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.
This is a great idea – congratulation! I predict it is going to be a named reagent/cyclization method.
I was impressed that you can even use PhCH2CHO, known troublemaker (in comparison, hydrocinnamaldehyde is usually so much better behaved). To improve yield, by limiting self-condensation of phenylacetaldehyde: have you looked into syringe-pumping freshly distilled phenylacetaldehyde into the reaction mix, as a limiting reagent, or using some in situ aldehyde-releasing synthetic equivalent like dimethylacetal, beta methoxystyrene? Dimethyl acetals of arylacetaldehydes are remarkably cheap and widely commercially available.
Thanks for the comment. This is actually a good idea that we have not investigated yet… We should look at this (and maybe throw in bisulfite adducts too). Solomon: I hope you are reading this.
It’s very exciting to see what Solomon will be up to at University of Toronto! Best wishes to him from a former organic instructor.
Thanks Monica. Solomon is doing well! He just gave a nice talk at QOMSBOC conference (http://qomsboc2016.uwaterloo.ca/sponsors.html). Not bad after 2 months in grad school. I heard the lecture was very well received. Literally a sec ago I heard that he got the second place prize for his presentation at the conference!
Fantastic! Congratulations Solomon!