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的作用。最近，我们能够证明烷氧基诱导的14-羟基类固醇的重排可能允许两类非常不同的类固醇，即danksterone和swinhoeisterol。因此，以前讨论过的通过带电中间体进行这些天然产物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，Swinhoeisterol A是人肺癌和骨肉瘤细胞系的选择性抑制剂。该项目的目的是更深入地了解烷氧基重排，并将其用于合成丹卡斯特酮和swinhoeisterol类天然产品。该项目的初步工作可能已经建立了一条合成丹卡斯特酮B的路线。在丹卡斯特酮B的基础上，接下来将合成全类13(148)个异麦角甾烷。另一方面，swinhoeisterol类天然产物的合成工作必须解决两个结构特点，即4-外亚甲基和(24R)-甲基(后者在立体构型意义上与两个经典麦角烷相比较时是“颠倒的”)。然后，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，即在合成序列开始时生成整个碳骨架，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.