Baran Phil S, Hafensteiner Benjamin D, Ambhaikar Narendra B, Guerrero Carlos A, Gallagher John D
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
J Am Chem Soc. 2006 Jul 5;128(26):8678-93. doi: 10.1021/ja061660s.
In this article, full details regarding our total synthesis of avrainvillamide and the stephacidins are presented. After an introduction and summary of prior synthetic studies in this family of structurally complex anticancer natural products, the evolution of a final synthetic approach is described. Thus, a thorough description of three separate model studies is provided for construction of the characteristic bicyclo[2.2.2]diazaoctane ring system common to these alkaloids. The first and second approaches sought to build the core using formal Diels-Alder and vinyl radical pathways, respectively. Although these strategies failed in their primary objective, they fostered the development of a new and mechanistically intriguing method for the synthesis of indolic enamides such as those found in numerous bioactive natural products. The scope and generality of this simple method for the direct dehydrogenation of tryptophan derivatives is described. Finally, details of a third and successful route to the core of these alkaloids are described which features oxidative C-C bond formation. Specifically, the first heterocoupling of two different types of carbonyl species (ester and amide) is accomplished in good yield, on a preparative scale, and with complete stereocontrol. The information gained in these model studies enabled an enantioselective total synthesis of stephacidin A. The absolute configuration of these alkaloids was firmly established in collaboration with Professor William Fenical. A full account of our successful efforts to convert stephacidin A into stephacidin B via avrainvillamide is presented. Finally, the first analogues of these natural products have been prepared and evaluated for anticancer activity.
本文详细介绍了我们对阿夫拉维胺和斯蒂芬酸的全合成。在对这类结构复杂的抗癌天然产物的先前合成研究进行介绍和总结之后，描述了最终合成方法的演变。因此，针对构建这些生物碱共有的特征性双环[2.2.2]二氮杂辛烷环系统，提供了三项独立模型研究的详尽描述。第一种和第二种方法分别试图通过形式上的狄尔斯-阿尔德反应和乙烯基自由基途径构建核心结构。尽管这些策略未能实现其主要目标，但它们促进了一种新的、机理有趣的合成吲哚烯酰胺方法的发展，这类吲哚烯酰胺存在于众多生物活性天然产物中。描述了这种用于色氨酸衍生物直接脱氢的简单方法的适用范围和通用性。最后，描述了第三条成功合成这些生物碱核心结构的路线细节，其特点是通过氧化形成碳-碳键。具体而言，两种不同类型的羰基化合物（酯和酰胺）的首次异质偶联以良好的产率在制备规模上完成，并且具有完全的立体控制。这些模型研究中获得的信息实现了斯蒂芬酸A的对映选择性全合成。这些生物碱的绝对构型与威廉·费尼卡尔教授合作得以确定。全面介绍了我们通过阿夫拉维胺将斯蒂芬酸A转化为斯蒂芬酸B的成功努力。最后，制备了这些天然产物的首批类似物并评估了其抗癌活性。
