Azadirachtin has a complex molecular structure; it presents both secondary and tertiary hydroxyl groups and a tetrahydrofuran ether in its molecular structure, alongside 16 stereogenic centres, 7 of which are tetrasubstituted. These characteristics explain the great difficulty encountered when trying to prepare this compound from simple precursors, using methods of synthetic organic chemistry. Hence, the first total synthesis was published over 22 years after the compound's discovery: this first synthesis was completed by the research group of Steven Ley at the University of Cambridge in 2007. The described synthesis was a relay approach, with the required, heavily functionalized decalin intermediate being made by total synthesis on a small scale, but being derived from the natural product itself for the gram-scale operations required to complete the synthesis.
Occurrence and use
Initially found to be active as a feeding inhibitor towards the desert locust, it is now known to affect over 200 species of insects, by acting mainly as an antifeedant and growth disruptor. It was recently found that azadirachitin possesses considerable toxicity towards African cotton leafworm, which are resistant to a commonly used biological pesticide, Bacillus thuringiensis. Azadirachtin fulfills many of the criteria needed for a good insecticide. Azadirachtin is biodegradable and shows very low toxicity to mammals. This compound is found in the seeds of the neem tree, Azadirachta indica. Many more compounds, related to azadirachtin, are present in the seeds as well as in the leaves and the bark of the neem tree which also show strong biological activities among various pest insects Effects of these preparations on beneficial arthropods are generally considered to be minimal. Some laboratory and field studies have found neem extracts to be compatible with biological control. Because pure neem oil contains other insecticidal and fungicidal compounds in addition to azadirachtin, it is generally mixed at a rate of 1 ounce per gallon of water when used as a pesticide. Azadirachtin is the active ingredient in many pesticides including TreeAzin, AzaMax, BioNEEM, AzaGuard, and AzaSol, Terramera Proof and Terramera Cirkil. Azadirachtin has a synergistic effect with the biocontrol agentBeauveria.
Biosynthesis
Azadirachtin is formed via an elaborate biosynthetic pathway, but is believed that the steroid tirucallol is the precursor to the neem triterpenoidsecondary metabolites. Tirucallol is formed from two units of farnesyl diphosphate to form a C30 triterpene, but then loses three methyl groups to become a C27 steroid. Tirucallol undergoes an allylic isomerization to form butyrospermol, which is then oxidized. The oxidized butyrospermol subsequently rearranges via a Wagner-Meerwein 1,2-methyl shift to form apotirucallol. Apotirucallol becomes a tetranortriterpenoid when the four terminal carbons from the side chain are cleaved off. The remaining carbons on the side chain cyclize to form a furan ring and the molecule is oxidized further to form azadirone and azadiradione. The third ring is then opened and oxidized to form the C-seco-limonoids such as nimbin, nimbidinin and salannin, which has been esterified with a molecule of tiglic acid, which is derived from L-isoleucine. It is currently proposed that the target molecule is arrived at by biosynthetically converting azadirone into salanin, which is then heavily oxidized and cyclized to reach azadirachtin.
