August 20, 2007

Volume 85, Number 34

p. 12

Organic Synthesis

Azadirachtin At Last

After more than two decades, chemists succeed at making complex natural product

Bethany Halford

IT TOOK 22 YEARS and the efforts of more than 40 chemists, but Steven V. Ley's group has finally managed to complete a 64-step synthesis of azadirachtin, a naturally occurring insecticide (Angew. Chem. Int. Ed., DOI: 10.1002/anie.200703027 and 10.1002/anie.200703028).

Isolated from the Indian neem tree Azadirachta indica, azadirachtin possesses a small but densely functionalized architecture. It has 16 stereogenic centers, seven of which are tetrasubstituted, and a diverse array of oxygenated functionalities.

"This has been a tough project from start to finish, as the molecule is so prone to rearrangement under acidic, basic, or photolytic conditions," says Ley, a chemistry professor at England's Cambridge University. "It has forced us to be inventive."

Of the many hurdles the researchers had to overcome, Ley reckons the most challenging was coupling the molecule's two main fragments. After years of attempts at this convergent approach, the group was finally able to marry these two fragments by means of a propargylic enol ether Claisen reaction. The next step, a radical-induced cyclization, elegantly constructed one sterically dense portion of the molecule.

"Making a molecule such as this is not an Everest-climbing exercise; it's about what you learn from the experience," Ley says. "We can be proud of the new methods and solutions to the tough problems we have encountered, and now we have the tools and procedures to really work out how this molecule functions biologically."

Amos B. Smith III, a chemistry professor at the University of Pennsylvania, calls the work "an outstanding achievement, further demonstrating Ley and colleagues as superb tacticians in the art of complex-molecule total synthesis."

Smith adds: "More important than the actual conquest is the exciting new chemistry that has emanated over the past 22 years from the Ley and other laboratories who have participated in this monumental challenge. Clearly, the science of synthesis is the winner."

Chemical & Engineering News

ISSN 0009-2347

Copyright © 2011 American Chemical Society