Credit: © 2008 Wiley

Access to large libraries of compounds that have a wide range of structures and shapes is essential in the search for new drugs. However, the compounds that have actually been prepared and exist in the chemical libraries of researchers and pharmaceutical companies represent only a very small fraction of possible structures. Diversity-oriented synthesis is aimed at solving this problem by rapidly preparing compound libraries with high substitutional and stereochemical diversity.

Now, Adam Nelson and co-workers, from the University of Leeds in the UK, have developed1 a method that allows the preparation of over eighty distinct scaffolds using a combination of just six reactions. Each unique molecular scaffold is produced by the attachment of two simple unsaturated building blocks to a linker, followed by a metathesis cascade — which not only forms the scaffold but releases the product from the linker. Using a polyfluorinated linker enables easy purification throughout the synthesis, and avoids the need for column chromatography until the final product is released.

Nelson and co-workers have used the method to produce a huge variety of acyclic and cyclic compounds — including carbocycles and nitrogen- and oxygen-containing heterocycles — with different ring sizes and in good yields (an average of 46%). The dense substitution and multiple stereogenic centres in the products mean that they can truly be described as natural-product-like.