Synthetic Studies on Furan-fused Polycyclic Natural Products and Its Derivatives

呋喃稠合多环天然产物及其衍生物的合成研究

• 批准号: 12672049
• 负责人: NEMOTO Hideo
• 金额: $ 2.18万
• 依托单位: TOYAMA MEDICAL AND PHARMACEUTICAL UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12672049/
• 关键词: halenaouinol; sodium salt of sulfate; anti-virus activity; o-quinozimethane; benzocyclobutene; dihydrofuran; retro-electron-demanded Diels-Alder reaction; Sendai virus; 多環系天然物; 分子内環化付加反応; 四環系化合物; アマンタジン; フラン環; 抗ウィルス剤

Halenaquinol and sodium salt of its sulfate were isolated from the Okinawan sponge Xestospongia sapra by Kitagawa and co-workers in 1985. These interesting marine natural products possess the significant biological activities such as cytotoxic, antibiotic protein tyrosine kinase inhibitory activities, especially, the sodium salt of sulfate showed unique anti-virus activity. We designed the furan-fused polycyclic compound based on the structure of sodium salt of sulfate as a new type of anti-virus agent, and applied the o-quinozimethane chemistry as the key step for the construction of the above polycyclic ring system. The thermal reaction of the benzocyclobutenes, precursors of oquinozimethane, proceeded nicely to give the intramolecular [4+2] cycloaddition products as a single isomers. The stereochemistry at the newly formed quartanary benzylic and dihydrofuran position was determined to be cis form by an X-ray analysis. This stereoselectivity could be rationalized in term of secondary orbital effect between the electron deficient o-quinozimethane ring and electron rich furan ring in the retro-electron-demanded Diels-Alder reaction. Consequently, the reaction proceeded via the endo transition state to afford the cis products. Among the compound synthesized above, the TIPS derivative showed significant activity against Sendai virus, and inhibited the growth of the virus at the concentration more than 1.25μg/mL.

Halenaquinol及其硫酸盐的钠盐由Kitagawa及其同事于1985年从冲绳海绵Xestospongia sapra中分离出来。这些海洋天然产物具有明显的生物活性，如细胞毒活性、抗菌活性、蛋白酪氨酸激酶抑制活性等，其中硫酸钠具有独特的抗病毒活性。基于硫酸钠盐结构设计了呋喃稠合多环化合物作为新型抗病毒剂，并应用邻醌偶氮甲烷化学作为构建上述多环体系的关键步骤。苯并环丁烯类化合物是醌偶氮甲烷的前体，它们的热反应进行得很好，得到了分子内的[4+2]环加成产物。在新形成的四元苄基和二氢呋喃位置的立体化学通过X射线分析确定为顺式形式。这种立体选择性可以用反电子需求的Diels-Alder反应中缺电子的邻醌基甲烷环和富电子的呋喃环之间的次级轨道效应来解释。因此，反应通过内过渡态进行，得到顺式产物。在上述合成的化合物中，TIPS衍生物显示出显著的抗仙台病毒活性，并且在大于1.25μg/mL的浓度下抑制病毒的生长。

项目成果

Toyooka, N., Nagaoka, M., Kakuda, H., Nemoto, H.: "Rapid Access to the Potential Intermediate for the Synthesis of Halenaquinol and Halenaquinone"Synlett. 1123-1124 (2001)

Toyooka, N.、Nagaoka, M.、Kakuda, H.、Nemoto, H.：“快速获得用于合成海萘醌和海萘醌的潜在中间体”Synlett。

Yoshida.M, Abdel-Hamid, Ismail.M, Nemoto.H, Ihara.M.: "Asymmetric total synthesis of (+)-equilenin utilizing two types of cascade ring expansion reactions of small ring systems"J. Chem. Soc, Perkin Trans. 1. 2629-2635 (2000)

Yoshida.M、Abdel-Hamid、Ismail.M、Nemoto.H、Ihara.M.：“利用两种类型的小环系统级联扩环反应不对称全合成 ( )-马萘雌酮”J。

Toyuoka, N., Nagaoka, M., Kakuda, H., Nemoto, H.: "Rapid Access to the Potential Intermediate for the Synthesis of Halenaquinol and Halenaquinone"Synlett. 1123-1124 (2001)

Toyuoka, N.、Nagaoka, M.、Kakuda, H.、Nemoto, H.：“快速获得用于合成海萘醌和海萘醌的潜在中间体”Synlett。

Yoshida, M., Abdel-Hamid Ismail M, , Nemoto, H., Ihara, M.: "Asymmetric total synthesis of (+)-equilenin utilizing two types of cascade ring expansion reactions of small ring systems"J. Chem. Soc., Perkin Trans. 1. 2629-2635 (2000)

Yoshida, M.、Abdel-Hamid Ismail M、、Nemoto, H.、Ihara, M.：“利用两种类型的小环系统级联扩环反应不对称全合成 ( )-马萘雌酮”J。

Hamada, H., Tanaka, T., Furuya, T., Takaharta, H., Nemoto, H.: "Hydroxylation of benzylic and allylic sites by plant cultured suspension cells"Tetrahedron Lett.. 42. 909-911 (2001)

Hamada, H.、Tanaka, T.、Furuya, T.、Takaharta, H.、Nemoto, H.：“植物培养的悬浮细胞对苯甲基和烯丙基位点的羟基化”Tetrahedron Lett.. 42. 909-911 (2001)