Thanks to Dr. Yusheng Xiong, I had a very informative visit to Merck in Kenilworth (New Jersey) this past Friday. The location of this site is very close to Rahway, which used to be Merck’s primary medicinal chemistry center. Since the acquisition of Schering-Plough several years ago, Kenilworth has been steadily turning into the main discovery hub for Merck.

While I can’t describe the proprietary details I learned during this trip, I can make several general statements that define the overall visit. When compared to the days past, there is clearly a new approach to drug discovery at Merck. This company used to be very much a small molecule-driven operation. It is now more about “whichever modality fits the target in question”. This is the main reason why there is so much interest in macrocycles, which was one of the topics covered in my lecture.

My second point is more scientific. Throughout the day, I had several discussions that involved some stereoelectronic arguments. While I cannot talk about them, I think I can mention a paper that just came out in J. Med. Chem. It describes the role of divalent sulfur in the structures of therapeutic agents and provides an excellent demonstration of intramolecular oxygen-sulfur interactions. Take a close look at the two structures below. There is no way (in my view) of guessing which one of these two extremely similar compounds is more effective in inhibiting VEGF. Interestingly, one of them is potent, whereas the other is completely inactive. People are just beginning to fully appreciate the involvement of sigma hole-driven interactions and, in the example below, conformational stabilization is evidenced in the shorter through-space O-S distance in the active molecule compared to the “dud”.

http://pubs.acs.org/doi/abs/10.1021/jm501853m

Tonight I am not covering anything from the recent literature. My post is very much need-driven, rather than current literature-based. My lab has contemplated ways of putting together alpha-substituted proline derivatives. Our long-standing plan is to use them in a range of reactions, including our peptide macrocyclization. While you can buy the alpha-methyl variant, good luck finding something that is a bit more elaborate. In this regard, you might say that there has to be a way to use sigmatropic reactions and induce transfer of a nitrogen-bound group to the alpha carbon. Something like this rings a bell and formally corresponds to the Stevens rearrangement. The trouble is, this process is never clean due to the competing Sommelet-Hauser rearrangement. By the way, there is nothing wrong with this “competition” because the Sommelet-Hauser process is equally attractive from the endpoint perspective. However, the rule of reciprocity tells us that, in this case, the product will be contaminated by the amino acid derivative emanating from the Sommelet rearrangement.

There is a delightful Angewandte paper by Tayama and co-workers that shows how control can in fact be exercised. Take a look. I definitely want to use some of these amino acid building blocks in our chemistry. There is something really interesting about potassium tert-butoxide (I’ve also heard that if you have a bottle of this stuff, you do not need any transition metal catalysts anymore… I refer to that curious Grubbs/Stoltz paper, of course).

http://onlinelibrary.wiley.com/doi/10.1002/anie.200703832/abstract

I want to talk about the levity with which organic molecules are sometimes depicted. More specifically, my point tonight deals with how biologists bastardize chemical structures.

Some background is in order. This past weekend we had prospective graduate students visit our department from other schools. This is one of those annual events that serve to remind us what our craft is all about. For me, one of the appeals of synthesis is in finding a low molecular weight entity that can interrogate a protein that is hundreds, if not thousands, of times larger in size. This is nothing but a spectacular manifestation of ligand efficiency, which bolsters the notion that all it takes in order to shut down some sophisticated cellular machinery is a few correctly positioned hydrogen bonds and hydrophobic contacts. Chemists who make such molecules deserve some respect in terms of how their compounds are rendered by the end users (biologists). This is where I have a problem. Some representative cases on display below prove my point. While there can be numerous semi-legitimate reasons for these egregious errors, it is strange to see this sort of stuff in reported crystal structures. Annoyingly, on several occasions, I heard the following comment: “Well, we did not really spend a lot of time refining the small molecule ligand because all we cared about was the protein“. Really? And which pivotal factor contributed to you solving the crystal structure? It was the protein’s low molecular weight “partner”. Ironic, isn’t it?

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.

http://pubs.acs.org/doi/abs/10.1021/ol5031734

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…

http://onlinelibrary.wiley.com/doi/10.1111/cbdd.12227/abstract

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 5–endo–trig 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.

http://www.nature.com/nchem/journal/v7/n2/full/nchem.2150.html

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:

http://pubs.acs.org/doi/abs/10.1021/ja982050y

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 -80^oC, whereas NMM clearly does not have “enough” in it even at room temperature. Those adjacent nitrogen lone pairs… Pure magic.

http://pubs.acs.org/doi/abs/10.1021/acs.orglett.5b00261

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.

http://pubs.acs.org/doi/pdf/10.1021/jp0726687

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).

http://pubs.acs.org/doi/abs/10.1021/ja00856a001

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.

http://pubs.acs.org/doi/abs/10.1021/ja5077684