著者

小口 剛正 渡邉 一弘 阿部 秀樹 加藤 正

出版者

天然有機化合物討論会

雑誌

天然有機化合物討論会講演要旨集

巻号頁・発行日

no.49, pp.521-526, 2007-08-24

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(-)-Nalanthalide (1), isolated from the culture of Nalanthamala sp., was found to be a novel blocker of the voltage-gated potassium channel Kv 1.3 by Merck research group. In human T cell, to block Kv1.3 channels cause to prevent membrane depolarization, which attenuates intarcellular Ca^<2+> levels for T cell activation and proliferation. Therefore, (-)-1 is expected to be a promising new lead for the immunosuppressant. A closely related diterpenoid α-pyrone (+)-sesquicillin (2), wherein the γ-pyrone ring of (-)-1 is replaced with an α-pyrone ring, was previously isolated from Acremonium sp. It was reported that (+)-2 shows a variety of biological properties such as glucocorticoid antagonist. anti-inflammatory, anticancer, and G1 phase arrest activities. We envisioned that (+)-(2) would be elaborated through conversion from the γ-pyrone ring of (-)-1 to the corresponding a-pyrone ring. And (-)-(1) would be available through a coupling of 4 with 3. The intermediate 5 would be available through the strategic [2,3]-Wittig rearrangement of 6. The synthesis began with the preparation of intermediate 6, the substrate for the key [2,3]-Wing rearrangement, starting from 8. After conversion of 8 to 6, we carried out the [2,3]-Wittig rearrangement under several reaction conditions. Finally, we found that the designed [2,3]-Wittig rearrangement of 6 proceeded smoothly and cleanly by treatment with n-butyllithium in n-hexane at-50℃→room temperature. In this reaction, the use of n-hexane as the solvent was crucial. After conversion of 5 into 4, the coupling of 4 with 3-Iithio-γ-pyrone was achieved an initial bromine/lithium exchange on 3. The coupling product was converted to the key intermediate 19. Acetylation of 19 furnished (-)-(1). Next, we attempted direct conversion of (-)-(1) to (+)-(2) under several basic conditions; however, undesired deacetylation of the C3 acetyl group in (-)-1 occurred. Consequently, conversion of the γ-pyrone ring in 19 to the α-pyrone ring under basic conditions was conducted; the desired diacetate 20 was obtained upon acetylation of the product. Finally, selective deacetylation of the α-pyrone moiety in 20 under mild basic conditions furnished (+)-(2).