Manipulation of Steroid Core and Sidechain: Methodology for the Synthesis of Steroid Natural Products Strophasterol A-D and Glaucoposterol A

Abstract

The first part of this thesis deals with studies on the synthesis of a platform for the targeted synthesis of the natural product class of strophasterols. The second part describes the development of a method for access to abeo steroids. The strophasterols are four rearranged steroids that were isolated in 2012. Strophasterols A and B were synthesized by HERETSCH et al. and KUWAHARA et al. in 2016 and 2017, respectively, whereas strophasterols C and D still lack synthetic access. In addition, the absolute stereo configuration of strophasterols C and D is unknown and should be elucidated. Based on the synthesis of strophasterol A by HERETSCH et al., known and new methods for the oxidative functionalization of the ergosterol side chain were tested in order to introduce the required oxidation state at position C23. En route towards the required platform, known methods for the functionalization of the ergosterol side chain were applied and evaluated. Due to low yields or undesired regioselectivity, no suitable method for the targeted installation of the required oxidation state at C23 could be identified. Nevertheless, valuable results for the general and improved functionalization of ergostane and other steroidal systems could be generated. The application of an intramolecular, LEWIS acid mediated carbonyl-ene reaction made a significant contribution to the generation of the desired platform. On the basis of these results, an elegant, efficient and selective access to each member of the natural product class of strophasterols can be envisioned. The second part of the thesis deals with the development of a method for contraction of the B-ring of steroidal systems based on α-hydroxy ketones. Conventional methods often have the disadvantage of poor yields, low reproducability or difficult accessible starting materials. A mild and effective alternative with a high tolerance for functional groups was developed on the basis of benzilic acid rearrangement, thus enabling the synthesis of abeo steroids. In addition, access to B-nor ketones has been developed without the use of harmful reagents such as lead(IV) acetate. This way, the developed method provides advanced and reliable access to the described class of substances, enabling future work on biologically relevant compounds.