13 細胞周期阻害活性を有するFR901464の立体選択的な合成研究(口頭発表の部)

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FR901464 1, FR901463 2, and FR901465 3 are new antitumor substances which were isolated from a culture broth of a bacterium of Pseudonionas sp. No. 2663. These compounds show transcriptional regulating activity and induce characteristic G1 and G2/M phase arrest in the cell cycle. Related to these activities, they show potent antitumor effect. Especially, FR901464 1 exhibits the most prominent antitumor activity among the three compounds. The unique structure as well as the significant biological activities prompted us to undertake the synthesis of this class of compound. Herein, we describe a stereoselective synthetic approach to 1. The retrosynthetic analysis is presented in Scheme. 1. Our analysis divided 1 into three segments, the carboxylic acid 4, the sulfone 5, and the aldehyde 6. We thought that 4, 5, and 6 would be obtained from commercially available compounds respectively, and the target molecule 1 should be synthesized via convergent route by condensations of these segments. According to this synthetic plan, we carried out our study. The acid 4 was prepared from a lactate 8 using the reported method. N-Boc-L-threonine 11 was used as the starting material to synthesize 5. The Garner aldehyde 14 was prepared from 11. Its side chain was elongated by the Wittig reaction, and was led to a lactone 10 by acid catalyzed ring closure. Treatment with Lawesson's reagent and the following Wittig reaction gave the olefin isomers, 17 and 18. After the base catalyzed deconjugation of olefin, catalytic hydrogenation gave the tetrahydropyran with the desired all-cis stereochemistry as a sole product, and the successive DIBAL reduction afforded the aldehyde 19, which was converted into the sulfone 5 through 4 steps. The aldehyde 6 was synthesized from 2-deoxy-D-glucose 13. First, 4,6-dihydroxyl groups of 13 were protected as benzylidene acetal. Selective oxidation of hemiacetal with bromine, followed by the protection of the remaining free hydroxyl group gave the lactone 12. Methylation and acetalization followed by deprotection of benzylidene group afforded diol 23. It was converted into aldehyde 6 via protection-deprotection process and Dess-Martin oxidation. Having completed the synthesis of the three segments 4, 5 and 6, we next examined the coupling processes. Condensation of 4 with 5 was achieved by using HBTU to give the amide 26. Using Julia olefination method, coupling of 26 and the aldehyde 6 afforded the diene 27. The successive selective desilylation and oxidation afforded the diene 29. The diene 29 possesses most of the carbon framework with the requisite asymmetric carbons involved of 1. Since 29 is considered as a potential key intermediate in our synthetic strategy, conversion of 29 to the target molecule 1 is now under investigation.
天然有機化合物討論会の論文
1999-09-01

13 細胞周期阻害活性を有するFR901464の立体選択的な合成研究(口頭発表の部)

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