Collective synthesis of highly oxygenated (furano)germacranolides from Elephantopus mollis and Elephantopus tomentosus

Germacranolides, secondary metabolites produced by plants, have garnered academic and industrial interest due to their diverse and complex topology as well as a wide array of pharmacological activities. Molephantin, a highly oxygenated germacranolide isolated from medicinal plants, Elephantopus mollis and Elephantopus tomentosus, has exhibited anti-tumor, inflammatory, and leishmanicidal activities. Its chemical structure is based on a highly strained ten-membered macrocyclic backbone with an (E,Z)-dienone moiety, which is fused with an a-methylene-g-butyrolactone and adorned with four successive stereogenic centers. Herein, we report the first synthesis of molephantin via 12 steps starting from readily available building blocks. The synthesis is featured by the highly diastereoselective intermolecular Barbier allylation of the b,g-unsaturated aldehyde with optically active 3-bromomethyl-5H-furan-2-one intermediate and ensuing intramolecular Nozaki-Hiyama-Kishi (NHK) macrocyclization for the construction of the highly oxygenated ten-membered macrocyclic framework. This synthetic route enabled to craft another germacranolide congener, tomenphantopin F. Furthermore, cycloisomerization of molephantin into 2-deethoxy-2b-hydroxyphantomolin could be facilitated by irradiation with ultraviolet A light (lmax = 370 nm), which opened a versatile and concise access to the related furanogermacranolides such as EM-2, phantomolin, 2-O-demethyltomephantopin C, and tomenphantopin C.