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.

已经成功实现了与抗肿瘤毒素相关的化合物与抗肿瘤活性以及对映选择性不对称反应的新策略的发展。位点和电子密度的增加在羰基组的氧原子上。设计靶的融合已成功地从相应的氨基酸开始的短步骤中成功地进行。（2）新型不对称反应有效的不对称反应的开发依赖于从有机代表素中构成的三个成分复合物的复杂性，依赖于cymemememememememememememememememememememememememememememememememememememememememememememememememememetals reutent reutent reutent refent refent，Chirrig and Chirrig and chirrig和Chirrig和Chirrig。我们设计了一个模型，该模型在五个成员螯合物的螯合杂原子的两个部位都有两个立体控制组。模型复合物的真实性将从有机矿的配位到手性差异，这形成了预期的复合物。有机岩与α，β-不饱和的酯或酯的反应在手性息缘存在的情况下，在高对映体过度和三个成分复杂模型预测的绝对构型中提供了相应的共轭添加产物。鉴于使用二二元计算的二聚体催化剂均匀含量的反应，也已在繁殖的反应中进行了反应，这也已在繁殖中的反应也已被施加了浓度的反应。 1-和2-萘甲基羧酸的酯提供高EE中相应的缀合物添加产物。