Macrocycles and what I think about them

This past Summer I was asked by the Editorial Board of Chemical Science to write a Perspective on macrocycles. At first I was not sure what I would do because there were so many detours I could have taken (from synthesis all the way to applications). No matter how hard I wanted to narrow in on one theme, I ultimately decided to focus on the evolution of this exciting field, using various landmarks to weave my story around. I chose to talk about many different, seemingly unrelated, subjects that bear on macrocycles as a class of molecules with tremendous upside in drug discovery. Overall, this turned into a fun exerience. As they say in Russia “anything new is a well-forgotten past,” which is certainly a good thing to remember when looking at a field of research that is interesting to so many people. One of the attractive things about a perspective is that its author is not expected to be comprehensive. The choice of material is up to you. Deciding on interesting examples is what I did on my train rides from home to work over the past several months as I was writing this paper. You will note that I am the only author. I suppose this is something that is much easier to do nowadays with software such as Papers3 that allows one to nicely organize manuscripts. I also think that it is also appropriate to write papers without graduate students or postdocs once in a while, especially when it comes to opinionated pieces. Actually, I think that perspectives should ideally be written by one person, otherwise the whole point is not entirely clear. I love writing papers with my students, but I also found this solo business to be satisfying. As a prelude to this work, I would offer this: it is really tough to control the so-called chi-space, the one that defines conformational movement of side chains. There is a big irony in overemphasizing the significance of new ways to form macrocyclic ring structures: these studies offer constraints over phi and psi dihedral angles, but they provide little towards control of chi-space, which defines the orientation of side chains. Many of the problems I have outlined in my article can be fixed if synthetic chemists think more about how to modify the existing rings, understand their conformational preferences, and control side chains in effort to make bioactive structures for protein targets.