35(D-5) Sordaricinの合成研究(口頭発表の部)

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Sordarin, isolated in 1971 as a metabolite of Sordaria araneosa, is a potent and selective inhibitor of fungal protein synthesis. The aglycon of sordarin, sordaricin (1), has a unique tetracyclic diterpene core containing trans-perhydroindene and a strained bicyclo[2.2.1]heptene frameworks with successive chiral centers. Sordaricin (1) is proposed to be biosynthesized through an intramolecular [4+2] cycloaddition. There have been two reports on the syntheses of sordaricin (1), both of which employed the intramolecular [4+2] cycloaddition as a key step. We planed to synthesize (±)-sordaricin (1) by developing a new synthetic strategy to construct the strained norbornene system. The bicyclic[5.3.0]decan-3-one 5 bearing four successive chiral centers [C(9), C(10), C(13), C(5)] could be synthesized stereoselectively from cyclopropanol 9 by the oxidative radical cyclization with Mn(pic)_3 via β-keto radical intermediate. Stereoselective and regioselective introduction of β-ketoester unit at C(3) of bicyclic ketone 10 derived from 9 and the successive Knoevenagel cyclization worked well to afford tricyclic compound 4, which was transformed to 3 in good yields. The construction of the strained bicyclo[2.2.1]heptan-2-one 2 was successfully achieved from tricyclic compound 3. When 3 was exposed to a catalytic amount of Pd(PPh_3)_4 and NaH, the desired intramolecular allylation (the Tsuji-Trost reaction) proceeded to furnish 2 in 92% yield. The structure of 2, which contains all of the stereogenic centers of sordaricin (1), was secured by X-ray crystallographic analysis. The ketone 2 was converted into 24 by the transformation to enol triflate 23 and the successive treatment with higher order cuprate derived from (2-Th)Cu(CN)Li and isopropylmagnesium bromide in the presence of HMPA. Dialdehyde 26 was derived from 24 by two-steps sequences: (i) conversion to bis(phenylboronic ester) 25 by the oxidation with OsO_4-PhB(OH)_2 and (ii) oxidative cleavage of the 25 with NalO_4. The resulting dialdehyde of 26 was reduced with NaBH_4 to the corresponding diol, and the selective protection of the less hindered C(19)-hydroxy group with TBS was subsequently carried out to afford 27. Oxidation of the C(17)-hydroxy group of 27 to aldehyde, followed by desilylation with TsOH, provided sordaricin ethyl ester 28. Finally, deethylation of ester 28 proceeded smoothly with propanethiolate to give (±)-sordaricin (1).
天然有機化合物討論会の論文
2004-10-01

35(D-5) Sordaricinの合成研究(口頭発表の部)

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