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

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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.