What’s in a name?

Where do some of the more obscure functional groups get their names? This is the topic for tonight’s discussion. For instance, everyone is familiar with amidines – you get them by replacing oxygen atoms with nitrogens in carboxylic acids. The properties change rather drastically, but I am not talking about them tonight. In fact, I will not even go into a protracted discussion about where amidines got their name from. There is a certain logical connection to amides here, and I am just going to leave it there. Now let’s switch the letters “m” and “d” in the name “amidine”. We are going to end up with adimines. Who are they? Maybe this name hints at some imine character? Well, despite the fact that I cannot, for the life of me, figure out the origins of adimines, these intermediates are absolutely fascinating, if rare. Take a look at the sequence shown below. The arylpyridinium salt is first hit with a hydrazine, followed by ring-closure to generate the adimine skeleton. In this particular work, courtesy of Alvarez-Builla’s lab, adimine serves as a springboard into other heterocycles by way of palladium catalysis. The reactions are interesting, especially to me since I am very fond of unusual nitrogen arrangements (here we have a all-sp2 NCNN sequence, which is really rare).



In regards to names, I recall Nicos Petasis’s story of how his 5-year old daughter (at the time) corrected his mistake when she thought he misspelled “aminal”. Of course, she thought it must be “animal”…

Soaking in inorganic cages

I love reading papers that describe crystallization conditions and I make it a habit to read the experimental section. As you are probably well aware, Professor Fujita published some thought-provoking papers some time ago that described what he calls “crystal-free crystallography”. In this method, a molecule that is reluctant to form single crystals suitable for X-ray analysis, is coaxed into forming inclusion compounds that diffract reasonably well. This process has a number of far-reaching implications, particularly in structure determination of natural products. I have to admit that, for me, this process has always been reminiscent of what people routinely do in protein crystallography. In fact, my lab has been involved in experiments of this type in collaboration with our colleagues at the SGC (I refer to soaking experiments I mentioned several times in the past). The main difference is that the lattice is based on metal/ligand complexes in the Fujita technology. Another aspect is that when we run protein/small molecule soaking experiments, we already know which molecules we put in (or do we?). Fujita’s trick is to use well-defined inorganic materials that provide a “surrogate” lattice, so to say, and enable diffraction data to be collected for the guests that have been entrapped in nanocompartments. There was a lot of press surrounding this methodology, some of which hinted at some difficulties encountered in attempts to repeat the procedure, which the authors later admitted, aiming to work on process improvements. I was glad to see a Nature Protocols published by the Fujita team that provides a step-by-step recipe for how to run these crystallization experiments. It appears that making the metal-organic framework is a piece of cake and sounds like a lot of fun: you take a test tube and set up diffusion of a metha
nol solution of zinc diiodide layered onto a nitrobenzene/methanol solution that contains 2,4,6-tri(4-pyridyl)-1,3,5-triazine. Single crystals of the networked material form at the boundary (I enjoyed looking at the images). 
The rest is no different from how one would soak a small molecule into a protein crystal.


Transannular events

Of late, I have not come across too many unusual reactions that involve silicon (if you have any recent examples – do let me know), which is why I am going a couple of years back to the rescue. One of the reasons I am keen on transannular collapse processes will become evident once you will (hopefully) read the Perspective on macrocycles I am putting together for Chemical Science. Tonight, though, I am showing an eight-membered ring that undergoes a very interesting and unusual contraction to generate the cyclopropyl-containing seven-membered heterocycle shown below. When a silicon-bearing molecule is being “hit” with fluoride anions, one typically expects a fairly mundane silyl group removal. There are, of course, some really useful reactions (such as aldol processes using silyl enol ethers) that accompany the process of desilylation. Here is a good example that is unusual in terms of what goes in the course of desilylation. According to this report by Dowden and coworkers, clean “ablation” of the trimethylsilyl group from the eight-membered ring triggers conjugate addition and generates the cyclopropane ring that you see. What’s more, attempts to induce conjugate addition to the unsaturated amide intermolecularly (e.g. by adding thiophenol and base to the starting 8-membered ring) did not result in anything tractable. Thus, it is clear that the conformation of the 5,6-dihydroazocinone helps to guide the observed cyclopropanation. This example attests to how medium sized rings are full of surprizing features when it comes to uncommon reactivity patterns such as transannular ring formation. hth


Cyclic enzymes – how rare is that?

