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Gambierol (1) was isolated from cultures cells of ciguatera causative dinoflagellate, Gambierdiscus toxicus. The structure of 1 consists of trans-fused 6,6,6,6,7,6,6,7-membered octacyclic ether core (ABCDEFGH-ring) containing 18 chiral centers and a triene side chain including a conjugated (Z,Z)-diene systems. Gambierol (1) enhibits potent toxicity against mice at (LD_<50>=50μg/kg), and its symptoms resemble those caused by ciguatoxins, the principal toxin which is a very widespread seafood poisoning. The total syntheses of 1 have been accomplished based on the convergent strategy by the Sasaki, Kadota-Yamamoto, and Rainier groups, independently. We now report a formal total synthesis of gambierol (1) based on our developed two-directional strategy using SmI_2-induced cyclization and convergent strategy using an intramolecular Barbier reaction of iodo ester with t-BuLi. Synthesis of the AB-ring system: The synthesis of the AB-ring started with the B-ring 5, prepared from 2-deoxy-D-ribose. α-Hydroxy group of the A-ring was stereoselectively introduced by the SmI_2-induced intramolecular Reformatsky reaction of 6. Intramolecular hetero-Michael reaction of 8 constructed the A-ring to give 9, which was converted into the AB-ring iodo-alcohol 12 in a straightforward manner. Synthesis of the EFGH-ring system: The EFGH-ring 23 was stereoselectively synthesized by two synthetic routes through two-directional strategy. (1) The first synthesis of 23 started with the G-ring 13 prepared from 2-deoxy-D-ribose. The regioselective reactions of 14 led to diol 17 having the same functional groups at the left and right sides. The G-ring 17 was converted to the FGH-ring 19 based on double reaction at the left and right sides; i.e., hetero-Michael reaction, removal of thioacetal and SmI_2-induced double cyclization. The E-ring was then constructed by SmI_2-induced cyclization. (2) An alternative synthesis of the EFGH-ring 23 also started with the G-ring 13. The F-ring 25 having 1,3-diaxial Me groups was efficiently constructed by SmI_2-induced cyclization of 24, prepared from 13. The construction of the E- and H-rings was accomplished by using SmI_2-induced double cyclization to give trans-fused EFGH-ring 23. Treatment of 23 with disiamylborane chemoselectively reduced lactone to give ester-diol 32, which was hydrolyzed to the EFGH-ring carboxylic acid 33. Formal total synthesis of 1: The coupling of both segments 12 and 33 was performed by Shiina's procedure using MNBA and DMAP to give the iodo-ester 34. Upon treatment of 34 with t-BuLi at -78℃, the desired intramolecular Barbier reaction took place to give hemiacetal, which was dehydrated to give dihydropyran C-ring 35. Stereoselective hydroboration of 35 and protective group manipulation afforded the required α-alcohol 36, which was oxidized to cyclic ketone 37. Ring expansion of 37 by treatment with TMSCHN_2 gave the required oxepanone E-ring 38, corresponding to the key intermediate in Sasaki's total synthesis of gambierol (1). Thus, the formal total synthesis of gambierol (1) was accomplished.
