Azadirachtin is a C-seco limonoid, which was isolated as an insect antifeedant from the seeds of Azadirachta indica A. Juss in 1968. The highly functionalized structure, along with its biological activities, attracts many synthetic chemists; however, the total synthesis has not been achieved yet. Our strategy involves the coupling of the two fragments by Claisen rearrangement. We describe the syntheses of the decalin compound, the left fragment of azadirachtin, and the tricyclic compound, the right fragment. Furthermore, we investigated the Claisen rearrangement for construction of the C-8 and C-14 bond using the model compounds. At first, we elucidated the intramolecular Diels-Alder (IMDA) reaction to construct the decalin part of azadirachtin. The IMDA reaction of the hydroxyl-triene substrate proceeded under thermal conditions, which afforded a 2:1:1 mixture of decalin compounds. On the basis of these experiments, we developed the chiral synthesis of the decalin compound via asymmetric reduction, and obtained the chiral decalin product, which was converted into the desired four-cyclic compound in 16 steps. However, the attempted introduction of α-OH to C-1 of the product was unsuccessful. Therefore, we investigated an alternative route, and the carbonate of 1,3-dihydroxy triene compound was prepared in 17 steps from ethyl malonate. Its thermal IMDA reaction proceeded smoothly to afford two desired 1,3-oxidized decalin compounds, exclusively. On the other hand, the tricyclic acetal moiety could efficiently be obtained as an enantiomerically pure form from cyclopentadiene and the known acryloyl derivative in 21 steps in 25% overall yield. Furthermore, we also studied the coupling of the right and the left segments of azadirachitin. The Ireland-Claisen rearrangement using two model compounds proceeded selectively to afford the coupling products in good yields, respectively.
