Stereoselective syntheses of epothilones A and B via directed nitrile oxide cycloaddition
Stereoselective syntheses of epothilones A and B via directed nitrile oxide cycloaddition
复制标题
DOI：
10.1021/ja0155635
复制
发表时间：
2001-04-18
影响因子：
15
通讯作者：
Carreira, EM
中科院分区：
文献类型：
--
作者：
Bode, JW;Carreira, EM
对模拟非常成功的抗癌药物紫杉醇活性的分子的研究激发了令人印象深刻的研究活动，合成化学家特别强调主要候选物，discodermolide和epothilones。2本文描述了以非对映选择性、羟基定向环加成和会聚片段偶联为特征的埃博霉素A和B的简明、完全立体控制的合成。这种策略提供了一个方便的路线，进一步正在进行的，紧张的调查，旨在开发一个可扩展的approaches.The埃坡霉素提出了两个主要的立体化学障碍，他们的有效合成的组成片段。首先，C3-C8区域的构建受到了严格的审查，特别是Danishefsky的优雅研究。[3]此外，Nicolaou、4 Schinzer、5 Grieco、6白色、7 Panek、8和Shibasaki也记录了一些值得注意的方法。[9] Mulzer最近报道了这一领域的一个重要进展，[10]他描述了涉及C7-C15环氧醛片段的高度立体选择性的羟醛加成反应。[11]解决第二个障碍的方法，即C12-C15顺式高烯丙基环氧醇的构建，一致地依赖于烯烃的立体选择性合成及其氧化官能化。虽然这种方法已经看到了相当多的使用，它遇到了一些困难与立体控制合成的顺式烯烃以及最终的立体选择性环氧化的缺点。
The search for molecules which mimic the activity of the highly successful anticancer drug Taxol has inspired impressive research activity with particular emphasis by synthetic chemists on the leading candidates, discodermolide and the epothilones. 2 Herein we describe concise, fully stereocontrolled syntheses of epothilones A and B featuring diastereoselective, hydroxyl directed cycloadditions and convergent fragment couplings. This strategy provides an expedient route to the constituent fragments that furthers the ongoing, intense investigations aimed at developing a scalable approach.The epothilones present two major stereochemical obstacles to their effective syntheses. The first, construction of the C3-C8 region, has enjoyed intense scrutiny, particularly in the elegant studies by Danishefsky. 3 Additionally, notable approaches have been documented by Nicolaou, 4 Schinzer, 5 Grieco, 6 White, 7 Panek, 8 and Shibasaki. 9 An important advance in this field was recently reported by Mulzer, 10 who described a highly stereoselective aldol addition involving a C7-C15 epoxy aldehyde fragment. 11 Approaches to the second obstacle, construction of the C12-C15 cis-homoallylic epoxy alcohol, uniformly rely on the stereoselective synthesis of the olefin and its oxidative functionalization. While this approach has seen considerable use, it encounters some difficulties associated with the stereocontrolled synthesis of the cis-olefin as well as drawbacks of the ultimate stereoselective epoxidation.