Development of novel radical rearrangement cascades of 14-hydroxy steroids and application in the syntheses of the swinhoeisterols and dankasterones
Final Report Abstract
Many recently isolated steroidal secondary metabolites consist of rearranged carbon skeletons and often exhibit remarkable biological activities. The project of examining the synthesis of such natural products was ignited by the development of an alkoxy radical-mediated framework reconstruction, which enabled access to not only 13(14→8)abeo- but also 13(14→8),14(8→7)diabeo-steroids starting from a common γ-hydroxy enone precursor. Dankasterone A and B are 13(14→8)abeo-steroids that both share the same rearranged carbon backbone. Structurally related periconiastone A, a recently isolated anti-MRSA agent, includes an additional 4,14-cyclo-motif. Due to their remarkable biological activities, intriguing structural features, and because none of them had been synthetically accessed, these natural products were chosen as synthetic targets. The radical cascade mentioned above enabled selective access to the 13(14→8)abeo-skeleton when employing (diacetoxyiodo)benzene and iodine to generate the alkoxy radical. Additional steps yielded dankasterone B, which could either be converted to dankasterones A via further oxidation or undergo an aldol reaction to provide pentacyclic periconiastone A. To date, the swinhoeisterol class of natural products consists of nine members, whereof all display a 6/6/5/7 carbon skeleton and several exhibit interesting biological properties. When employing mercury(II) oxide and iodine to initiate the radical cascade, the diabeo-backbone was obtained in a highly selective manner. Initial synthetic attempts focused on the accessibility of the C29 skeleton, including the crucial C4 exo-methylene group. After setting the oxidation state of the tetracyclic ring system, the introduction of C28 proved difficult, but was successfully accomplished when applying the Nishiyama–Stork protocol, and final elimination of a primary alcohol gave the desired exocyclic double bond. After establishing this route to derivatives of swinhoeisterol A, adjustments were made to supply the actual natural product. Oxidative cleavage of the ergostane side chain and subsequent olefination installed the side chain fragment with the correct configuration at C24. However, hydrogenation of this double bond was unsuccessful, and the application of a hydroboration/oxidation/deoxygenation sequence became necessary to obtain the desired, saturated campestane side chain, which enabled the first synthesis of swinhoeisterol A. Another alkoxy radical-mediated reaction provided access to 5,6-epoxy-5,6-secosteroid herbarulide. The synthesis of this secondary metabolite and its C24-epimer, applying the afore-established strategy, enabled the unambiguous structural assignment of the natural product.
Publications
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Rearranged ergostane-type natural products: chemistry, biology, and medicinal aspects. Organic & Biomolecular Chemistry, 17(7), 1624-1633.
Duecker, Fenja L.; Reuß, Franziska & Heretsch, Philipp
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Synthesis of Swinhoeisterol A, Dankasterone A and B, and Periconiastone A by Radical Framework Reconstruction. Journal of the American Chemical Society, 142(1), 104-108.
Duecker, Fenja L.; Heinze, Robert C. & Heretsch, Philipp
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Discoveries and Challenges en Route to Swinhoeisterol A. Chemistry – A European Journal, 26(44), 9971-9981.
Duecker, Fenja L.; Heinze, Robert C.; Steinhauer, Simon & Heretsch, Philipp
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Synthesis of the Alleged Structures of Fortisterol and Herbarulide and Structural Revision of Herbarulide. Organic Letters, 22(4), 1585-1588.
Duecker, Fenja L.; Heinze, Robert C.; Mueller, Mira; Zhang, Sudong & Heretsch, Philipp
