I meant to write about this paper at the time, but there’s no harm in highlighting it now. A group at the University of Toronto reports a neat way to make some unusual macrocycles, by closing down an amine and a carboxylic acid into an oxadiazole with the known isonitrile phosphorane reagent shown. You bring in one more carbon from an added aldehyde (propionaldehyde in most of their examples, so you turn an X-atom-long chain into an X+2-sized macrocycle.
The paper has a whole list of example where oligopeptides are closed to peptidic oxadizole macrocycles, giving 15- to 24-membered rings. Yields are often down in the 30s and 40s, sometimes below, but sometimes up into the 60% range as well. You may well be wondering why that works even to that extent, since closing macrocycles is often a capricious process. The phosphorane reagent, though, takes the mechanism through a stage where one end of the chain has a positive charge and the other end is a negatively charged carboxylate, so you have electrostatics bringing things together.
The resulting macrocycles seem to partake of some of the interesting features of their type, specifically enhanced cell permeability. (Here’s a fairly recent book on the topic). The authors took a list of their macrocycles through a PAMPA assay (which for those who haven’t run into it is an in vitro test with an artificial membrane), and found that in every case the macrocycles were significantly more permeable than the open-chain precursors. We certainly don’t understand what’s going on with such compounds, once you get past some bulk physical properties, but they do have a lot of potentially useful features.
My first thought when I saw this paper was “Hey, I’ll bet that works on things that aren’t peptides”, and I’m sure that it does. There are surely a huge number of interesting structures that you can put together relatively quickly that have an open primary or secondary amine on one end and a carboxylic acid on the other, and which could be zipped up into a library of most unusual macrocycles. I note that the folks behind this are the founders of Encycle Therapeutics, so similar thoughts have no doubt occurred to them as well!