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David Bradley ISSUE #68
September 2007
Steven Ley
Insecticidal Synthesis

Professor Steven Ley of Cambridge University and his colleagues over the last two decades have been on a chemical odyssey. They have endeavored to find a way to make a natural insecticide originally extracted from the Indian neem tree in 1968. Finally, the efforts of forty PhD chemistry students and many others they have found a way to construct azadirachtin in a total synthesis of 64 individual chemical reaction steps.

Without tooth or claw, plants often turn to chemical weapons to defend themselves against insect attack. Azadirachtin is one such natural chemical weapon. It is a hugely complex natural product molecule with numerous different types of carbon centers, various molecular rings and joints, and a host of other conundrums with which the chemist is faced in attempting to make it from simple starting materials.

Azadirachtin occurs naturally in the neem tree, or Indian lilac (Azadirachta indica) and inhibits the development of insect larvae among a wide range of destructive insects. It is harmless to mammals and does not affect beneficial insects, such as bees and ladybirds. Understanding the chemistry of azadirachtin could improve our understanding not only of insect behavior but may also lead to simpler and stable analogs that might be used as safe, naturally derived insecticides in agriculture.

Ley's team recently published their total synthesis in the journal Angewandte Chemie where they described the molecule as an "exceptionally challenging synthetic target by virtue of its sixteen contiguous stereogenic centers and complex pattern of oxygen-containing functionalities."

The structure of this complicated molecule was published in 1985, after a long, intensive research effort. The difficulties in devising a total synthesis stems partly from the sixteen stereocenters in the molecule—carbon atoms to which different chemical groups can be attached in mirror image arrangements. Those, coupled with the complex pattern of oxygen-containing groups, the molecule's complex conformation, and its chemical reactivity and light sensitivity, all conspired against brave chemists for decades.

"While we have been working on this complex synthesis," says Ley, "we have also developed a number of new methods that are of general use for the construction of other important molecules." One of the key steps in making the molecule involve a so-called Claisen rearrangement and a novel radical cyclization reaction.

Angew Chem, Int Edn, 2007, in press http://dx.doi.org/10.1002/anie.200703028

http://www.ch.cam.ac.uk/staff/svl.html