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

• Applicant: Professor Dr. Philipp Heretsch
• Subject Area: Organic Molecular Chemistry - Synthesis and Characterisation
• Term: from 2018 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 413718753

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.

• DFG Programme: Research Grants