18 The Total Synthesis of Tricycloclavulone
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Tricycloclavulone (1) was isolated from Okinawan soft coral Clavularia viridis by our group as a novel marine prostanoid. This molecule has a unique tricyclo[5,3,0,0^<1,4>]decane skeleton and 6 chiral centers. Although relative stereochemistries of 1 was determined by spectroscopic analysis, the stereochemistry of a chiral center on the α-chain and the absolute stereochemistry have not been determined yet. The biological activity of the compound 1 has not been examined owing to its small amount obtained as a natural product. For the solution of above mentioned problems, the total synthesis of tricycloclavulone, which might be challenging synthetic target for organic chemists, was performed. We described here the total synthesis of (±)-tricycloclavulone as well as the effort for the synthesis of 1 as an optically active form. We designed the synthetic route as follows (Scheme 1). The tricyclic compound 2, which has a vinyl sulfone moiety on the C-ring, was an important intermediate. Two side chains would be constructed stereoselectively through 1,4-addition of organometallic species to the vinyl sulfone moiety and the following capture of the resulting anion on the sulfone bearing carbon atom with an appropriate electrophile. The compound 2 could be prepared from the compound 4 through [2+2]-cycloaddition reaction and ring closing olefin metathesis as key steps. Copper trifluoromethanesulfonate catalyzed [2+2]-cycloaddition reaction gave bicyclic compound 6 in good yield (Table 1). After introduction of two vinyl groups to 6, the construction of tricyclic skeleton was achieved by ring closing olefin metathesis using Grubbs catalyst (Scheme 2). Stereoselective addition of side chains to the tricyclic skeleton was also achieved on the convex face of the C-ring through 1,4-addition of dibutylcopper lithium to 13 and the following intramolecular ester transfer reaction (Scheme 3). Elongation of the α-chain and reduction of the ketone on the α-chain completed the first total synthesis of 1 as a racemic form (Scheme 4). For the preparation of tricycloclavulone (1) as an optically active form, enantioselective [2+2]-cycloaddition reaction was also examined (Table 2). In the presence of a catalytic amount of ligand 21, CuCl_2, and AgSbF_6, the reaction proceeded to give (1S,5R)-6 as 61% ee in 69% yield (Scheme 5).
