4CHCO2H CH3 CH3(CH2) 4CH(CO2 Et)2 CH3 + CH3CH2(CO2Et)2
CH3(CH2)4CHCO2H CH3
80%
99%
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Application of Ethyl Acetoacetate
H O O OC2H5 O O OC2H5
酮式
烯醇式
pKa ＝ 11
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O CH3 O CH3 CH2 O OEt CH3 EtONa O CH CH