56(P-31) トレハラーゼ阻害剤(+)-トレハゾリンの立体選択的形式全合成(ポスター発表の部)
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概要
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Trehazolin (1) was isolated from a culture broth of Micromonospora, strain SANK 62390 as a powerful trehalase inhibitor. The unique structure and biological activity attracted synthetic chemists, and many syntheses have been reported. Here we present the stereocontrolled asymmetric synthesis of 3, a precursor of 1, via C-H insertion reaction of the alkylidenecarbene, followed by regioselective opening of the epoxide ring. Since our early plan for 3 was direct synthesis of cyclopentene 4 by C-H insertion reaction, ketone 6, derived from D-tartrate, was treated with TMSCLiN_2 to generate the alkylidenecarbene. The main product obtained, however, was a compound which arose from the oxonium ylide intermediate. The yield of 10 was only 5% at maximum. Then our attention turned to the disubsituted epoxide 16 that seemed to be a good precursor of cyclopentene 4. It was expected that addition of oxygen nucleophile (R_2OH) occurs at the allylic position of epoxide 16. Ketone 21 derived from cis-2-butene-1,4-diol in 7 steps was treated with TMSCLiN_2 in DME at 0℃. Warming the reaction mixture to an ambient temperature (20-25℃) produced the cyclopentene 22 as a single diastereomer with a 51% yield. Opening of the epoxide ring of 22 was successful with allyl alcohol under acidic conditions and removal of the TBS group of the product using TBAF gave the desired diol 25. Sharpless epoxidation of 25 furnished epoxide 28 as a single isomer. ^1H NMR spectra of (S)- and (R)-MTPA esters of 28 indicated that both are single diastereomers, namely, 28 is enantiomerically pure. Then 28 was converted to tris-MOM derivative 30 through 3 steps. 30 was treated with sodium azide and ammonium chloride to afford azido alcohol 31 which has the desired stereochemistry. Deprotection of the PMB group followed by reduction of the azido group of 31 provided amino diol 32. Finally, manipulation of protecting groups of 32 furnished 3, whose physical properties were identical with those reported.
- 天然有機化合物討論会の論文
- 2004-10-01
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