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

14-羟基类固醇的新型自由基重排级联的开发及其在 swinhoeisterols 和 dankasterones 合成中的应用

• 批准号: 413718753
• 负责人: Professor Dr. Philipp Heretsch
• 金额: --
• 依托单位: Institut für Organische Chemie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/413718753?language=en
• 关键词: Development; novel; radical; rearrangement; cascades

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.

重排在类固醇的生物合成中起重要作用。最近，我们能够表明，烷氧基自由基诱导的14-羟基类固醇的重排可能允许获得两个非常不同的类别的abeo类固醇，即丹司酮和swinhoeisterols。因此，先前讨论的通过带电中间体进行的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令人感兴趣的生物活性，例如，猪胆固醇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自由基重排，并将其应用于丹卡斯特酮和猪胆固醇类天然产物的合成。该项目的初步工作可能已经建立了一条通往丹卡斯特龙B的路线。基于丹卡斯特酮B，接下来将合成整个类别的13（148）种阿贝奥-麦角甾烷。另一方面，猪胆固醇天然产物类的合成工作必须解决两个结构特性，即4-外-亚甲基和（24 R）-甲基（当与两种经典麦角甾烷相比时，后者在立体构型的意义上是“倒置的”）。进一步的合成工作将集中在建立第一个结构-活性-关系。该项目的总体战略纲要，即在合成序列开始时产生整个碳骨架，非常适合实现这一目标。