紫杉醇手性侧链的合成

Holton； Nicolaeu 1994[2]
全合 成
半合成
O Ph Ph OH OH H OcA OcA O OcA NH O o O OH
人工合成
植物提取
紫杉醇手性侧链的不对称合成方法
O
1 2 3 4
Ph
HN Ph
CO2R
O
O Ph Ph NH O oR OH
OAc
Ph
Ph
NR1
NO2
O Ph CO2R
Preparation of tetrazoles
inspiration to our woking
R
R N N N O O O O
HN O
O NH
O O
O O
H3CO H3CO
OCH3
H3CO H3CO
OCH3
inspiration to our woking
O H N N O N H
R N N N
来自百度文库
1. H to F replacement
Fluorine has similar size with hydrogen most electronegative halogen, C-F bond very stable Ideal replacement to study the effect of electronegativity change . Thus, F (or other halogens when size is not critical) are frequently place on easily oxidized aromatics, Methyl groups often substituted by CF3
Examples
Examples
3. Halogen replacements
-CN and -CF3 may be used as alternative electronwithdrawing groups instead of halogens. The two groups have comparable effects on electronics, but -CN will increase the overall hydrophilicity.
Ring replacements
-COOH replacements
Carboxyl group may be replaced in order to alter acidity, or modify lipophilicity without affecting pKa.
Tetrazoles have comparable pKa with carboxylic acids, but greater lipophilicity
Tetrazoles are used in drugs as replacements for CO2H by change the pKa.
H O H Me N O Cl
Indomethacin
O Me N O Cl O
N N N N
Tetrazole derivative
Anti-arthritis drug - Non steroidal anti-inflammatory drug – reduces fever, pain, stiffness, delays premature labour & other uses
PMP N
O
PMP N Ph NEt3
Ph OAc
CAN
O
1) 2)
Ph
LDA
TMS N
HN Ph OAc
TMSCl\MeOH
PhCOCl NEt3
O O Ph Ph N OPG
KOH或
TMSCl\MeoH
Ph
NH2 COOMe POG
Several classic replacement
H to F replacement -OH to -NH2 or –SH Halogen replacements Ring replacements -COOH replacements
161: dopamine D3 inhibitor 162: maintained affinity for the dopamine D3 receptor and introduced modest selectivity over the dopamine D2 receptor. 163: exhibits dopamine D3 and dopamine D4 binding affinities comparable to those of the atypical neuroleptics sultopride and clozapine.
NH3 EtOH
NaN3 ,ZnCl2
NH2 O Ph OH
1)Ba(OH)2 2)PhCOCl
N3 O
NH2
Ph OH
1)PhCOCl 2)H2,Pd\C
OR
O Ph Ph OH NH O oR
1由 -苯基环氧丙酸酯合成
Ph
O CO2R
1) Ph
CH2OH
1)t-BuOOH,TI(Oi-Pr)4,L-(+)-DET 2)RuCl3,NaIO4;CH2N2
By changing ethyl ester with a bioisostere oxazole moiety, 151 is metabolically stable against esterases, maintains the selectivity and shows increased CDK2 inhibitory potency as well as potent antiproliferative activity in cancer cell lines
2) Ph
NaOCl,PPNO,Mn CO2Et
OH
3)
1)DQCB,NMO CO2Me 2)TsCl,Et3N Ph
Ph
CO2Me OTs
K2CO3
O
O N O
Ph
OH O 1)Bu2BOTf,NEt3 2)PhCHO
Ph
O N O LiOEt
Ph
4)
Br
Br
由-内酰胺合成
COCl OAc
O OEt OPG
2. -OH to -NH2 or –SH (also C=O to C=NH or C=S)
Replacement of -OH with -NH2 can stabilize a different tautomer, especially in the case of heterocyclic systems
O Ph Ph OH NH O OH Best wishes to our laboratory
紫杉醇手性侧链的不对称合成
师少宇 2010、9、 12
紫杉醇（taxol）:短叶红豆衫树皮中分离得到的具 有很强抗肿瘤活性化合物[1]，迄今3种最重要植物 来源抗癌药之一。
O Ph Ph OH OH H OcA OcA O OcA NH O o O OH
`R N H
R
O O O O
H3CO H3CO
OCH3
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