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

本文研究了一种新型的分子内不对称Heck反应，该反应利用了具有旋回异构体的底物。结果表明，通过对映异构体的平衡，建立了一种基于动态动力学解析的新型不对称Heck反应，该反应在高温下进行顺利，偶联产物产率高，对映异构体含量高。作为Heck反应的应用，我们设计了具有4a-甲基四氢芴骨架的standisinal及其类似物的不对称全合成，其对芳香化酶具有较强的抑制活性。也就是说，具有相同骨架的双氯醌、双氯醌和台湾喹酮等甾烷类似物有望作为女性激素依赖性癌症的药物具有良好的活性。综上所述，我们成功地合成了天然存在的含4a-甲基四氢芴的二萜，即(-)-二氯萘酮B、(-)-二氯萘酮和(-)-台湾喹酮h。而不对称合成具有反融合5,6元环体系的(-)-二氯萘酮则非常困难。因此，利用二醛中间体的醛醇型成键代替上述Heck反应合成dl- standiinal。通过对合成的斯坦丁醛及其相关化合物对芳香酶抑制活性的构效关系，发现比斯坦丁醛更有活性的化合物。

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.