Did you know that more than 30% of therapeutic agents exert their mode of action by some sort of covalent mechanism? I find this number quite impressive, considering the continuing fear of covalence in the pharmaceutical industry. What is most interesting is that the number quoted includes molecules that were developed to act as covalent inhibitors as well as those (the vast majority) whose mechanism of action was only later determined to be covalent.
My lab has interest in covalent inhibitors and I included this subject in one of my recent 4th year chemistry classes. I realized today that there was one paper I forgot to mention. It is a good one because avibactam’s mechanism of action is unique: the strained urea engages beta-lactamase covalently and is subsequently “resurrected” to its original form. Incidentally, I am not making any strong hints to the origin of the 70% “truly” non-covalent drugs mentioned earlier and I do not want you to think that there are even more covalent inhibitors out there, but you never know.
Here is a thought-provoking recent study from Professor G. K. Surya Prakash, my PhD mentor. The work, done in collaboration with Professor Herbert Mayr, reports a surprising outlier in what might otherwise be an intuitively clear nucleophilicity trend. It turns out that fluorine-containing carbanions can be up to 35 times more nucleophilic than their hydrogen congeners. While the authors do not suggest a simple explanation for the observed effect, one might hazard to guess that a heteroatom in place of hydrogen would increase the pyramidalization of the proximal anionic carbon centre. This increase, induced by the electron-withdrawing heteroatom, could lead to augmented nucleophilicity. While this is admittedly sound, the chlorinated analog does not follow the trend, throwing a wrench into what we all crave – a simple explanation. Fluorine is never boring and this Angewandte report provides yet another illustration.
What a nice choice for this year’s Nobel Prize in Chemistry (https://www.nobelprize.org/nobel_prizes/chemistry/laureates/2016/press.html)! I am particularly glad that we now have an example of research, which, at the time of conception, was not rooted in anything utilitarian. This is pure science, castles in the sky sort of stuff at its best, which is particularly welcome at a time when students of synthetic chemistry are too preoccupied with the ultimate application of their work. The language they pick up from the literature is a decent indicator. It seems to me that every other draft I see has some “broadly applicable” wording in it. I think that the pragmatic, application-driven science has been a bit of an overkill. The works of Sauvage, Stoddard, and Feringa serve as a reminder that asking fundamental, curiosity-driven questions is a what it’s all about. In closing, here is an interesting fact: Ben Feringa, one of the winners, founded Organic and Biomolecular Chemistry (OBC), the journal where I currently serve as the Chief Editor. Ben has published 41 papers in OBC and we hope to see more!
When I met with Professor Greg Dudley’s students two weeks ago at Florida State University, I was pleased to learn about the general utility of their fragmentation method to access medium sized rings. This chemistry employs vinylogous acyl triflates shown below. Upon halogen/lithium exchange and subsequent addition to the ketone, the intermediate lithium alkoxide fragments to generate a 9-membered ring. Looking at the ChemDraw rendering of this molecule does not give it all the credit it deserves. This crystallogaphically characterized ketone features a transannular π to π* interaction between the electron-rich alkyne and electron-poor ketone units. This proximity has consequences and allows various transannular reactions to take place. I am showing just one of them. As you might imagine, the primary application of this strained system is in bioorthogonal chemistry. But I got the biggest kick out of the unusual spatial arrangement between the π systems. Molecules of this kind are rich in chemistry.
We have been moving to a new house over the past few days and now that it is over, I want to talk about my action-packed trip to Florida State University last week. Professor Igor Alabugin (http://www.chem.fsu.edu/~alabugin/) invited me to Tallahassee, where I gave two talks. One of these lectures was for a general audience, while and the other was more specialized for the organic folks. Igor has been keeping a vibrant research program. I had a chance to attend Igor’s group meeting and met some of his students over lunch. I want to draw your attention to the book on stereoelectronic effects he recently published. A previous book dedicated to this enduring concept dates back to Pierre Deslongchamps’s herculean effort. Upon my return, I ordered Igor’s contribution from amazon.com and I recommend that you take a look at it as well (https://www.amazon.com/Stereoelectronic-Effects-Between-Structure-Reactivity/dp/1118906349). The coverage of the field is outstanding and I am really glad that there is no need to have hard copies anymore. Go iBooks, baby!
During my trip down south I also had a chance to meet Jim Frederich (http://www.frederichlab.org), an assistant professor at FSU. Jim has established an active research program in chemical synthesis. Below is a link to his first paper, which I think is outstanding, particularly for someone like me who, in his spare time, loves to keep track of oxidation states. The manuscript documents a photochemical conversion of pyridazine N-oxides into pyrazoles. Pyrazoles are typically derived from 1,3-dicarbonyl compounds in a transformation that does not require oxidation state adjustment. The pyridazine starting materials used by Jim have their nitrogen atoms at a higher oxidation state compared to pyrazole. Superficially, the transformation of an N-oxide into a pyrazole raises an eyebrow or two, but only if you forget that the product’s ketone functionality shifts “the redox burden” outside the ring. I encourage you to think of a reasonable mechanism (one of these days, I might use this reaction in my cume).