Highly enantioselective synthesis of anti-cancer epothilone and its stereoisomers

采用手性恶唑硼烷酮促进的不对称醛醇反应策略进行了不对称全合成。首先，研究了由埃波霉素不对称中心凝聚而成的C1-C9片段的不对称合成。第一个立体中心被我们的不对称醛醇技术高度控制，得到98%的ee。然而，醛上的不对称醛醇反应，由于其在季碳上具有庞大的取代基，即使在什么样的条件下也没有成功地构建期望的立体化学（Tetrahedron Lett, 1999）。通过本研究，可以确定手性恶唑硼烷酮促进的不对称醛醇反应的局限性。因此，Schinzer等人利用LDA实现了C6-C7键的非对映选择性缩合，改变了C6-C7键的立体选择性结构。用我们的方法成功地合成了用于此目的的酮。研究了从杂环侧进行的不对称合成，并通过不对称醛醇反应成功地首次引入手性中心。目前正在检查链条的延伸。同时，建立了三取代环氧化合物的立体选择性结构（Tetrahedron Lett.）。虽然目前尚未完全合成埃泊霉素，但在不久的将来将接近完成。

The asymmetric total synthesis of epothilones was carried out by the strategy based on the chiral oxazaborolidinone-promoted asymmetric aldol reaction. First, the asymmetric synthesis of the C1-C9 fragment which is comprised of the condensed asymmetric centers of epothilones was examined. The first stereocenter was highly controlled by our asymmetric aldol technique as to give 98% ee. However, the asymmetric aldol reaction on the aldehyde, which is possessing bulky substituents at the quaternary carbon, did not succeed for the construction of the expecting stereochemistry, even if what kind of conditions was examined (Tetrahedron Lett, 1999). From this research, it was possible to determine the limitation of the chiral oxazaborolidinone-promoted asymmetric aldol reaction. Thus, the stereoselective construction of C6-C7 bond was changed in achieving the diastereoselective condensation using LDA by Schinzer et al. The ketone available for the aim was successfully synthesized by our strategy. While the asymmetric synthesis from the heterocyclic side of epothilones is examined and the first introduction of chiral center has succeeded as expected by the asymmetric aldol reaction. At present the extension of the chain is being examined. In the meantime, the stereoselective construction of the tri-substituted epoxides was also established (Tetrahedron Lett.). Though the total synthesis of epothilones has not been achieved yet the completion will be close in the near future.