Development of novel radical rearrangement cascades of 14-hydroxy steroids and application in the syntheses of the swinhoeisterols and dankasterones

重排在类固醇的生物合成中起着重要作用。最近，我们能够证明烷氧基自由基诱导的14-羟基类固醇的重排可能允许两种非常不同的类固醇，即丹卡酮和猪甾醇。先前讨论的这些天然产物通过带电中间体进行的生物合成似乎不太可信。所述天然产物具有多种有趣的生物活性，例如，猪甾醇a是人类肺癌和骨肉瘤细胞系的选择性抑制剂。该项目的目的是获得对烷氧基重排的更深入的了解，并将其应用于丹卡酮和猪甾醇类天然产物的合成。本项目前期工作已初步建立了丹卡酮B的合成路线，下一步将以丹卡酮B为原料合成13（148）个阿贝麦角甾类化合物。另一方面，猪甾醇类天然产物的合成工作必须解决两个结构特性，即4-外显亚甲基和(24R)-甲基（后者在与两种经典麦角甾相比较时在立体构型意义上是“倒置的”）。进一步的综合工作将集中于建立第一个结构-活动-关系。该项目的总体战略大纲，即在合成序列的开始生成整个碳骨架，非常适合实现这一目标。

Rearrangements play an important role in the biosynthesis of steroids. Recently, we were able to show that alkoxy radical-induced rearrangements of 14-hydroxy steroids potentially allow access to two very different classes of abeo-steroids, i.e. the dankasterones and swinhoeisterols. Previously discussed biosyntheses of these natural products that proceed through charged intermediates thus appear less plausible. Said natural products possess a variety of interesting biological activities, as an example, swinhoeisterol A is a selective inhibitor of human lung cancer and osteosarcoma cell lines. The aim of this project is to gain a deeper insight into alkoxy radical rearrangements and to employ them in the synthesis of the dankasterone as well as swinhoeisterol classes of natural products. Preliminary work in this project could already establish a route to dankasterone B. Based on dankasterone B, the whole class of 13(148)abeo-ergostanes will be synthesized next. On the other hand, synthetic work in the class of swinhoeisterol natural products has to address two structural peculiarities, i.e. the 4-exo-methylene and (24R)-methyl groups (the latter are "inverted" in a sense of stereoconfiguration when compared two classical ergostanes). Further synthetic work will then concentrate on establishing first structure-activity-relationships. The general strategic outline of this project, i.e. generating the entire carbon backbone at the beginning of the synthetic sequence, is well suited to achieve this goal.