52 光学活性キノカルシンの合成研究(口頭発表の部)

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Quinocarcin(1), the novel antitumor antibiotic isolated from Streptomyces melanovinaceus, exhibits promising antitumor activity. On treatment with sodium cyanide, 1 can be converted to the more stable cyano derivative, DX-52-1(3), which retains significant antitumor activity. Quite recently, the total synthesis of optically active 1 was completed by Garner et al., confirming its absolute stereochemistry. The novel structure and remarkable antitumor activity of 1 distinguish this molecule as one of the most intriguing targets for total synthesis. We embarked on the studies aiming at the total synthesis of optically active 1, and succeeded in developing a novel synthetic scheme to enantiomeric pairs of the A B E (10 and ent- 10), the A B C(23, ent- 23, 24, and ent- 24), and the A B C D ring systems(44, ent- 44, 45, and ent- 45) of 1. The key feature of our synthetic approach to optically active 1 and its analogues consists of diastereoselective reduction of the 3,4-dihydroisoquinoline(6)and the isoquinoline derivatives(7, 8, and 9) to control the stereochemistries at C-1 and C-3 positions(isoquinoline numbering). For construction of the A B E ring system(10), crucial reduction of 6 derived from the anisole(13) and the D-threose derivative(5) with sodium cyanoborohydride was found to proceed in a highly diastereoselective manner to afford the tetrahydroiso-quinoline(15) as a sole product. This was further elaborated to 10 in 6 steps. By employing the L-threose derivative(ent- 5) instead of 5, ent- 10 could be similarly produced by way of ent- 15. The syntheses of the A B C(23, ent- 23, 24, and ent- 24) and the A B C D ring systems(44, ent- 44, 45, and ent- 45) have also been achieved by application of the above synthetic strategy. Furthermore, in vitro cytotoxicity assay(P388) performed on the congeners of 1 obviously disclosed that 44 and 45 are at least 10 times more cytotoxic than 1.
天然有機化合物討論会の論文
1992-09-10

52 光学活性キノカルシンの合成研究(口頭発表の部)

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