Back in 2010, amphoteric aziridine aldehydes allowed us to exercise electrostatic control over macrocycle formation. I do not want to open up the Pandora’s box of less-than-reasonable mechanistic proposals, but the data we have so far suggests that the amphoteric nature of aziridine aldehydes helps establish productive contacts between the termini of the macrocyclization intermediate (see left figure below). We have just disclosed an exciting new process. The reaction allows us to cyclize peptides and seamlessly incorporate oxadiazole rings in the structures of macrocycles (http://www.nature.com/nchem/journal/vaop/ncurrent/full/nchem.2636.html). Dr. Stu Borman of the Chemical and Engineering News had some nice things to say about the reaction (http://cen.acs.org/articles/94/i43/Cyclic-peptides-heterocycles-cell-membrane.html?type=paidArticleContent). I feel indebted to Drs. John Frost and Conor Scully, my co-authors on this particular work. Coincidentally, John just packed his car and drove back to the US this past weekend. He accepted a job at Merck in New Jersey. I envy Merck because they are going to get a stellar researcher with a no-nonsense approach to science. John is a straight shooter, who weighs what he says carefully and is not afraid to voice his opinion. His arguments are lucid and they are always presented with conviction. I have to thank Professor Rudi Fasan of the University of Rochester, John’s PhD advisor, for excellent mentorship.

Back to oxadiazole grafts in macrocycles. Ever since we discovered the role of aziridine aldehydes in re-routing the Ugi reaction (http://pubs.acs.org/doi/abs/10.1021/ja910544p), we have been on the lookout for other ways to disrupt the mechanism and forge ring formation. This goal has been elusive for some time and has entailed testing various components, including isocyanides. I am telling you: we’ve tried a lot of them and “Pinc” (our internal acronym which, I suspect, will stick) is what allowed John to develop a robust process to not only make macrocycles but to ensure that they possess favourable cellular membrane permeability. The icing on the cake is a conceptual relationship with our 2010 process in that “Pinc” allows for electrostatic control over ring closure.

With this vignette, I am going to send a special hello to John, who will be missed. This area of research is now in the hands of Solomon Appavoo, a first year graduate student in my lab. Let’s see where he takes it.