紫杉醇手性侧链的合成.pptVIP

紫杉醇手性侧链的不对称合成 师少宇 2010、9、 12 Best wishes to our laboratory 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。 全合成 半合成 Holton； Nicolaeu 1994[2] 人工合成 植物提取 紫杉醇手性侧链的不对称合成方法 1 2 3 4 1由? -苯基环氧丙酸酯合成 由?-内酰胺合成 CAN Several classic replacement H to F replacement -OH to -NH2 or –SH Halogen replacements Ring replacements -COOH replacements 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 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 Examples Examples 3. Halogen replacements -CN and -CF3 may be used as alternative electron-withdrawing 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 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 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. Indomethacin Tetrazole derivative Tetrazoles are used in drugs as replacements for CO2H by change the pKa. Anti-arthritis drug - Non steroidal anti-inflammatory drug – reduces fe