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.