Brevenal (1), a new family of marine polycyclic ether, was isolated from the Florida red tide dinoflagellate Karenia brevis by Baden and co-workers in 2004. This compound inhibits the binding of tritiated dihydrobrebetoxin-B to the voltage-sensitive sodium channels in a concentration dependent manner and acts as a nontoxic brevetoxin antagonist. Moreover, a significiant improvement of tracheal mucus velocity was observed in an animal model asthma. As well as the novel biological activities, the unique structural features have attracted attention of synthetic chemists. In 2006, the first total synthesis and structure revision of 1 were reported by Sasaki and co-workers. In this paper, we wish to report eht recent results and our efforts on the total synthesis of brevenal (1). The ABC ring segment 3 was prepared from the known compound 7 the B-alkyl Suzuki-Miyahara coupling of the phosphate 11 and the alkylborate from the iodine 5. Direct methylation of the O,S-acetal 16 was performed by using Me_2Zn/Zn(OTf)_2 in highly stereoselective manner. The ABC ring fragment obtained and the known alchol 4 were connected by our own synthetic strategy including the intramolecular allylation of α-acetoxy ether followed by ring-closing metathesis to furnish the pentacyclic ether 2. The right hand diene was introduced by the Nicolaoua's protocol. Construction of the left hand side chain, highly substituted dienyl moiety, was archieved by the modified Horner-Wadsworth-Emmons reaction with the phosphonate 33, newly developed, to afford the dienyl ether 34 as the sole product. A seris of functional transformation and deprotections of 34 furnished brevenal (1). The synthetic 1 exhiibited physical and spectroscopic data identical to those reported previously.
