37 海産毒ガンビエロールの全合成(口頭発表の部)

抄録

Gambierol (1) is one of the characteristic polycyclic ethers, which was isolated from ciguatera causative dinoflagellate Gambierdiscus toxicus. It shows strong neurotoxicity and the syptoms resemble those caused by ciguatoxins. Its structure has a ladder-shaped trans-fused octacyclic ring system, four axial methyl groups at fused ring positions, and a triene side chain. Because of the intersting biological activity andn characteristic architecture, many synthetic efforts have been devoted, culminationg three total syntheses and one f ormal total synthesis. Herein we report the total synthesis of gambierol (1). The salient features of the route include: 1) direct carbon-carbon bond formation on an oxirane ring and the subsequent sulfonyl-assisted 6-endo cyclization, 2) a ring-expansion approach to seven-menbered ether rings, and 3) radical cyclization. Our synthesis commenced with the coupling reaction between griflate 8 and epoxy sulfone 16 to provide 17, which was sequentially treated with MgBr_2 and DBU to afford the D ring 18. After Wacker oxidation of 19, the resulting methyl ketone was transformed into keto acrylate 20. Samarium iodide-mediated ketyl radical cyclization of 20 furnished the CD ring 21, which was converted to the BCD ring 15 via an acid-catalyzed 6-endo cyclization of epoxy olefin 23. Stereselective epoxidation of 15 with VO(acac)_2-TBHP followed by the reaction with dithiane 2 and hydrolysis of the dithioketal group provided hydroxy ketone 26. Reductive etherification with Et_3SiH and SnCl_4 followed by manipulation of the protecting groups furnished the ABCD ring triflate 29. For the construction of the EF ring, triflate 29 was treated with the anion derived from epoxy sulfone 5, and the subsequent 6-endo cyclization afforded ketone 31. Treatment of the ketone with TMSCHN_2 followed by reduction yielded the ABCDE ring alcohol 32. The alcohol was converted into keto acrylate 38, which was then subjected to ketyl radical cyclization with SmI_2 to afford the ABCDEF ring ester 39. The ester was transformed into triflate 42 by a nine-step sequence. Construction of the G and H rings was carried out by the doupling reacton of the oxiranyl anion derived from 6 with triflate 42 to provide heptacyclic ketone 44 after 6-endo cyclization. Iteration of the coupling of 6 with triflate 45 followed by cyclization furnished octacyclic ketone 46. Ring expansion reaction of 46 and stereoselective methylation of 47 afforded the ABCDEFGH ring alcohol 48. Conversion of the alcohol to (Z)-vinyl iodide 49 was achieved by TRAP oxidation followed by Wittig reaction. Removal of the benzyl groups with DDQ in dichloroethane and the TES group with TsOH privided triol 50. Finally, Stille coupling of 50 with vinyl stannane 7 afforded gambierol (1).