The Synthesis of Azadirachtin: A Potent Insect Antifeedant

• Published in: Chemistry : a European journal Vol. 14; no. 34; pp. 10683 - 10704
• Main Authors: Ley, Steven V., Abad-Somovilla, Antonio, Anderson, James C., Ayats, Carles, Bänteli, Rolf, Beckmann, Edith, Boyer, Alistair, Brasca, Maria G., Brice, Abigail, Broughton, Howard B., Burke, Brenda J., Cleator, Ed, Craig, Donald, Denholm, Alastair A., Denton, Ross M., Durand-Reville, Thomas, Gobbi, Luca B., Göbel, Michael, Gray, Brian Lawrence, Grossmann, Robert B., Gutteridge, Claire E., Hahn, Norbert, Harding, Sarah L., Jennens, David C., Jennens, Lynn, Lovell, Peter J., Lovell, Helen J., de la Puente, Mary L., Kolb, Hartmuth C., Koot, Win-Jan, Maslen, Sarah L., McCusker, Catherine F., Mattes, Amos, Pape, Andrew R., Pinto, Andrea, Santafianos, Dinos, Scott, James S., Smith, Stephen C., Somers, Andrew Q., Spilling, Christopher D., Stelzer, Frank, Toogood, Peter L., Turner, Richard M., Veitch, Gemma E., Wood, Anthony, Zumbrunn, Cornelia
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 26-11-2008; WILEY‐VCH Verlag
• Subjects: Allene; azadirachtin; Bonding; Claisen rearrangement; Decalin; epoxidation; Insecticides - chemical synthesis; Insecticides - chemistry; Insects; Ketones; Limonins - chemical synthesis; Limonins - chemistry; Molecular Conformation; Natural products; Stereoisomerism; Synthesis; Synthesis (chemistry); total synthesis
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.200801103

We describe in full the first synthesis of the potent insect antifeedant azadirachtin through a highly convergent approach. An O‐alkylation reaction is used to unite decalin ketone and propargylic mesylate fragments, after which a Claisen rearrangement constructs the central C8C14 bond in a stereoselective fashion. The allene which results from this sequence then enables a second critical carboncarbon bond forming event whereby the [3.2.1] bicyclic system, present in the natural product, is generated via a 5‐exo‐radical cyclisation process. Finally, using knowledge gained through our early studies into the reactivity of the natural product, a series of carefully designed steps completes the synthesis of this challenging molecule.
The final chapter! We report full details of the first synthesis of azadirachtin, achieved in our laboratories following 22 years of study. This extremely complex natural product has finally succumbed to synthesis through a highly convergent strategy. We describe the iterative research process in which many synthesis pathways were explored.