Finding real gems

I don’t know about you, but sometimes all I want out of reading papers is pure basic science. I get particularly upbeat when I see an occasional outlandish structure that reminds me that not all ground states are created equal. Truth be told, with fewer and fewer people doing “blue sky” research, it is difficult to find such examples in the sea of utility-oriented manuscripts. While it is easy to get inundated with the amount of information being published, TOC (Table of Contents) graphics offer a glimpse into what to expect in a given paper. These devices were introduced by the publishers only about 13-14 years ago, which sounds crazy given how indispensible they seem to be. The trouble is that some of the most interesting vignettes and detours hardly ever appear in these graphics. As a result, it is virtually impossible to find real gems unless you read the whole thing (and who has the time for that?). Here is a good example: based on the TOC graphic alone, I could have easily missed some of the fascinating details in the paper from Hosoya and co-workers that appeared in Org. Lett. not too long ago. Upon perusing the contents of the article, I saw one of the characterized by-products. To me, this happens to be one of the most interesting results in this contribution.


Bromine Division of the ACS?

As a first year graduate student many years ago, I was teasing my friends who were going to attend a symposium organized by the Division of Fluorine Chemistry of the ACS. At that time, I was not into fluorine chemistry (this subsequently changed) and, understandably, found it funny that among 30 or so divisions of that society, one was entirely dedicated to a single element in the periodic table. It is probably fair that fluorine has its central role as there are just so many applications of this halogen. But what about the rest of that venerable group? Are they all just “ugly cousins” of fluorine?

Below is a reference to a cool paper that shows how valuable organobromine libraries are. On the surface, there is nothing new here: the effect of anomalous scattering has been known for a long time. But, in the context of fragment-based screening, bromine is turning into a very useful tool when one needs to soak organic molecules in protein crystals with the goal of detecting which fragments stick. My students perform soaking experiments together with our colleagues at the SGC and we know all too well how unhappy crystallographers get when they have to solve 40 or so crystal structures of a protein (corresponding to a 40 compound library), only to find out that they are all identical and nothing got stuck in the lattice. When you have a bromine atom in your molecule, there is no need to run full structure determination: due to anomalous scattering, you will see really fast if your molecule is “in”. So there you have it: bromine is special. If we add its central role in halogen bonding (my colleague Mark Taylor is one of the leaders in this field), all of a sudden there are many gains to be made by placing bromine atoms in selected positions of our molecules. I think we need to approach ACS and ask them to start the Bromine Division


Treading lightly

I think scientists need to approach their research from the standpoint of Ocham’s razor. This way of thinking is by far the best way to analyze complex experimental data where many parameters are interconnected and cause / effect relationships are convoluted. From time to time, I will be posting cases in which Ocham’s razor might not have been applied. But first – what is it? This tool of logic posits that out of several plausible hypotheses, the one with the fewest assumptions is the winner. In other words, the simplest explanation is usually the correct one.

We were discussing an interesting Nature Chemistry paper at our journal club today. The asymmetric phase transfer-catalyzed reaction described by Paton and Smith is billed as a violation of Baldwin’s rules. On a cursory look, it does appear to be an example of the disfavored 5endotrig process (see top equation in the graphic below). A theoretical rationale put forth by the authors includes a sophisticated quantum mechanical backing. I like the reaction, but if I were to apply Ocham’s razor here, I would consider a simpler resonance-based explanation shown at the bottom. Here I am using the methoxy substrate (incidentally, one of the better ones in the paper), although we all know that the Curtin-Hammet principle might “rescue” the less fortunate reactants. My goal here is not to say that the more elaborate explanation offered by the authors does not have merit. It is possible that my suggestion is energetically unattractive, but I think it ought to be considered and thoroughly evaluated in addition to the more complex ideas that are being presented. By the way, I have always liked how Eric Carreira refers to Baldwin’s rules as Baldwin’s “suggestions”. One can often avoid violating these “commandments” using resonance structures.


