Brevetoxin-B (BTX-B, 1), a potent neurotoxin produced by the red tide organism Gymnodium breve Davis, is the first and representative member of marine polycyclic ethers. Its unique complex structure and potent biological activity have attracted the attention of synthetic organic chemists and the first total synthesis of 1 was achieved by Nicolaou and co-workers in 1995. We describe herein the stereoselective total synthesis of BTX-B (1). The Michael addition of 5 with MeMgBr-TMSCl in the presence of copper catalyst 6 afforded only α-adduct 7. After construction of the D-ring by SmI_2-induced intramolecular cyclization, treatment of bis(β-alkoxy acrylate) 13 with SmI_2 effected double cyclization with complete stereoselection to give trans-fused ester-lactone 14, corresponding to the CDE-ring. Then, 14 was converted into bis(α-epoxide) 19 via one-pot Wittig reaction of 15 with Ph_3P=C(Me)CO_2Et and Ph_3P=CHCOMe, and consecutive Sharpless AE of bis(allylic alcohol) 17, and double olefination. The ABCDEFG-ring was then constructed via consecutive 6-endo-cyclization of 19 and 20, ring-closing olefin metathesis of 22, and 6-endo-cyclization of 26, to give 27, which was successfully converted into the Wittig reagent 2. The UK-ring 3 was stereoselectively constructed via SmI_2-induced cyclization of 30, 6-endo-cyclization of 33, SmI_2-induced intramolecular Reformatsky-type reaction of 35, and direct introduction of the side chain. Both segments 2 and 3 were coupled by Wittig reaction to give 41, which was converted into 43 by intramolecular cyclization to monothioacetal followed by Ph_3SnH-AIBN reduction. Double oxidation of the left and right sides with PCC followed by deprotection of TBS group furnished BTX-B (1).
