Synthesis and biological activity of the QRS ring system of maitotoxin

Maitotoxin (MTX) is a ladder-shaped polyether produced by an epiphytic dinoflagellate. As a part of our structure-activity relationship studies using synthetic partial structures of MTX, the QRS ring comprising a 6/6/7 tricyclic system was synthesized through stereoselective construction of five contiguous stereogenic centers on the Q ring via i) coupling of a Weinreb amide and a furyllithium, followed by ii) Noyori asymmetric transfer hydrogenation, iii) the Achmatowicz reaction, iv) chemoselective methylation of a methyl acetal in the presence of a carbonyl group by treatment with Me₂Zn/BF₃·OEt₂, v) highly diastereoselective dihydroxylation, and vi) ring expansion of a six-membered to a seven-membered ring ketone. The synthetic specimen inhibited MTX-induced Ca²⁺influx with an IC₅₀ value of 44 μM.