35 タクスシンの合成研究(口頭発表の部)
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概要
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Members of taxane family (e.g. 1 and 2) with their unique tricyclo[9.3.1.0^<3,8>]-pentadecane skeleton and significant anticancer activities of a congener, taxol (2), are important targets in synthetic organic chemistry. Aiming the total synthesis of taxol (2) as the final goal, we have examined synthetic studies on taxusin (1). Cyclization precursor 13 possessing the desired 1,4-relative stereochemistry was prepared. The 1,4-relative stereochemistry was controlled by Michael addition of lithium enolate of isobutyrate ester to enone 8 under high 1,4-diastereoinduction and the Mitsunobu inversion. The tricyclic skeleton of taxusin 14 was constructed by means of the TMSOTf-mediated intramolecular eight-membered ring cyclization reaction of 13 between the dienol silyl ether and the acetal. Though the cyclization yielded undesired spirocyclization product 15 as the major product, TiCl_4-induced isomerization of 15 afforded the desired 14 in good yield. In addition that 14 has the correct stereochemistry at C9 and C10 it appeared to possess the endo conformation which is suitable for the subsequent stereoselective transformations on the ring system. Chemo- and stereoselective functional group transformations of 14 gave allyl alcohol 17, setting up the stage for investigation of the 19β-methyl group installation. The 4β-hydroxy group directed cyclopropanation of Δ^<3,8>-double bond smoothly afforded β-methylenation product, PDC oxidation of which led to cyclopropyl ketone 18. Though attempted reductive opening of the cyclopropane ring of 18 failed, resulting in formation of presumed hydroperoxide 19, reduction of 13α-hydroxy derivative 20 accomplished cyclopropane ring opening and at the same time stereoselective protonation at C3 to afford 21. Thus, we succeeded in introduction of the 19β-methyl group on the ring system in high yield. The obtained intermediate is suitably functionalized for the synthesis of taxusin (1). We are currently pursuing the accomplishment of the total synthesis.
- 天然有機化合物討論会の論文
- 1994-09-20
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