Total synthesis of (ent)-linderolide E and (ent)-15-hydroxy- and 15-acetoxyisogermafurenolides, and structural revision of (ent)-linderolide E

Abstract

Sesquiterpenoid scaffolds such as the eudesmane-type linderolides and elemanolide-type isogermafurenolides remain synthetically challenging despite their structural interest and documented biological activities. While prior studies have addressed the parent isogermafurenolide through racemic and asymmetric approaches, the linderolides and the 15-acetoxy isogermafurenolide congeners have not been accessed synthetically. Herein, we report the first total synthesis of the ent-linderolide E, ent-15-hydroxy isogermafurenolide (ent-linderolide F), and ent-15-acetoxy isogermafurenolide, along with a concise synthesis of ent-isogermafurenolide. The route features four key transformations: a Tanabe lactonisation for lactone formation, a site-selective allylic oxidation, a Luche reduction, and a ring-closing metathesis constructing the eudesmane framework. Additionally, single-crystal X-ray diffraction analysis of synthetic material establishes a revised structural assignment for natural linderolide E.