Total Synthesis of 2‴,5‴-Diepisilvestrol and Its C1‴ Epimer: Key Structure Activity Relationships at C1‴ and C2‴

The first total synthesis of the low-abundance natural
product
2‴,5‴-diepisilvestrol (4) is described.
The key step involved a Mitsunobu coupling between cyclopenta­[b]­benzofuran phenol 7 and dioxane lactol 6. Deprotection then gave a 1:2.6 ratio of natural product
2‴,5‴-diepisilvestrol (4) and its C1 epimer
1‴,2‴,5‴-triepisilvestrol (15) in
50% overall yield. An in vitro protein translation inhibition assay
showed that 2‴,5‴-diepisilvestrol (4) was
considerably less active than episilvestrol (2), while
the unnatural isomer 1‴,2‴,5‴-triepisilvestrol
(15) was essentially inactive, showing that the configuration
at C1‴ and C2‴ has a large effect on the biological
activity.