8 光学活性FR900482の合成研究(口頭発表の部)

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FR900482 (1) isolated from the culture broth of Streptomyces sandaensis No. 6897 at Fujisawa Pharmaceutical Co. in 1987, exhibits potent antitumor activity against various types of mammalian solid tumors. 1 shows the antitumor activities equal to or superior to those of mitomycin C (MMC) (2) and is also found to be effective against MMC- and vincristine-resistant P388 leukemia cells. The structure of 1 is quite unique in that the hydroxylamine function forms a hemiacetal array. Its remarkable antitumor activity and unique structure make 1 an exceptionally intriguing and timely target for total synthesis. Although two total syntheses of racemic 1 had been accomplished by Fukuyama and Danishefsky, none of the total syntheses of optically active 1 have been reported to date. We embarked on the project directed at the total synthesis of 1 and its congeners in optically active forms with an aim to elucidate the structure-activity relationships of 1, and succeeded in completing the first enantioselective total synthesis of (+)-1. Our synthetic strategy involves the following three key steps: (i) coupling of the aromatic fragment 7 with the optically active aziridine fragment 8 (7+8→24); (ii) aldol cyclization of dialdehyde 6 to construct the desired eight-membered ring system 27 (6→27); (iii) Epimerization at the C-7 position of hydroxyketone 28 (28→29). We commenced the synthetic studies by pursuing the synthesis of the aromatic fragment 7 and the optically active aziridine fragment 8. Thus, 7 was prepared in fifteen steps starting from commercially available 5-hydroxyisophthalic acid (9). On the other hand, 8 was synthesized from commercially available L-diethyl tartrate (10) by sequential fifteen step operations. Reaction of 7 with 8 proceeded smoothly to give the desired coupling product 24 in a quantitative yield. 24 was further converted to 6 by way of alcohol 25 and the aziridine 26. Crucial aldol cyclization of 6 was effected by employing LiN(TMS)_2 (1.0 equiv.) as a base in dry THE at -78→-5℃, giving rise to 27 in 42% yield after treatment with NaBH_4. Base-catalyzed epimerization at the C-7 position of hydroxyketone 28 derived from 27 followed by reduction with NaBH_4 gave the aziridinobenzazocine 5 possessing the requisite functional groups with correct stereochemistries. With 5 in hand, we further pursued the synthetic studies to complete the total synthesis of (+)-1. Towards this end, 5 was elaborated to the pentacyclic compound 33 in five steps by way of the aniline 30, acetate 31 and hemiacetal 32. Finally, 33 was converted to (+)-1 by sequential six step operations by way of the tetracyclic compound 3 and the phenol 34. The synthesized (+)-1 was identical with a natural sample of 1 in all spectroscopic properties (IR, ^1H-NMR, MS). In summary, we have succeeded in completing the first enantioselective total synthesis of (+)-FR900482 (1) in a convergent manner starting from 5-hydroxyisophthalic acid (9) and L-diethyl tartrate (10). Since the explored synthetic scheme appears to be highly general and flexible to produce various structural types of the congeners of 1, these studies may open an opportunity for developing a novel anticancer agent.
天然有機化合物討論会の論文
1995-09-01

8 光学活性FR900482の合成研究(口頭発表の部)

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