Synthetic Studies on Insect Repellent Agent, Azadirachtin, and its Mechanistic Studies

驱虫剂印楝素的合成研究及其作用机理研究

• 批准号: 13680665
• 负责人: ISHIHARA Jun
• 金额: $ 2.3万
• 依托单位: HOKKAIDO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13680665/
• 关键词: insect antifeedant; azadirachtin; Diels-Alder reaction; Claisen rearrangement; 昆虫忌避物質; 昆虫摂食阻害物質

Azadirachtin is a C-seco limonoid, isolated as a strong insect repellent agent and an insect antifeedant, from tropical neem tree Azadirachta indica. Despite its high activity against insects, azadirachtin shows no apparent phytotoxicity and is remarkable non toxic to higher forms of life. Thus azadirachtin is expected as a top candidate for ecological and ideal insecticides. Its highly functionalized structure as well as biological activities urged us toward the total synthesis of this compound, which has not yet been reported. In particular, the connection of the right and left segments remains unsolved due to the seriously hindered positions at C-8 and C-14. Our synthetic strategy involves coupling the right and left segments using Ireland-Claisen rearrangement. We have already reported the syntheses of the decalin portion as the left segment and the tricyclic dihydrofuran moiety as the right segment by means of Diels-Alder reaction. However, resulting decalin ester could not be hydrolysed to the corresponding carboxylic acid. In the present studies, we found that the TMSE ester is convertible to the desired decalin acid in a good yield. This acid was coupled with allylic alcohol to the precursor of rearrangement. On the other hand, we also found that the Ireland-Claisen rearrangement of Li-enolate of the modeled ester with Me_2SiCl_2 in toluene afforded the desired limonoid framework stereoselectively. The coordination of the chlorodimethylsilyl group would be attributed to the predominance of the Z-silyl ketene acetal, generating the desired rearranged product. This type of stereocontrolled Claisen rearrangement is unprecedented to the best of our knowledge. This novel Claisen rearrangement could be applied to the functionalised ester, and the functional transformation of the rearranged product was also investigated. Consequently, the investigator believes that this present studies can open a path to the total synthesis of azadirachtin.

印楝素是从印度印楝中分离得到的一种C-开环柠檬苦素类化合物，具有强烈的驱虫和拒食作用。尽管印楝素对昆虫有很高的活性，但它没有表现出明显的植物毒性，对高等生物也是无毒的。因此印楝素有望成为一种理想的生态杀虫剂。它的高度功能化的结构以及生物活性促使我们对这个化合物的全合成，这是尚未报道。特别是，由于C-8和C-14的位置严重受阻，右节和左节的连接仍然没有解决。我们的合成策略涉及使用Ireland-Claisen重排偶联左右片段。我们已经报道了通过Diels-Alder反应合成作为左链段的十氢萘部分和作为右链段的三环二氢呋喃部分。然而，所得十氢萘酯不能水解成相应的羧酸。在本研究中，我们发现TMSE酯可以以良好的产率转化为所需的十氢萘酸。该酸与烯丙醇偶联成为重排的前体。另一方面，我们还发现，在甲苯中，模型酯的Li-enolate与Me_2SiCl_2的Ireland-Claisen重排立体选择性地提供了所需的柠檬酸类骨架。氯二甲基甲硅烷基的配位将归因于Z-甲硅烷基烯酮缩醛的优势，产生所需的重排产物。据我们所知，这种立体控制的克莱森重排是前所未有的。这种新的克莱森重排反应可以应用于功能化酯，重排产物的功能转化也进行了研究。因此，本研究为印楝素的全合成开辟了一条新的途径。

项目成果

T.Tsujimoto: "Asymmetric Construction of the Azaspiro[5.5]undec-8-ene System towards Gymnodimine Synthesis"Synlett. No.3. 399-402 (2002)

T.Tsujimoto：“Azaspiro[5.5]undec-8-ene 系统的不对称构建，用于 Gymnodimine 合成”Synlett。

J.Ishihara: "Asymmetric Construction of the Azaspiro[5.6]dodec-9-ene System in Marine Natural Toxins"Synlett. No.3. 403-406 (2002)

J.Ishihara：“海洋天然毒素中 Azaspiro[5.6]dodec-9-ene 系统的不对称构建”Synlett。

T. Tsujimoto: "Asymmetric Construction of the Azaspiro[5.5]undec-8-ene System towards Gymnodimine Synthesis"Synlett. (in press). (2002)

T. Tsujimoto：“Azaspiro[5.5]undec-8-ene 系统的不对称构建，用于合成裸二胺”Synlett。

T.Fukuzaki: "Studies Aimed at the Total Synthesis of Azadirachtin. A Modeled Connection of C-8 and C-14 in Azadirachtin"Organic Letters. 4・17. 2877-2880 (2002)

T.Fukuzaki：“印楝素的全合成研究。印楝素中 C-8 和 C-14 的模拟连接”有机快报 4・17（2002 年）。

J. Ishihara: "Asymmetric Construction of the Azaspiro[5.6]dodec-9-ene System in Marine Natural Toxins"Synlett. (in press). (2002)

J. Ishihara：“海洋天然毒素中 Azaspiro[5.6]dodec-9-ene 系统的不对称构建”Synlett。