23 カイトセファリン及びその類縁体の合成研究(口頭発表の部)
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概要
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Kaitocephalin (1), a novel AMPA receptor antagonist, was isolated from Eupenicillium shearii PF1191 by Seto, Shin-ya and co-workers, and its absolute configuration was shown to be 1. We were interested in this unique structure and its potent biological activities, and have been investigating stereoselective synthesis of kaitocephalin and its analogs to determine the absolute configuration of 1 and to clarify the structure-bioactivity relationships. A synthesis of compound 1b was accomplished employing a stereoselective C-C bond formation reaction under sonication condition with zinc and CuI (6b+7→8b) as a key step (Scheme 1). Unfortunately, ^1H-NMR spectral data of 1b was not identical with those of natural compound. Then, 9-epi-1b was synthesized in the same manner (Scheme 2), but this compound was not identical either. It was assumed that the stereochemistry of natural kaitocephalin have been assigned incorrectly. So, ^1H-NMR spectra of model compounds 14a-d (14c has not been synthesized yet), particularly, chemical shifts and coupling constants of H-2 and H-3 were compared. As shown in Fig. 1, 14d showed the most similar pattern to that of natural kaitocephalin. We therefore assumed that the correct stereostructure of natural kaitocephalin should be 1d and a synthesis of 1d was carried out in the same manner as shown in Scheme 4. The ^1H-NMR spectrum of compound 1d was identical with natural one. At present, we are confirming the stereochemistries of the intermediates and optimizing the each reaction condition. Thus, we developed the efficient route to the synthesis of kaitocephalin skeleton and tentatively concluded the correct relative configuration of natural kaitocephalin to be 2R^*, 3S^*, 4R^*, 7R^*, 9S^*. Antagonistic activity of 1b, 9-epi-1b, 14a, 14b, 14d and 15 to the kainate toxicity on rat hippocampal neurons are shown in Table 1. Compounds 1b and 9-epi-1b showed weaker activities than the natural compound. On the other hand, analogs 14a, b, d and 15 showed no inhibition activities.
- 天然有機化合物討論会の論文
- 2001-09-01
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