The curious case of PTAD

The Org. Lett. paper by Michiko Sasaki and co-workers from Japan contains a reminder of how unusual N-phenyl-1,2,4-triazolinedione (PTAD) is as a dienophile. PTAD is one of the most reactive participants in the Diels-Alder process described to date; attempts to understand its reactivity date back many years. If you are keen to find out more about the strange behavior of PTAD in Diels-Alder reactions, I would recommend the 1998 paper by Houk and co-workers:

The extreme characteristics of PTAD are seen, for instance, in how it reacts with dienes that cannot easily adopt the requisite s-cis conformation. PTAD engages these molecules, leading to products of 1,4-addition – and this is just one of the pathways that were examined by Houk. Coming back to the Sasaki paper, I liked the comparative study with N-methylmaleimide (NMM): the reaction between one of the allene-containing silyl enol ethers and PTAD goes smoothly at -80oC, whereas NMM clearly does not have “enough” in it even at room temperature. Those adjacent nitrogen lone pairs… Pure magic.


On going through barriers

Professor Dean Tantillo of the UC Davis visited us last Friday and gave a thought-provoking talk that made me consider, once again, the way reactants traverse barriers on their way to products. No process is more fundamental to our understanding of chemical reactivity than the one that describes how energy barriers are being overcome by activated molecules. In a departure from textbooks, several of Dean’s recent works describe bifurcations of reaction paths, wherein the selectivity-determining step occurs after the transition state. I mentioned this on my blog in the past. Now that I heard the details in Dean’s talk, I really marvel at what computational tools offer these days. I think we have all witnessed the evolution of quantum chemistry approaches from mere explanation of experimental facts to prediction and uncovering some of the “unknown unknowns.” Bifurcation of reaction pathways is just that.

As I was listening to Dean’s lecture I noted a certain analogy between bifurcation – that “fork” in the downhill slope – to tunnelling. The analogy does not have anything to do with any causes of these clearly different phenomena, but there is something to be said about how Nature “cheats us” in both cases. Tunnelling describes how particles slip through energy barriers rather than surmount them. There are no (to my knowledge) enabling applications of tunneling in chemistry (I mean none of the “Hey, why don’t I use tunnelling to design my new catalyst…” sort of stuff), but tunnelling certainly helps understand some processes, especially when it comes to light atom transfer.

Below is an example of tunneling in organic chemistry. Without going into the details, let’s just say that it is possible to spectroscopically differentiate the syn and anti forms of the hydroxyl-substituted pyridine derivative shown below. The authors have found that the rate constant for the syn-to-anti conversion in the deuterated case is several orders of magnitude smaller than that of the protio derivative. Thus, this process is very likely a tunneling reaction.


The Randic index: 40 years and counting

I have been meeting with some undergraduate students who are keen to do research over the Summer. While answering their questions, I kept coming back to how I myself was drawn to research many years ago. As I found rocket science boring, I eventually stumbled upon chemistry, which really captivated my attention. But you might ask me: what was it that got you interested in organic chemistry back in 1988 (this is when I just started my second year of undergrad in Moscow). I was trying to recall the first paper I had read that really made me think more about organic chemistry. In fact, I now remember that paper quite well. It was the 1975 account by Randic in JACS (given to me by my advisor, V. Palyulin). In it, Randic introduced a mathematical index that later became associated with his name. The most fascinating thing about this parameter is that it looks at molecules as if they were “graphs”. Below is how this index is calculated. There are several molecular properties that show a linear correlation with the Randic index. I think there is something magical in correlating a measurable physical property with something that has nothing to do with any advanced quantum mechanics, but is merely a reduction of a chemical structure to a number. This seems really bizarre. Underneath the formula you see how a correlation with boiling points in a hydrocarbon series would look like (but please look at the JACS paper for the “real” thing, I just reproduced what I saw there using ChemDraw). For me, this is pretty interesting (and I still do not fully understand this stuff).


