P-48 転位反応を活用したアゲラスタチンAとコナゲニンの合成研究(ポスター発表の部)

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Over the last few years, we have embarked on the development of the synthesis of allyl cyanate and its rearrangement. This reaction offers an efficient transformation of the ally alcohols into the allyl amines with high stereospecific manner even when the allyl alcohols are highly substituted at the γ-positions. Applications of this rearrangement in the context of the natural products synthesis have realized a new approach to the synthesis of agelastatin A and total synthesis of conagenin. Agelastatin A (1) is an architecturally unique cytotoxic tetracyclic alkaloid. Pietra and co-workers first isolated (-)-1 from the axinellid marine sponge Agelas dedromorpha in 1993. Importantly, at low concentration this alkaloid exhibits potent cytotoxicity against L1210 in mice and human KB nasopharyngeal tumor cell lines. Synthetic approach to the agelastatin A (1) is presented. Conagenin (1) is a unique biologically important secondary metabolite isolated from the culture broths of Streptomyces roseosporus by Ishizuka and co-workers. This compound stimulates activated T cells as a low molecular weight immunomodulator, and was found to improve the antitumor efficacy of adriamycin and mitomycin C against murine leukemias, which suggest its potential utility for cancer chemotherapy. Not surprisingly, therefore, conagenin has been attractive target for the synthetic chemist, and two total syntheses of 1 have now been reported, in addition to formal synthesis and synthesis of its analogues. An efficient total synthesis of (+)-conagenin was achieved. The right fragment of conagenin, α-methylserine containing quaternary stereocenter attached to nitrogen, was synthesized using allyl cyanate-to-isocyanate rearrangement. The left fragment, 2,4-dihydroxy-3-methylpentanoic acid, has three contiguous stereogenic centers, which was efficiently constructed by enantioselective monoreduction of 2-alkyl-1,3-diketones reported by Cossy, and chelation-controlled stereoselective reduction of β-hydroxy ketone. These two fragments were coupled through intramolecular amide bond formation with high efficiency.
天然有機化合物討論会の論文
2005-09-15

P-48 転位反応を活用したアゲラスタチンAとコナゲニンの合成研究(ポスター発表の部)

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