Azides communicate through space

We had Professor Matthieu Sollogoub of Sorbonne University for a seminar last Friday and were treated to an outstanding lecture on cyclodextrin functionalization and utility. This foray included many aspects of catalysis, materials science, and drug delivery. Of course, you probably know where cyclodextrins are used the most: they are the main component of Febreze, a remarkable innovation to eliminate bad odour. Apparently, the reason cyclodextrins (there are several types, depending on the cavity size) cost on the order of 4 euros per kilogram is because of Febreze. The hydrophobic cavity of these molecules is destined to encapsulate a range of chemicals, including those that are volatile and offensive in smell. In the interest of time, I will not draw the whole molecule of a cyclodextrin (check it out here), but I will say this: the amount of insightful stuff Prof. Sollogoub has been able to find in this area is quite remarkable. My favourite part of the presentation was when he described the way in which azide-functionalized cyclodextrins stick to each other and form higher order assemblies on the nanoscale. The driver here is the interaction between adjacent azide functionalities. I am afraid I do not know other examples that convincingly demonstrate similar through-space interactions between two resonance forms of a functional group. This finding, characterized crystallographically, was the highlight for me and I encourage you to read the Angewandte paper below.



Moving along the pyridine ring

A couple of weeks ago, I finished teaching the synthesis of pyridine and its derivatives in my 4th year synthesis class. Whenever I present this material, I can’t help but appreciate the value of N-oxidation. While there are N-oxides of other heterocycles (thiazole N-oxide stands out for its interesting properties), nowhere else do I feel the same level of enthusiasm about N-oxidation than in the case of pyridine. And new applications attributed to the role of N-oxides keep coming out! The one that attracted my attention comes from the lab of Nuno Maulide. This chemistry, described in a recent Angewandte paper, documents thermal modification at the 3-position of pyridine. According to the authors, the reaction likely involves a series of [2,3]-sigmatropic rearrangements. I think this “merry-go-round” sort of activation is amusing. Given the value of 3-substituted pyridines in drug discovery, this simple reaction should find many applications.



Necessity and sufficiency

Understanding the difference between necessity and sufficiency is supremely important in order to build solid arguments in science. While I am sure you all agree this to be the case, it is interesting how often we fall prey to fallacy if we disregard this fundamental distinction. Sadly, there are research projects that hinge on shaky grounds because it is often enticing to be selective about which parts of causal relationships to pursue and which to ignore. There are many examples I could quote, but none come close to the idea of enzyme mimicry, which is one of the most absurd and ludicrous notions. Time and again we see claims of simple systems that approach enzymatic efficiency. These ideas persist and, unless weeded out from the literature, confuse students who take sand castles for their face value. It happened with Atassi’s claims of cyclic peptide-based miniature enzymes in the 1990’s and it happened again more recently, when Ser-His was billed as an efficient catalyst with protease-like qualities. The truth is that the presence of catalytic groups in close proximity is necessary, but not sufficient for enzymatic activity. Stable and precise alignment of the said functionalities would make a catalyst, which is not achevable with small molecules. There is a nice recent Org. Lett. paper by Don Hilvert and Sam Gellman, which takes on Ser-His, goes through a number of control experiments, and delivers the lasting verdict (again): do not try to mimic enzymes.


A mechanistic revision

Some of you might recall me writing about the tremendous therapeutic success of anticancer agents whose structures were inspired by epoxyketone natural products. The reason this is a compelling package from a synthetic chemist’s point of view is that the mechanism of action appears to involve a neat reaction between proteosome’s N-terminal threonine and the epoxyketone warhead, resulting in a 6-membered ring formation. While this seemed to be a reasonable mechanism of action, which was captured crystallographically, there is a new interpretation and, while the difference might appear minor to some of you, I think it is quite substantial.

Oprozomib is an orally bioavailable epoxyketone derivative currently in clinical trials for the treatment of solid tumors. The high resolution electron density maps obtained by Bourenkov and Chari reveal an electron density for the inhibitor-threonine conjugate that is larger than morpholine. It appears that a seven-membered 1,4-oxazepane ring structure is formed instead.


It is interesting that the Sn2-type 7-endo-tet reaction appears to be the preferred pathway. I am curious to know if this finding has any bearing on Onyx’s patent claims. The composition of matter that is being protected by a patent is sometimes linked to the mode of action. As a corollary to that, what is to prevent someone from designing follow-up molecules with higher propensity to form 7-membered rings? There is probably room to innovate here.

More with less

It is tempting to overemphasize the role of sophisticated equipment and fancy set-ups in modern chemistry. This is why I am encouraged when people do more with less. Of particular significance are colorimetric tests that do not involve any dyes that undergo insane conformational changes to reveal what is happening at the molecular level. Below is a simple reaction I came across while looking for examples of boron/amide interaction (something that is of interest to our lab at the moment). This is Matteson’s old work and the best part of the experimental section is the description of how the starting boronic acid was stripped off the boric acid impurity. The authors state that “… was freed from boric acid by treatment with 50 mL of methanol and distillation until the distillate showed no green boron color in the flame when ignited.” We need our students to never forget that trivial tests such as this simplify life and make practitioners of synthesis look resourceful when they present research findings at conferences or job interviews. The irony is that this can look more impressive than the seemingly more elaborate modern techniques. Let me know if you are aware of additional examples where deep insights about chemical matter are made using everyday tools.


Pariahs of chemistry

They always give this advice to aspiring chemists: spread your wings, use the whole palette of the Periodic Table and improvise, because there is likely a lot of unexplored reactivity at the fringes. While this might be true, I sometimes wish we could all take it easy and allow ourselves to appreciate the chemistry of super toxic elements such as thallium, lead, and mercury… While relatively inexpensive, they are all outcasts that are truly offensive from today’s green perspective. Look at the delightful molecule featured below. I was going through a folder of old papers on the ride home and came across this mercurial (no pun intended) aldehyde. My interest in structures of this kind stems from our lab’s quest to expand the scope of metal- and metalloid-containing aldehydes. The crystallographic characterization of the mercury derivative reveals some interesting stereoelectronic features, which result in unusual bond angles. The synthesis of these Hg(II) derivatives comes from the seminal work by Nesmeyanov in the 1960’s. I am positive that there is a ton of interesting chemistry awaiting compounds of this type, yet we will never find out.


Getting rings grafted

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 ( Dr. Stu Borman of the Chemical and Engineering News had some nice things to say about the reaction ( 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 (, 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.

3.jpgWith 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.