4 抗腫瘍性物質カズサマイシンの全合成研究(口頭発表の部)

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Kazusamycin, which was isolated as a metabolite of actinomycete strain 81-484, attracts much attention due to its potent antitumor activity on P388 leukemia and sarcoma 180. It was also effective in completely preventing growth of HeLa cells at a concentration of 3.3ng/ml. On the other hand, from the structural point of view, only its planar structure was elucidated, and both its absolute configuration and complete relative configuration remain unknown. We are making an effort on the total synthesis of Kazusamycin in order to determine its absolute configuration and to establish a practical synthetic route for the biological assay. Retrosynthetic fragmentation of Kazusamycin affords two major segments, which we planned to prepare from medium-sized synthetic units, Segment A-E (Fig. 1). Segment A was prepared by using Pd(0) mediated coupling reaction between a chiral zinc homoenolate 3 and an alkenyl halide 4. On the preparation of Segment B, we initially planned to desymmetrize a dihydroxyketone 1 by enzymatic acetylation, however, the ee of the product never exceeded a moderate level. After several investigations, it was found that enzymatic kinetic resolution of rac-7 was successfully employed in the preparation of almost optically pure hydroxy ketone 7, which was protected by silylation to afford Segment B. The pivotal step in this synthetic study is the construction of four contiguous chiral centers, which might be realized by the stereoselective aldol reaction between Segment A and B. We performed the aldol reaction under the conditions developed by I. Paterson et al., in which high stereoselectivity was obtained with a related substrate by means of chelation control with tin(II) triflate. It was revealed that a comparable level of stereoselection was also observed in our case, and this methodology was applicable to the connection of A and B, affording an intermediate leading to one of the two major segments. We have also succeeded to synthesize another Segment D and E (Segment C is commercially available). Studies on the connection of these segments to construct the whole structure of Kazusamycin are now underway.
天然有機化合物討論会の論文
2002-09-01

4 抗腫瘍性物質カズサマイシンの全合成研究(口頭発表の部)

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