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Development of a Novel Asymmetric Heck Reaction based on Dynamic Kinetic Resolution and Its Application

基于动态动力学解析的新型不对称Heck反应的研制及其应用

基本信息

批准号：
18590022
负责人：
NODE Manabu
金额：
$ 2.57万
依托单位：
Kyoto Pharmaceutical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18590022/
关键词：
asymmetric Heck reaction atropisomer dynamic kinetic resolution standishinal analogs dichroanal B dichroanone taiwaniaauinone H inhibitory activity against aromatase アトロブ異性 standishinal 類縁体構造-活性相関

项目摘要

We have investigated a novel intramolecular asymmetric Heck reaction by use of the substrate having atropisomers. As the results, we could established a new type of asymmetric Heck reaction based on dynamic kinetic resolution through equilibration of atropisomers, which proceeded smoothly in high temperature to give the coupling product in high yields and in high enantiomeric excess.As application of the Heck reaction, we designed asymmetric total syntheses of standishinal and its analogs having 4a-methyltetrahydrofluorene skeleton, which showed potent inhibitory activity against aromatase. Namely, standishinal analogs possessing the same skeleton such as dichroanone, dichroanals, and taiwaniaquinones, are expected to have promising activities as medicines for female hormone-dependent cancers. In conclusion, we succeeded in the asymmetric total syntheses of naturally occurring diterpenes having 4a-methyltetrahydrofluorene, i.e., (-)-dichroanal B, (-)-dichroanone, and (-)-taiwaniaquinone H.On the other hand, asymmetric synthesis of (-)-standishinal having trans fused 5,6-membered ring system was very difficult. Therefore, dl-standishinal was synthesized by the use of aldol type bond formation of dialdehyde intermediate instead of above Heck reaction. We found more active compound than standishinal by the structure-activity relationship of inhibitory activity against aromatase using synthesized standishinal and its related compounds.

我们利用含有阻转异构体的底物研究了一种新的分子内不对称Heck反应。结果表明，通过阻转异构体的平衡，我们建立了一种新型的基于动态动力学拆分的不对称Heck反应，该反应在高温下顺利进行，以高产率和高的对映体过量得到偶联产物，作为Heck反应的应用，我们设计了具有4a-甲基四氢芴骨架的斯坦迪辛醛及其类似物的不对称全合成，其对芳香酶显示出有效的抑制活性。也就是说，具有相同骨架的standishinal类似物，如二色酮、二色烷醛和台湾醌，预期具有作为用于女性乳腺癌依赖性癌症的药物的有希望的活性。总之，我们成功地不对称全合成了天然存在的具有4 α-甲基四氢芴的二萜，即，（-）-二色醛B、（-）-二色酮和（-）-taiwaniaquinone H。另一方面，具有反式5，6-元环系统的（-）-standisinal的不对称合成非常困难。因此，利用双醛中间体的羟醛型成键取代上述Heck反应合成dl-斯坦迪什醛。通过对合成的斯坦迪辛醛及其相关化合物抑制芳香化酶活性的构效关系分析，发现其活性高于斯坦迪辛醛。