I have always been fascinated by the fact that close to one half of the single domain proteins in the Protein Data Bank have their N- and C-terminal elements in close proximity. Some years ago, Krishna and Englander pointed out that this number is rather high. In fact, it is much higher than what one would expect on a random probability basis. The exact reasons for this peculiar observation are still being debated:


Now, if we go 30 years back, we would find a classic study by Creighton, which showed a clean cyclization of the BPTI protein (its structure is shown below). Remarkably, the cyclization was triggered by a “middle of the road” carbodiimide reagent, so there is nothing fancy in this chemistry. In the graphic below you can clearly see that the ends of BPTI are fairly close to each other and can be forced to cyclize without much trouble.



I wonder why we do not see more naturally occurring cyclic enzymes (although David Craik has been talking about some really cool ones of late)? The artificially cyclized versions can be significantly more stable than the corresponding non-cyclized ones, which can be seen time and again, for instance in the following paper by Howarth, although here the authors used a fairly “fancy” cyclization brew (you just can’t beat Creighton’s carbodiimide…):


Being resourceful

My lab has been interested in challenging hemiaminals to do things they are typically not known for. Below is an example from Kim’s lab, showing how one can be really resourceful with hemiaminals. I have always been a fan of this sort of chemistry and, earlier today, rediscovered this cool sequence while going through my “paper vault”. Access to either of the two amino alcohol diastereomers is at stake in this chemistry. The syn diastereomer is accessible directly from the hemiaminal by way of conjugate addition. What about the anti version? In order to get that, you oxidize the hemiaminal into the corresponding hydroperoxy species, which transfers its oxygen atom to the nearby olefin under basic conditions the way any hydroperoxide would do. While this chemistry is now several years old, it does attest to how useful hemiaminals can be.



Don’t worry too much…

When it comes to making cyclic peptides, we have a tendency to recall all sorts of nightmares. Choosing the right protecting group and running reactions under high dilution in order to avoid polymerization are two of the most common sources of headaches. These are presumed headaches, I must add. We know that exceptions prove the rule and I fully admit that outliers in this field probably possess some very special features. The corresponding outlier peptide would stand out as a sore thumb, challenging widely accepted views and fears. This is therapeutic to all of us. A case in point is a solution phase reaction developed by Fairlie and co-workers some years ago. This cyclization is: a. not run at high dilution, b. not associated with protecting groups, c. run over 2 hours on a 100g scale, affording 33g of the desired product. So, next time you are performing your cyclization with a laundry list of precautions in mind, think of such outliers and do not fall victim to default assumptions that dominate this field.



New roles for old actors

There are several reasons, some of which are top secret in nature, that lead me to say that I am very interested in the chemistry reported by Xiao and colleagues in the Org. Lett. paper shown below. I like this work because it showcases a rather mundane solvent (dimethylformamide, or DMF) in an unusual role: that of a methyl group donor. The way this chemistry occurs is by a process that involves oxidation of DMF into an N-formyl iminium cation, followed by a Mannich-type reaction. There is a nice scope of substrates in this work and I am not even focusing on what really matters to the authors – the metal catalysis part – but I just don’t have time (I am about to barbeque a juicy slice of pork, as part of a dress rehearsal for this Sunday’s lab get-together at our place)… Anyhow, Dr. Xiao and colleagues are to be congratulated on this feat. We need to see more studies that showcase how boring molecules get accustomed to new and exciting roles. Speaking of DMF, even its synthesis can be very cool. I still recall hearing awesome talks by Professor Noyori in the early 1990’s. He would dedicate his whole lecture to the use of hydrogenation catalysis in efforts to make DMF on the cheap. There was something Tom Sawyer-esque in that work (I refer to painting the proverbial fence)…



Uncorrelated properties

Association vs causation… While medicine is the domain of knowledge where one really needs to have a good grasp on whether or not two observations in question cause each other or are merely associated with each other, our daily forays in chemistry are filled with these same types of dilemmas, only the stakes are lower. Parsing out association from causation is where real science starts and ends. You might spend a lot of effort chasing after a parameter you think is important because your data analysis suggests that it is, only to find out that there is no causal connection to what really matters in your system.