Destroying C-B bonds in prodrugs

As someone who is interested in using boron-containing molecules as biological probes, I do not like seeing cases in which boron plays second fiddle… I refer to the applications that build on the known propensity of organoboron compounds to undergo oxidation. While this is good from the standpoint of benign metabolism (after all, boric acid is fairly innocent and compares to table salt in terms of toxicity), I cringe when I think about what might prematurely happen to those boron-bearing molecules that are supposed to derive their effect from a productive protein/boron interaction. Take, for instance, the prodrug approach recently reported in JACS by Kim and co-workers. This nice chemistry hinges upon hydrogen peroxide-mediated boronate oxidation. As a result, a fluorescent molecule of coumarin is produced along with the release of camptothecin. This application builds on the fact that cancer cells tend to overproduce reactive oxygen species (ROS) such as hydrogen peroxide. The latter selectively react with the boronate moiety on the camptothecin-containing prodrug. In cellular experiments, the carbonate prodrug shown below delivered fluorescent signal localized in lysosomes, confirming cellular delivery of the therapeutic agent. While this example is really nice, we need to watch out for the unintended and premature destruction of C-B bonds in the molecules we are building.


Anodic oxidation brings back some good memories

Here is an interesting electrocatalytic aziridination reaction just published by Dan Little of UCSB ( Reading this work was akin to a flashback, at least for me. My lab developed very similar chemistry about 13 years ago ( Our postulated mechanism was different, though, and I still think we were correct because we were able to show that iodosobenzene derivatives oxidized N-aminophthalimide in a similar manner to our anodic process. I have always liked the analogy between the hydroxylamine intermediate and mCPBA. Atkinson used to run these sorts of processes way before any of us, although he used super-stoichiometric amounts of lead tetraacetate, which is one nasty reagent. In his Org. Lett. paper, Dan postulates a radical mechanism and it very well may be operating in the present reincarnation of the nitrene transfer. I was really surprised to see that both cis and trans alkenes lead to the cis-aziridine isomer. Ordinarily, cis-epoxides and aziridines are less stable than their trans-counterparts, but N-aminophthalimide substituent is special… These peculiarities aside, it is too bad that N-aminophthalimide is more or less the only amine that reliably participates in these kinds of reactions. Why? There are many reasons, but the most obvious one is this: the amino terminus of N-aminophthalimide is fairly nucleophilic, yet sterically unencumbered. In addition, there are no hydrogens at the alpha position. Taken together, these features lead to oxidation reactions that are relatively free of by-products.


Boron baits

My lab’s interest in boron-containing compounds has led to a sustained exploration of electrophiles that engage nucleophilic residues in proteins. In contrast to aldehydes, acrylates and epoxides, which are widely used as “baits” for nucleophilic residues in active sites, small boron-containing electrophiles have received relatively little attention. This is mainly due to their lack of stability and relative difficulty of preparation, especially when it comes to molecules with C(sp3)-B bonds. Over the past year or so, we have been working together with Ben Cravatt of the Scripps Research Institute, trying to get off the ground a research program aimed at “borofragments”. Our first paper just came out in Chem. Comm. In it, we describe a reagent that enables straightforward linking of biologically relevant heterocycles with boron. The stability of our molecules depends on the MIDA group, which acts as a slow-release element under biological conditions. This group stabilizes borofragments against premature decomposition and is released under biological conditions to unmask an active boronic acid. Borofragments can be used to discover inhibitors of enzymes that use catalytic oxygen nucleophiles. We have resorted to Ben’s activity-based protein profiling and employed our method to identify inhibitors of ABHD10 and the predicted carboxypeptidase CPVL. This technique should be applicable to other classes of targets. Given the diversity of heterocycles that are either commercially available or exist in the historical collections of the pharmaceutical industry, our straightforward method of linking molecular recognition units with stabilized boron electrophiles should enable facile exploration of previously uncharted covalent inhibitor space. I really have to thank my Japanese co-worker, Dr. Shinya Adachi, for developing this useful chemistry.


New England travels

I visited Boehringer-Ingelheim (Connecticut) last Friday, where I was hosted by Dr. Nick Desroisiers. During my visit I gave a talk and had a chance to meet many people with both process and medicinal chemistry interests. This Ridgefield site is being superbly run by Dr. Chris Senanayake, Vice-President of Chemical Development. I came away impressed by the high quality of scientific publications that have been emerging from this organization over the past 10 years. This commitment to outstanding output is due to Chris’s leadership, which is why he has my utmost respect. I always learn a lot during these trips and, today, I want to comment on a scaleable carbamoyl anion addition process that has been practiced in several different forms at Boehringer-Ingelheim. Various types of amphoteric organolithium species have been generated on 100+ kg scale. I am particularly fond of the dipeptide synthesis using this technology.