The title of the paper by Richard Taylor and colleagues speaks for itself: “Rings in Drugs”. Below you can see the top 6 rings from marketed pharmaceuticals. I am also showing a morpholine (number 29) and a beta-lactone (the last ring on the list of top 100). Macrocycles were not considered in this study as maximum single ring size was set at 9. There are several interesting “ring” anecdotes in this paper. For instance, approximately six new ring systems enter drug space annually. Here is a somewhat surprising fact for those of us who are interested in asymmetric synthesis: 40% of drugs do not contain any sp3 carbons in a ring system.
In my view, this paper provides a compelling rationale for going after novel heterocycles. In this regard, I recalled an interesting study published by Erick Carreira’s lab several years ago. In it, the authors made a point about a novel spirocyclic ring that had subtly perturbed the established electronic structure of morpholine. In the graphic below, you can see the relative orientation of the oxygen lone pairs that is clearly different in the two structures. Due to the fact that biological activity of a small molecule can often be traced back to the vectorial relationship of electron pairs on heteroatoms at key positions, the oxetane unit has been employed to expand the chemical space around morpholine. Because morpholine is common (number 29 in the Taylor study), its oxetanyl analogues have found wide use. And so shall many other, yet to be identified, heterocycles that are “vectorially challenged”!