111(P-38) 新規抗腫瘍活性天然物TMC-69及び誘導体の合成研究(ポスター発表の部)
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A novel antitumor antibiotic, TMC-69 (1) has been isolated from the fermentation broth of Chrysosporium sp. TC 1068. Although 1 was very unstable compound, hydrogenation of 1 gave the stable derivative TMC-69(6H) (2). 2 showed cytotoxic activities in vitro against various tumor cell lines (cf., HCT-116, IC_<50>=0.70μM) and exhibited potent antitumor activity in vivo against B16 melanoma in mice (ip-ip, 1.25mg/kg, ILS=106%). It has also been turned out that 2 has inhibitory activity against protein phosphatase cdc25A (IC_<50>=3.1μM), the key enzyme of cell cycle progression. The unique structure as well as significant biological activities of TMC-69 derivatives prompted us to investigate the synthesis of this class of compounds to clarify the structure-bioactivity relationship. Herein we wish to report concise and efficient route to TMC-69 derivatives using Knoevenagel condensation as a key step. First, the simplified analogue, 17-demethyl derivative 8, was chosen as a target compound. Thus the known pyranone 9 was silylated to 10 followed by 1,4-addition of methylcuprate gave the ketone 11. The Wittig olefination of 11 using n-octyltriphenylphosphonium bromide gave 12a (Z-isomer) and 12b (E-isomer). The major product 12a was desilylated to give the pyranol 13. The Knoevenagel reaction of the pyridone 20 and the pyranol 13 using ethylenediammonium diacetate proceeded stereoselectively and the desired 7,8-trans isomer 21 was obtained as a sole product. Stereoselective hydrogenation of 21 using Ir-black, followed by debenzylation under catalytic hydrogenation condition gave 17-demethyl analogue 8. Next, we turned our attention to enantioselective synthesis of TMC-69(6H)(2). Since the absolute stereochemistry of TMC-69(1) was not determined, degradation study of 1 was performed. As the results, the absolute stereochemistries on the pyrane ring were tentatively assigned as 7R, 8R by the modified Mosher's method. Synthesis of optically active TMC-69(6H)(2) is under investigation.
- 2000-10-01
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