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

印楝素是一种C-seco类柠檬素，是从热带印楝树印楝中分离出来的一种强驱虫剂和昆虫拒食剂。尽管它对昆虫有很高的活性，但印楝素没有明显的植物毒性，对高等生命形式也没有明显的毒性。因此，印楝素有望成为理想的生态杀虫剂。它的高功能化结构和生物活性促使我们朝着全合成的方向发展，但尚未有报道。特别是，由于C-8和C-14的位置严重受阻，左右节段的连接仍然没有解决。我们的合成策略包括使用Ireland-Claisen重排来耦合左右段。我们已经报道了用Diels-Alder反应在左段合成十氢化萘部分，在右段合成三环二氢呋喃部分。但是，所得到的十氢萘酯不能水解成相应的羧酸。在目前的研究中，我们发现TMSE酯可以很好地转化为所需的十萘酸。这种酸与烯丙醇偶联成重排前体。另一方面，我们还发现模型酯的锂烯醇酯与Me_2SiCl_2在甲苯中进行了Ireland-Claisen重排，可以立体选择性地获得所需的类柠檬骨架。氯二甲基硅基的配位可归因于z -硅基烯缩醛的优势，从而产生所需的重排产物。据我们所知，这种立体控制克莱森重排是前所未有的。这种新的Claisen重排可以应用于功能化酯，并对重排产物的功能转化进行了研究。因此，研究者认为本研究可以为印楝素的全合成开辟一条道路。

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.