55 タキソールの合成研究(ポスター発表の部)
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概要
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Taxane family(1-3) is one of the most challenging targets due to their unique carbon skeleton as well as the highly potent anticancer activities of a congener, taxol(1). Recently, we have developed a powerful methodology based on the Lewis acid mediated intramolecular eight-membered-ring cyclization between the dienol silyl ether and the acetal for the taxane B ring. In the present studies, this methodology was applied to the synthesis of taxol (1). We chose a convergent route as shown in Scheme 1 which involves, as key steps, the chelation controlled addition reaction of the C ring unit to the A ring hydroxy aldehyde and the eight-membered-ring cyclization reaction between the dienol silyl ether and the acetal. The α-hydroxy aldehyde 11 as the A ring unit could be prepared by oxidation of the known aldehyde 8 via the enol silyl ether 9. It was further found that Sharpless's asymmetric dihydroxylation of 9b affords the optically active 28 with high enantiomeric excess. In the model study, m-anisaldehyde dimethylacetal was chosen as the C ring unit. Under the chelation conditions, the lithiated C ring unit 12 added to the α-hydroxy aldehyde 11 to exclusively afford 1β, 2α isomer 13, which was converted to the cyclization precursor 16 in two steps. The chelation controlled cyclization of 16 gave the desired product 17 only in moderate yield along with 18. The fact that 13, 15, and 16 consist of two stable rotational isomers around the C2-C3 single bond suggested that the drawback might arise from the rotational isomerism of the cyclization precursor 16. This proved to be true by cyclization reaction of structurally defined atropisomeric cyclization precursors 21-P and 21-M. Namely, while the P isomer 21-P could give the desired eight-member product 22, the M isomer 21-M in contrary gave the cyclic acetal 23. The ratio of the two rotational isomers revealed to be highly dependent on the protective group of 2-hydroxy group. Fortunately, completely selective formation of the P isomer was achieved by the protection of 1,2-diols as the cyclic methyl boronate. In the presence of TiCl_4 the methyl boronate 25 afforded the desired eight-membered product 26 in good yield with complete stereochemistry. Preliminary examination, based on the model study, afforded 33 which possesses the suitable functionalities with the desired stereochemistry for the subsequent manipulation toward taxol (1).
- 天然有機化合物討論会の論文
- 1993-09-10
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