92(P-20) 抗腫瘍性抗生物質phomopsidinの全合成研究(ポスター発表の部)

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Phomopsidin was isolated from Phompsis sp. TUF95F47 by Namikoshi and co-workers in 1997, and its absolute structure and biological activity have been reported. Phomopsidin and its geometrical isomer (MK8383) showed potent inhibitory activity against assembly of microtubule proteins, exhibiting strong antitumor activity. It has been proposed that phomopsidin could be generated via the IMDA reaction of 1. Therefore, the potent antitumor activity and this biosynthetic background draw our attention to the synthesis of phomopsidin. We planned to synthesize the cis-decalin core 2 of phomopsidin first, and the side chain in the last stage of the synthesis because we anticipated that the IMDA reaction of 1 would hardly proceed as the (E,Z,E)-triene must take the energetically disfavored s-cis conformation in the IMDA reaction. The compound 2 was surmised to be constructed via the IMDA reaction of the open-chain triene 4, which would be synthesized by one-pot Suzuki-Miyaura coupling of alkyne 5 with iodoalkene 6. The synthesis of triene 4 was started from commercially available chiral alcohol 8. Conversion of 8 to trienes 14 and 15 proceeded in high yield. However, the IMDA reaction of the open-chain triene 14 afforded no cycloadduct, and that of 15 afforded an undesired cycloadduct. Hence, next we planned to synthesize the compound 2 via the TADA reaction of macrolactone 19. Commercially available alcohol 23 was successfully converted to macrolactone 29 in 17 steps. Heating macrolactone 29 in toluene for 24h provided the desired cycloadduct 30 selectively (2:1). The structure of 30 was confirmed by NOE experiment. In summery, we have succeeded in an asymmetric, stereoselective synthesis of the cis-decalin core of phomopsidin via the TADA reaction of 29. The last stage of the total synthesis of phomopsidin, that is, constructing the side-chain moieties, is now in progress.
2003-09-01

92(P-20) 抗腫瘍性抗生物質phomopsidinの全合成研究(ポスター発表の部)

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