Synthesis of Swinhoeisterol A, Dankasterone A and B, and Periconiastone A by Radical Framework Reconstruction

Abstract

A switchable radical framework reconstruction approach to structurally unique 13(14 → 8),14(8 → 7)diabeo-steroid swinhoeisterol A was developed. The conversion of an ergostane skeleton proceeded through the intermediacy of a 13(14 → 8)abeo-framework as present in the dankasterone and periconiastone family of natural products and features a β scission of a 14-alkoxy radical with concomitant generation of the C8−C13 bond. From this intermediate, and dependent on the conditions employed, the cascade continues with a Dowd−Beckwith rearrangement and leads to the formation of the 13(14 → 8),14(8 → 7)diabeo-framework of the swinhoeisterol class of natural products. The synthesis of these frameworks then allowed for efficient access to swinhoeisterol A (1), dankasterone A (Δ 4 -2), dankasterone B (2), and periconiastone A (3).

Discoveries and Challenges en Route to Swinhoeisterol A

“…In the meantime, we were able to provide proof of the cage‐like 13(14→8) abeo ‐4,14‐cyclo structure of periconiastone A ( 5 ) by X‐ray single crystal analysis. Previously, we had synthesized 5 from dankasterone B ( 4 ) and now set out to explore the possibility to generate an enolate by 1,4‐reduction of dankasterone A ( 3 ), which would then undergo aldol addition and give the desired 4,14‐cyclo skeleton. Interestingly, reaction with L ‐selectride only gave 3α‐alcohol 21 , the product of 1,2‐reduction, presumably due to steric inaccessibility of C5.…”

“…As expected, no conversion of the starting material was observed in case of dione 23 , but the reaction of iodide 24 gave rise to 63 % of di abeo ‐compound 25 . As we reported earlier, it was possible to selectively access either the di abeo ‐framework ( 25 , HgO/I 2 , 68 % yield) or the mono abeo ‐skeleton ( 24 , PhI(OAc) 2 , 76 % yield), depending on the conditions to generate the initial alkoxy radical . To test if the rearrangement to the di abeo ‐structures could be initiated without employing toxic Hg or Pb reagents, 22 was treated with Ag 2 O and I 2 .…”

“…[a] Ratio of epimers determined from 13 C NMR spectra (see Supporting Information of Ref. ). [b] Crabtree catalyst: ( SP‐ 4)tris(cyclohexyl)phosphane[(1–2‐ η :5–6‐ η )‐cycloocta‐1,5‐diene]pyridineiridium hexafluorophosphate.…”

“…It was also a cascade of rearrangements initiated by an alkoxy radical that cleared the way to the dankasterone [13(14→8) abeo ‐steroids] and the swinhoeisterol class of natural products [13(14→8),14(8→7)di abeo ‐steroids] . Only recently, we achieved the synthesis of swinhoeisterol A ( 2 ), its 24‐ epi ‐counterpart (24‐ epi ‐ 2 ), dankasterone A ( 3 ) and B ( 4 ), and periconiastone A ( 5 ), the 4,14‐cyclo aldol product of the latter, starting from commercial ergosterol ( 1 ) by exploiting a radical cascade (Scheme ) . Regarding the biological activities of these natural products, dankasterone A ( 3 ) and B ( 4 ) show significant cytotoxicity against the P388 lymphocytic leukemia test system (ED 50 2.2 and 2.8 μg mL −1 , respectively) whereas di abeo ‐steroid swinhoeisterol A ( 2 ) exhibits a remarkable inhibition of the histone acetyltransferase (h)p300 with an IC 50 of 2.9 μ m .…”

Asymmetric Total Synthesis of Dankasterones A and B and Periconiastone A Through Radical Cyclization

“…[2] Dankasterones Aa nd B( 1)a nd periconiastone A( 2)a ll feature unprecedented 13(14!8)abeo-8-ergostane skeleton. With respect to periconiastone A( 2), it bears au nique pentacyclo [8.7.0.0 1,5 .0 2,14 .0 10,15 ]heptadecane system. It should also be mentioned that dankasterone B( 1b)a nd periconiastone A(2)contain cis-fused A/B ring.…”