Palladium nuances

Years ago, when Iain Watson was in my lab, we looked at palladium-catalyzed allylic amination. We came to the conclusion that this reaction was far more nuanced than people had thought ( Under acidic conditions, the process is under thermodynamic control and linear product originates from isomerization of kinetically formed branched allyl amine. The addition of base naturally suppresses this process and one can then isolate the branched derivative. I asked our grad students to identify the origins of this selectivity as part of a cumulative examination last December. I received some very reasonable proposals, but none was close to what is actually at play in this system. This is fine, but it exposes an interesting pedagogical challenge: people rarely turn to thermodynamic control as their first choice for explaining reaction outcomes. I suppose we are “wired” to seek uniquely distinct product-specific pathways and do not like to offer explanations that are based on a “path continuum” that is traversed differently according to conditions.

That was a longish prelude to an outstanding paper by Breinbauer and colleagues. My PhD student Frank Lee discussed this work at one of our weekly research updates. Here is another nuance attributable to palladium. What you see is an initial formation of the N-allylated heterocycle, which is followed by an aza-Calisen rearrangement. As a result, the reaction provides access to some interesting side chain-allylated products.


Still looking for dyotropic reactions

Happy New Year, everyone! Lets kick 2017 by looking at what is up with dyotropic rearrangements. I mentioned them in the past, but still have trouble finding too many of these fascinating reactions in papers. Perhaps one of the reasons for this lack of occurrence is that substrates for dyotropic processes tend to be fairly complex. This naturally brings me to total synthesis, where the starting material complexity is a moot point. The example below comes from the lab of Professor Thomas Magauer. I met him last summer in Munich and became acquainted with his innovative program. Now that his paper dedicated to the synthesis of dictooxetane is out, you can also enjoy the rare case of a dyotropic process that has been put to good use here. In this case, an epoxide/oxetane system participates in a dyotropic rearrangement. As a result of the bond switch, the scaffold gets transformed into a tetrahydrofuran/oxetane, which represents a downhill process. Copper tetrafluoroborate was used as the Lewis acid to trigger this process.


Tie that binds

A couple of weeks ago I gave a talk at the Scripps Research Institute. My visit was superbly organized by Professor Phil Dawson, for which I am thankful. The highlight for me was to interact with my mentor, Professor Barry Sharpless, who celebrated his 75th birthday earlier this year. We have not seen each other for a while, but we picked back up as if we never parted. As much as ever, I felt energized after our long meeting, where we shared some memories from days past. Barry told me about his new passion, which is the SuFEx reaction for stitching molecules together. SuFEx is a “click” process, with Barry’s well-known stamp written all over it. There are some spectacular new papers about to come out of the Sharpless lab on the subject, but you can take a look at this published one for starters: Speaking of Barry’s other famously known click transformation, I received a sweet present – a set of copper balls, in association with the copper catalysts used in the azide-alkyne cycloaddition. Barry told me: “Andrei, now you need to shine your new balls”. By the way, these things are heavy, about a pound or so each. The most memorable part of this trip, though, came during Q & A session after my talk. A good chunk of the lecture was related to one of my lab’s current interests, namely the relationship between hydrolase inhibitor design and boron / oxygen reversible interactions (we have an interesting paper with Professor Ben Cravatt’s lab that will be sent out soon). Toward the end, Barry made some insightful remarks related to the boron work and one of them has stuck with me. On the pervasive coordination of oxygen to boron in some of our systems, Barry quipped: “…these two deserve each other”. What can I say? This was vintage Barry.2.jpg

A nice way to transfer difluoroethyl groups

I have been intrigued by a series of papers from the lab of Professor Xiao of SIOC. The latest one just appeared in JOC and followed the Nat. Comm. report, which came out earlier this year. The reaction described in the JOC paper offers a route to difluoroethylated alcohols and amines. While it is easy to see why difluoroethylated molecules might be of interest in drug discovery programs, I am particularly intrigued by the mechanistic underpinnings of the Xiao process. Positively charged phosphonium cation is the source of the nucleophilic difluoroethyl group. The reaction appears to involve carbonate addition to phosphorous, at which points the “baton” is passed to the thermodynamics of the phosphorus-oxygen bond. This strong link is the reason why a nucleophile emerges from what is originally an electrophilic phosphorus component. By the way, this gives me an opportunity to lament, once again, on the ultimate origin of some common chemicals we take for granted. Take the venerable triphenylphosphine. Out of curiosity, I peeked into the Encyclopedia of Industrial Chemicals only to find out that this molecule is still produced from chlorobenene, sodium, and phosphorus tricholoride under intensive cooling. The corresponding oxide, which is made in almost all applications of triphenylphosphine in organic chemistry, is recycled by the likes of BASF using phosgene to first generate the Ph3PClderivative, which is then reduced with aluminum. Wow. Talk about tracing common chemicals to their metallic origins (see my previous post).


Rosie Ruiz chemistry

As 2016 is slowly winding up, let’s turn to Scopus and see what’s been cooking in this chemistry universe of ours. Tonight we will take the unfortunate misnomer “metal-free”. It turns out that in 2016 the synthetic community has churned out a whooping 1391 papers containing this topic. The vast majority of these papers are interesting and potentially useful. But this is despite being labeled “metal-free”, not due to some features of this dubious concept. This whole thing reminds me of Rosie Ruiz, who won the 84th Boston Marathon in 1980 in the female category. Her title was later taken away when it was uncovered that Rosie took the subway for a good chunk of that run. I liken many of the metal-free approaches to Rosie’s feat. Thankfully, these papers expose a huge gap in chemistry education: we do not provide our students with the origins of industrial chemicals. How many of us know how common components (such as benzaldehyde, pyridine, aniline, etc) of “metal-free” reactions are made in industry? Armed with this information, we might be able to better appreciate that the heavy lifting is often done early, using metal-based chemistry that is far less glorious than the picture painted later by those “metal-free” routes. In this age of sustainability, I always want to keep in mind that synthesis is not a sprint but a gruelling marathon.

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.