113(P-42) 抗腫瘍活性18員環マクロリド・テダノリドの全合成研究(ポスター発表の部)
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Tedanolide (1), a highly cytotoxic 18-membered macrolide, was isolated from a Caribbean sponge, Tedania ignis, and its structure was determined by Schmitz et al. in 1984. Recently, Matsushima reported the synthesis of a 18 membered lactone, although the procedure requires many improvements. We report here the highly efficient synthesis of the C_1-C_<12> (4) and C_<13>-C_<23> (5) moieties of 1. In macrolide synthesis, it is extremely important to design a seco-acid derivative suitable for macrolactonization. However, in the course of the synthessis of 1, such stable conformations cannot be expected in flexible acyclic intermediates before macrolactonization. The solution can only be provided by computational chemistry. This methodology was applied to plan the synthesis of 1; after conformational analysis with the aid of molecular mechanics (MM2) calculation in order to search for a key intermediate to 1, we designed the seco-acid (3). A retrosynthetic analysis is shown in Scheme 1. Our analysis divided seco-acid (3) into four fragments, ketones (7), (9) and aldehydes (8), (10). The ethyl ketone (7) was prepared from (S)-methyl-3-hydroxy-2-methylpropionate. Stereoselective aldol reaction of 7 with 8 followed by DIBAL-H reduction gave the1,3-diol (12). The C_5 alcohol was selectively protected as a benzylidene acetal by DDQ oxidation and the remaining secondary alcohol was converted to a MOM ether. DIBAL-H reduction of the benzylidene acetal afforded the primary alcohol (13), which was converted to the α,β-unsaturated ester (14) by Dess-Martin oxidation and Wittig olefination. When 14 was treated with AD-mix-α, the diol (15) was obtained in excellent yield with complete selectivity. 15 was converted into 4 via selective protection-deprotection processes and methylation. The synthesis of the C_<13>-C_<23> moiety was also started from (S)-methy1-3-hydroxy-2-metylpropionate, which was converted into the alcohol (18) through usual 7 steps. After introduction of a (Z)-olefin, construction of an epoxide ring on the C_<18> and C_<19> positions was achievesd by Sharpless' asymmetric epoxidation, and further conversion of 20 to the aldehyde (10) was carried out smoothly by Dess-Martin oxidation. Aldol condensation between 10 and ketone (9) by using ^cHex_2BCl, followed by reduction in situ by LiBH_4, gave the 1,3-diol (23) with required stereochemistry. Conversion of 23 into the C_<13>-C+<23> fragment (5) is now under investigation.
- 天然有機化合物討論会の論文
- 2000-10-01
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