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A Short Asymmetric Synthesis of Podophyllotoxin Related Antitumor Agent

鬼臼毒素相关抗肿瘤药物的简短不对称合成

基本信息

批准号：
01571143
负责人：
TOMIOKA Kiyoshi
金额：
$ 1.34万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1989
资助国家：
日本
起止时间：
1989 至 1990
项目状态：
已结题

项目摘要

Design and synthesis of podophyllotoxin related compound with antitumor activity and development of a novel strategy for the enantioselective asymmetric reaction have been successfully achieved.(1) Design and synthesis of azapodophyllotoxinSubstitution of a carbon atom by nitrogen atom alpha to the lactone carbonyl group of podophyllotoxin would be expected to solve the two problems, isomerization at the site and increase of electron density at the oxygen atom of the carbonyl group.Synthesis of the designed target has been successfully carried out in the short steps starting from the corresponding amino acid.(2) Development of the novel asymmetric reactionAn efficient asymmetric reaction relies on a rational design of three components complex constituted from organometallic reagent, substrate, and chiral ligand. We designed a model which has two stereocontrolling groups at the both sites of chelating heteroatoms up and down faces of the five membered chelate.Realization of the model complex would come from coordination of organolithium to a chiral diether which would form an expected complex. Reaction of organolithium with alpha, beta-unsaturated imines or esters in the presence of the chiral diether provided the corresponding conjugate addition products in high enantiomeric excess and in absolute configuration predicted from three component complex model.By employing a substoichiometric amount of the diether catalytic asymmetric carbon-carbon bond formation has also been realized in the reaction of aryllithiums with BHA esters of 1- and 2- naphthalenecarboxylic acid to provide the corresponding conjugate addition products in high ee.

本论文成功地设计合成了具有抗肿瘤活性的鬼臼毒素相关化合物，并发展了一种新的对映选择性不对称反应策略。(1)氮杂鬼臼毒素的设计与合成将鬼臼毒素内酯羰基α位的一个碳原子用氮原子取代，可望解决羰基位上的异构化和羰基氧原子上电子密度增加这两个问题，从相应的氨基酸出发，在短的步骤中成功地合成了所设计的目标化合物。(2)新型不对称反应的发展高效的不对称反应依赖于有机金属试剂、底物和手性配体组成的三元配合物的合理设计。我们设计了一个在五元螯合物的上、下两个螯合杂原子位置上都有两个立体控制基团的模型化合物，该模型化合物的实现是通过有机锂与手性二醚配位形成预期的配合物。有机锂与α反应，β-不饱和亚胺或酯在手性二醚存在下，以高对映体过量和三组分络合物模型预测的绝对构型提供了相应的共轭加成产物.通过使用亚化学计量量的二醚，在芳基锂与BHA的1-和2-酯的反应中，也实现了不对称碳-碳键的形成。萘甲酸，以提供高ee的相应共轭加成产物。