A nice catch

I have to get back to blogging, partly because I miss it and partly because RSC mentioned that I had a blog when they ran an announcement related to my new position as an Associate Editor of Chemical Science (http://blogs.rsc.org/sc/2018/12/20/meetandreiyudinchemicalscienceassociateeditor/?doing_wp_cron=1547228932.9969739913940429687500). Some people are wondering what has been going on, why I am not posting anything. So I guess this is as good a time as ever to get back to writing. Fittingly, we had Prof. Kei Murakami of Nagoya University visit us yesterday as part of his Canadian tour. Kei gave a great talk, and I want to focus on the paper he published not long ago (http://science.sciencemag.org/content/sci/359/6374/435.full.pdf). Apart from seeing an amazingly facile route to nanoribbons, I marvel at the simplicity of the reaction below that had enabled the rapid assembly of the graphene-like building blocks. I wonder why is it that this process has taken so long to reveal itself. Just look at what is happening here and never mind the mechanism, for which we do not have time. My question is how many times in the past, likely all over the world, students must have run a coupling between a biphenyl chloride and some amine, or a boronic acid, or what not. I know that homocoupling is a common by-product of palladium-catalyzed processes, but are you trying to tell me that no one ever ran control experiments in his/her mechanistic studies and did not notice the (homocoupling – 2) mass? Nope, which is why we now have a new reaction. Kei left for Queen’s University after his talk here, and I wish him all the best for what should be a notable career!


Triazines are tricky

In part due to my long-standing interest in heterocycle-driven drug discovery, I was kind of surprised to see this Org. Lett. paper. In this article, Boger and colleagues showcase a fascinating new way of making vinylogous formamides from 1,2,3-triazines. What is curious here is the very fact that triazines can participate in nucleophilic addition reactions. I have seen many attempts to introduce these rings into bioactive substances, but now that triazines have been shown to be excellent electrophiles toward amines, I should adjust my expectations for this class of molecules. In the Boger report, the reactivity of the parent 1,2,3-triazine was exemplified using secondary amines. The preparative sequence is straightforward: mix amine and triazine in THF at room temperature, and off you go. The C4 position is the preferred point of attack, leading to the extrusion of nitrogen gas. Clearly, the preferred delocalization of the negative charge is behind the documented regiochemistry. Orbital considerations are also consistent with this mode of reactivity. On balance, this is a nice method to make vinylogous formamides. It also suggests to never use 1,2,3-triazines as constituents of bioactive structures.



Amino acid mutation on a multiton scale

I was visiting Novartis in Basel, Switzerland, over the past 3 days. It is an amazing site, with astounding architecture. They even have a Frank Gehry building, a dinosaur skeleton, and a Japanese restaurant on campus. I went out for dinner with Dr. Fabrice Gallou last night and learned about the “business of cyclosporine A” at Novartis. The graphic below showcases the degree of sophistication achievable with complex molecules. The overall goal of the methylation reaction is to site-selectively cleave cyclosporine, run Edman degradation in order to remove the N-terminal amino acid, couple a new one, and recyclize. This represents a clever way of site-selectively mutate amino acids in complex macrocycles. The procedure discussed in the OPRD article was performed on a 186kg scale but things get even more impressive because the reaction is performed on a multi-ton scale at Novartis. As far as the site of methylation: it corresponds to the most nucleophilic amide. I wonder if more macrocycles do not possess an Achilles heel of this kind, which would allow site-selective chemistry to be applicable in other settings. I doubt it and, even if sites like this were to exist, they would likely be located in turn regions. Of particular interest to me was the description of effort to develop solvent/antisolvent combination in order to get consistent crystallinity of the linearized peptide product. 2-Methyltetrahydrofuran was the solvent and tert-butylmethyl ether was the antisolvent of choice. Go figure. I don’t think we use these two with linear peptides, but what do I know? Just imagine doing this on a multiton scale! Here is a quiz: why is cyclosporine’s OH acetylated? The authors discuss this, but try to guess the reason why having an unprotected OH is not a good idea.



Boron is special

My lab and I have been heavily entrenched in the design of boron-containing covalent inhibitors of proteases. In my view, synthetic students optimally relate to the challenges of chemical biology when they think about the fundamentals of polar bimolecular reactivity. This is exactly what I like to teach in my classes when I describe enzymes as giant nucleophiles. If you then take a look at the electrophilic options out there, you might first consider epoxides, aziridines, and acrylates. These molecules are useful, but are somewhat boring because they offer a singular outcome upon interaction with the enzyme target. This is not the case with boron, which is something my PhD student Diego Diaz and I realized and presented in a recent Nature Chemistry paper. We have analyzed well-known covalent inhibitors containing boron and concluded that this element is unique in its ‘chameleonic’ ability to display a range of coordination modes upon interaction with protein targets. It turns out that organoboron inhibitors leverage boron’s capacity to switch between an uncharged trigonal-planar structure to an anionic tetrahedral one. It is here where boron deviates from common electrophiles that display a singular type of interaction with active site nucleophiles. As a corollary, boron is well suited to act as a flexible anchoring element that is adaptive to structural changes upon binding. Where do you think we are taking this? If you have guessed that we are using these properties to adjust the residence time of boron-containing inhibitors, you are on the right track.



