103(P49) Epoxyquinomicin類の単離・構造決定および合成(ポスター発表の部)

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In the course of our screening program for novel antibiotics, we have isolated epoxyquinomicins A (1), B (2), C (3) and D (4) from the culture broth of Amycolatopsis sp. MK299-95F4. 1 and 2 showed weak antimicrobial activity against gram positive bacteria and cytotoxicity at the concentration of 2〜18μg/ml. 3 and 4 showed almost no antimicrobial activity and no cytotoxicity at the concentration of 100μg/ml. On the other hand, these antibiotics exhibited the improvement of collagen induced arthritis in vivo. The fermentation was carried out for 4 days with a medium consisting of glycerol, dextrin, Bacto-soytone, yeast extract and some inorganic salts. Butyl acetate extract of broth supernatant (1.8L) was concentrated, then purified by silica gel column chromatography to give pure 1 (18mg), 2 (19mg), 3 (44mg) and 4 (77mg). The structure of 1 was examined first. The molecular formula C_<14>H_<10>NO_6Cl was determined by HRFAB-MS. The structure of 1 was deduced by various NMR spectral analyses including ^1H-NMR, ^<13>C-NMR, ^1H-^1H COSY, HMQC and HMBC. X-Ray crystallography of 1 supported this structure in addition to absolute stereochemistry. Thus, 1 was determined to be (5R,6S)-2-(3-chloro-2-hydroxybenzoylamino)-5-hydroxymethyl-5,6-epoxy-2-cyclohexene-1,4-dione. 2 was elucidated to be dechlorinated derivative of 1 by comparison of the spectral data of 2 with those of 1. The differences in the molecular formula, ^1H- and ^<13>C-NMR spectra between 1 and 4 suggested that 4 possessed a hydroxyl group at C-1 position instead of keto group in 1. The trans orientation between C-1 hydroxy group and epoxy ring was determined by X-ray analysis. As the same manner, 3 was determined to be dechlorinated derivative of 4. Epoxyquinomicins have unique structures with highly oxidating. So we investigated the total synthesis of these compounds. 9 was prepared from commercially available 3-hydroxy-4-nitrobenzaldehyde in four steps (67% yield). During the reduction of nitro group in 9, salicyloyl group was migrated to give desired amide concomitant with the deprotection of phenolic acetate to afford 10. After deprotection of primary acetyl group, 11 was selectively oxidized with Fremy's salt to give a quinone 12. After epoxidation, the total synthesis of (±)-epoxyquinomicin B was achieved efficiently in 8 steps from 5 (11% total yield). Enantiomeric synthesis is now further investigating.
天然有機化合物討論会の論文
1997-07-20

103(P49) Epoxyquinomicin類の単離・構造決定および合成(ポスター発表の部)

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