Azadirachtin (1) is a C-seco-limonoid isolated from the neem tree Azadirachta indica A. Juss (Meliaceae) and possesses potent antifeedant and growth inhibitory activities. Its complicated structure as well as its activities fascinate synthetic chemists and many synthetic efforts have been made, but the total synthesis of Azadirachtin has not been reported yet. Now we achieved a synthesis of model compound 2 which was fully functionalized at the dacalin moiety using an intramolecular Diels-Alder reaction and a radical cyclization as key reactions. In order to construct A-ring and the bridged ether, the intramolecular Diels-Alder reactions of 12 and 15 were examined, but the desired endo adducts 13 and 16 were obtained in low selectivity. So we devised the Diels-Alder reaction-decarboxylation-Claisen rearrangement strategy to use the undesired exo adduct. The intramolecular Diels-Alder reaction of 37 gave a cyclization-decarboxylation product 38 which was converted into 39 through Claisen rearrangement. In this process one carbon atom which was lost by decarboxylation could be recovered. The correct stereochemistries at C-3 and C-4 positions of Azadirachtin was introduced by oxidative cleavage of hydroxycyclohexenone ring followed by ozonolysis and aldol reaction (40→43). B-ring formation was then examined and radical cyclization (48→2) was found to proceed smoothly with controlling the newly-introduced stereochemistries. In summary, model compound 2, which had a fully functionalized decalin unit of Azadirachtin, was synthesized efficiently in short steps (19 steps). Other possible modes of radical cyclization such as 50→52 and 51→52 toward the total synthesis of Azadirachtin are now under investigations.