Not just another way to remove Boc

I typically do not comment on deprotection conditions, but there is something special in the two papers below. When I read the one by Lattanzi and colleagues, I thought that their nice asymmetric chemistry had been somewhat overshadowed by a single carbamate cleavage condition using TBAF. I am not sure how many of you are experienced with aziridines, but they do not easily withstand typical Boc removal with TFA. When I saw the yield of 98%, I was literally floored. In the interest of full disclosure, I learned about this deprotection from a paper I recently refereed. I dug a bit deeper and found that the TBAF condition goes back to the 2004 Tetrahedron report by Coudert and colleagues. In it, the authors considered a number of substrates and even carried out mechanistic studies that seem to suggest that the reaction proceeds through the formation of carbamoyl fluoride. Really strange, I know, but there is some very clever evidence in the Coudert paper. That 2004 study centered on the use of common amines and there was nothing as exotic as aziridines. Unless you are familiar with the pain of dealing with these three-membered rings, you might not think that a new way to remove Boc is worthy of note. This simple TBAF trick might be consequential to a lot of people interested in the chemistry of aziridines.


Lattanzi: http://pubs.acs.org/doi/abs/10.1021/ol3017066

Coudert: http://www.sciencedirect.com/science/article/pii/S0040402004012487


Between my desk and recycling bin

I am a fan of small amine-containing compounds with relatively short history in synthetic organic chemistry. Such molecules are admittedly hard to come by, but when I see them, I marvel at what might be done with them and why people have not considered them more broadly.

The other day I was flipping through the 2017 Strem catalog for no logical reason other than I got this shiny new booklet in the mail and felt guilty to toss it straight into the blue recycling bin, the destination of all catalogs I receive on a weekly basis. My attention got piqued by 2-aminoethane-1,1-disulfonic acid (let’s call it ADSA), which is offered by Strem for some unknown reason (metal catalysts is their main focus). Unaware of ADSA’s existence, I looked through standard search engines and found very little prior to 2010. There was some work done by Wagner and co-workers in the 60’s, but not much since. The synthesis of this compound is simple, yet interesting as it involves a modified Ritter reaction with oleum, decarboxylation, and sulfonation of the enamide. ADSA offers as an outstanding way to improve aqueous solubility of fairly hydrophobic molecules such as Alexa Fluor dyes. I find the geminal bis(sulfonate) functionality rather interesting because it reminds me of bis(phosphonates), which are of course miles ahead in terms of demonstrated use and significance as components of drugs that prevent the loss of bone mass.



Residence time

It would be a good idea for me to get back to blogging. I have been busy with a couple of conferences and grant writing, which explains my lack of attention to what’s cooking in the science universe.

One of the most memorable talks I heard at a recent CSC meeting held here in Toronto (I was in charge of the organic program, by the way) was that by Professor David Fairlie of The University of Queensland in Australia, an expert in drug design and a long time aficionado of cyclic peptides. As you might recall, cyclic peptides are often erroneously associated with pretty dreadful drug-like properties. Their oral bioavailability can be particularly dismal. The Fairlie paper says: “Who cares?”. Residence time is the main theme of the article. This parameter relates to the duration that a ligand is bound to its target. Fairlie considers his 3D53 molecule, which is a C5A antagonist, and reminds us that it is easy to fall prey to the assumption that IC50 (the concentration of an inhibitor where the binding is reduced by half) is the one and only “holy grail” when it comes to bioactive molecules. The reality is that IC50 is concentration dependent, which propels residence time to the foreground of Fairlie’s arguments. The paper nicely demonstrates that one might have a compound that is way inferior to its competitor when judged through in vitro biochemical binding assays, but jumps way ahead when evaluated in cellulo. In other words, a “lousy” molecule that is not too orally bioavailable and is not particularly potent, can stick to its receptor when it really matters and override potential shortcomings. Incidentally, this is one of the main reasons why there has been a lot of interest in reversible covalent inhibitors: they can drastically improve residence time. Another interesting fact about 3D53 is its synthesis, which I mentioned it in the past. It is a perfect reminder that there are remarkably well-behaved cyclizations that proceed on 100g-scale without the need for dilution.