Total Synthesis of the Tubulin Inhibitor WF-1360F Based on Macrocycle Formation through Ring-Closing Alkyne Metathesis

摘要

Rhizoxin (1) is a 16-membered macrolide that was first isolated in 1984 from the plant pathogenic fungus Rhizopus chinensis by Okuda and co-workers and shown to be the causative phytotoxin of the rice seedling blight.'1,21 In 2005, Hertweck and co-workers demonstrated that rhizoxin (1) is not a fungal metabolite but is produced by a bacterial endosymbiont of the genus Burkholderia. Rhizoxin (1) is a potent inhibitor of eukaryotic tubulin polymerization and it exhibits pronounced in vitro and in vivo antitumor activity; the compound has been advanced to Phase II clinical trials but has not shown any relevant clinical efficacy. In addition to 1, a number of rhizoxin congeners have been isolated from fermentation broths of Rhizopus chinemis and Burkholderia rhizoxina.