How diverse are our drugs anyway? Assuming that molecular shape is dominant in pharmaceutical effectiveness, you would expect our drugs to come in all sorts of shapes otherwise they would all compete for the same biochemical spot. An intriguing plot presented by Beckmann et al. here reveals that is not the case and in the big triangle between disk (benzene), rod (acetylene) and sphere (adamantane) most drugs huddle together between rod and disk and few venture into sphere territory. But Beckmann et al. are doing something about that: producing more sphere-shaped molecules. The keywords are diversity-oriented synthesis , a build/couple/pair (B/C/P) strategy, fluorous chemistry and macrocycles.
Starting point in the Beckmann research research is a propargylic amine, the amine end of which is fitted with a detachable organofluorine segment for easy of separation later on, and with an azide carrying group. This is the build phase. In the couple phase the the azide is then converted to an aza-ylide which is then reaction with a number of electrophiles. In the third step, the pairing, the linear molecules are coupled end-to-end to macrocycles using a number of techniques such as click chemistry and enyne metathesis. In the final step in creation of diversity the fluorous tag was cleaved and replaced by a number of ester residues. In all, 59 compounds were created in 5 steps from a single precursor.
The sphere concept is here to stay? Not related in any way to the Backmann research it must explain the sudden interest in the otherwise totally obscure cavicularin as a target in total synthesis.