Frustratingly, sometimes you know that you have no chance of establishing a causal relationship between two experimentally determined parameters, but you hope that there is at least an association. Then you find out that there can never be one because the two events are governed by uncorrelated properties. How frustrating is that? Here is an example that has to do with cyclosporine A, the molecule I mentioned a couple of times on my blog. Below you see its solution state conformation on top and the conformation in its bound state with cyclophilin, which is its cellular target (pdb code 2Z6W). It is easy to see intramolecular hydrogen bonds in the solution conformation. These linkages are the main reason for cyclosporine’s oral bioavailability. You do not see these bonds in the pose that corresponds to cyclosporine’s mode of action, do you? Indeed, all of the polar groups now engage the target. This is a frustrating end of science. You can learn all you want from this molecule and emulate its foldable polar surface area in your favourite macrocycle, yet when it comes to designing analogs to improve bioactivity you will be driven by entirely different considerations. How to avoid these sorts of pitfalls? Phenotypic screens, no doubt.fff

Something old and something new: boron-containing carbonyl compounds

Not long ago, we took a liberty to sum up the progress made over the years in the area of alpha-boryl carbonyl chemistry. I was asked to write a perspective on this subject, which meant that I suggested that my able co-workers Zhi He and Adam Zajdlik work on the manuscript. These guys did an outstanding job and the paper is now on the Dalton Transactions website. You might say: “Wait a minute, this is an inorganic journal, are you an inorganic chemist?” I tell you what: if there is one thing I learned from my one of my heroes in chemistry, George A. Olah, it is that divisions among the branches of science are artificial crap.

Coming back to the subject of our paper, I just want to point out that there are some really interesting examples of alpha-boryl carbonyls out there and I am showing them below. It is difficult to regard these intriguing reagents as the mainstream of chemistry as they are not, dare I say, bench-stable. But these molecules did pave a way to some of the ideas we are pursuing in my lab. I view all of the entries below as part of our honour roll as their often unusual structures attest to the imagination of chemists who conceived them. ooo


The point of our Dalton paper was to sum up what had been done prior to our work on stable alpha-boryl carbonyl compounds and, of course, discuss our own inroads in this area. Unlike the O-boron enolates, which react primarily as nucleophiles, our C-bound tautomers contain an electrophilic carbonyl group next to the nucleophilic alpha-carbon. We like to refer to these molecules as kinetically amphoteric (to distinguish from the other type of amphoterism, which is driven by protons and is thermodynamic in origin).


Chemists are well familiar with the concept of umpolung, which describes a deliberate attempt to change the natural polarity of a functional group. Earlier today I was thinking about functional groups that “sneak” into known reactions and behave as if they were molecular components one is used to seeing in a particular process. These are not chameleons, and they are probably not even pretenders per se… But there has got to be a decent way of categorizing these functional groups. And, by the way, the title “pretenders” does not have any negative connotations. If anything, this is a compliment to a group that emerges as a replacement for something that is ingrained in the lore of a particular kind of reactivity. Take azide/alkyne cycloaddition as an example. The power of this process, and the reason it is likely to result in a Nobel Prize one day, is that azide and alkyne are considered to be unique in their orthogonality to almost everything out there, yet react very predictably and cleanly with each other under copper catalysis. Below is a case for a “pretender”, if you will. I refer to the phosphorous ylide molecule. The metal-free process you see allows one to make peptidomimetics containing triazoles as cis-amide bond mimetics. Among several notable features of this reaction, developed by Rademann and colleagues some years ago, is that it bypasses the need to use amino acid alkynes that are not always easy to make. For me, though, the most attractive feature of this chemistry is that identifies a functional group that does something that is “reserved” for another one.