As academic researchers strive to have their methods used in drug discovery, it is important to keep in mind that the reaction scope must include a large proportion of molecules that have a chance to have favourable drug-like properties. This is not always the case, and it is especially true when it comes to carbon-carbon bond forming reactions. Indeed, there are not many methods that accomplish carbon-carbon bond formation without turning synthetic precursors into “grease balls”. And what do you do when you are out of options? You turn to the other extreme and over-emphasize amide couplings, which creates molecules which are not exactly the stallions of drug discovery either.

The paper I intend to discuss is now a couple of years old (see the link below), but there are some practical items of substance in it that deserve attention. As rightly pointed out by Nakagawa and colleagues of Pfizer in their article, published methods tend to focus on excessively lipophilic model substrates, which is not what one wants to see in a molecule that is expected to be cell-permeable and have a chance to go through first-pass metabolism. In their efforts to find a reaction that accepts a broad range of building blocks, tolerates functional groups, and works well in the presence of moisture and air, the authors turned to BBC chemistry (Barluenga Boronic Coupling). This is a fascinating process that involves simple mixing of a boronic acid with a hydrazone. The reaction is reductive in nature and proceeds via an interesting mechanism. I was glad to see this process, originally published in 2009 in Nature Chemistry, in action. Despite the low isolated yields obtained by Nakagawa and colleagues, the simplicity of this protocol is attractive for rapidly assembling relevant molecules.

http://onlinelibrary.wiley.com/doi/10.1002/cmdc.201100339/abstract

At my group meeting earlier today, we were having a problem set related to the FMO theory. This brought to mind a discussion I had with a good friend of mine, Sergey Kozmin, of the University of Chicago (http://kozmin-group.uchicago.edu), who visited our house in Oakville this past weekend. As a matter of fact, this is a surreal coincidence because 24 hours prior to that I saw Vladimir Gevorgyan in Paris, who is also from Chicago (and, like Sergey and myself, hails from the former Soviet Union). In Bill Shatner’s words: “Is it weird, or what?” (https://www.youtube.com/watch?v=MmNgMJWEYJQ).

http://pubs.acs.org/doi/pdf/10.1021/ja00042a049

Continuing along the “weird” angle, I also like when well-known reactions we take for granted behave anomalously. Above is a classic paper by Daniel Singleton that probes the Diels-Alder process with vinyl boranes. Sergey brought this to my attention. What can possibly lurk out there in the old stomping grounds of [4+2] cycloadditions, you might say? Intriguingly, the LUMO coefficients at the vinylic carbon and boron centers are rather close. As a consequence, while the product of the reaction is the expected 6-membered ring, it is the [4+3] transition state that takes hold in this system, defining an interesting secondary orbital interaction. There have been other papers on this subject since Singleton’s report, so I encourage you to look into this literature.

The fight against entropy is omnipresent in efforts to find new reactions, develop advanced materials and design biologically active molecules. Many of us struggle with this factor and attempt to provide solutions. Take C-H activation as an example. This field has made remarkable strides over the years, but intramolecularity and reliance on the so-called directing groups has been common in finding solutions to some of the longest-standing problems in this field. While attending the FACS meeting in Avignon, I enjoyed listening to the talk by my good friend, Professor Vladimir Gevorgyan of the University of Illinois in Chicago. One of the topics covered in his lecture dealt with silicon tethers that enable the directing element to serve its function and be “erased” towards the end of synthesis using fluoride anion. Alternatively, the C-Si bond could be transformed into something else using cross-coupling or oxidation. The idea of using silicon tether is simple and certainly lifts some of the challenges associated with directing groups that are glued permanently. Below is a link to the paper in Nature Chemistry published by the Gevorgyan lab. There are many other contributions on this topic published by his Chicago team.

http://www.nature.com/nchem/journal/v6/n2/pdf/nchem.1841.pdf

I have been silent for a while and the reason is that I was in the south of France, attending the 15th Meeting of the French-American Chemical Society in Avignon (it’s a hard life we live in academia…). This was a splendid conference, but it was tough to get good access to the internet, which is why I did not post anything. The line-up was excellent, you can view it at the following link: http://facsxv.unistra.fr/speakers.html. I am going to post some thought-provoking highlights in the next few days. 

Every now and then we have a seminar that I miss because I consider it to lie outside my area of expertise. While this might help save time, I later regret not attending those “out of my comfort zone” kinds of talks because I know for a fact that one tends to learn the most out of people who work in unrelated areas. The reason is simple: those folks do not have any of my default assumptions and tend to ask great questions. I can speak from a personal experience as it is all too often that, when I visit other places and meet people who work in areas that are closely related to my lab’s interests, I refrain from asking about certain things because “well, they probably thought of THAT”. This is a mistake, and the only way to rectify it is to attend lectures that are not directly related to what one does. Needless to say, you also learn a lot just by listening to such talks. Today was no exception. I really enjoyed hearing Barney Grubbs of Stony Brooke University (http://www.chem.sunysb.edu/faculty/grubbs.shtml) speak about his lab’s work in the area of materials chemistry. One of the reactions caught my eye. You can read about it in the link below. In order to make the tellurium-containing molecule shown, Barney used an interesting coupling partner – a tertiary alcohol – in place of our “usual suspects” such as organotin or organoboron reagents. I don’t think I saw a transmetallation accomplished in this fashion too many times before! You can think of a mechanism… I think it is quite interesting.

http://pubs.rsc.org/en/Content/ArticleLanding/2014/CC/C4CC01862A#!divAbstract

Have you noticed how political correctness has made its imprint on the scientific discourse that is being shaped up at conferences? The days of hearing offensive remarks for the sake of scientific truth are more or less behind us, yet there is something to be said in defense of raw and unfiltered emotion that used to be omnipresent at scientific meetings. Maybe the feel-good atmosphere we experience these days is because the stakes are higher and people are thinking a lot more about their image and reputation? We used to say that arguments and politics in science get nasty because the stakes are low. This is true of the older days, but maybe not anymore? The way things used to unfold is almost inconceivable to those who embark on a career in science nowadays. And I am not even talking about one’s behavior at a conference. When I was a postdoc we used to have a special term when a confrontation between two people was taking place. That “blissful” moment, when one of the parties to an argument was being attacked, was compared to him/her being asked to bring out the “shinebox”. The video below explains this analogy. Here you see the immortal “Billy Batts” scene from Scorsese’s “Goodfellas” (I apologize for the coarse language, but this is Scorsese, not me). What you see is an analogy to how heated arguments used to develop. I love DeNiro’s role in this scene when he says “Insulted him a little bit…” at 3:08-3:13. DeNiro corresponds to a peacemaker (albeit a temporary one!). Notably, there is often someone like that in a scientific argument as well. This sort of stuff is not happening in science anymore, though, because we are more civilized. Are we not?

I am on a high-speed train from Xuzhou to Beijing, which means that my 3-day trip to China is coming to an end. You might ask: “Is it worth the trouble to spend all this time on an airplane, only to be 12 time zones away from home for a few days?”. I would say these trips are always worth it, particularly when there is a chance to see old friends and learn new things. I want to talk about a lecture by Professor Laszlo Kurti of the UT Southwestern Medical Center in Dallas. Laszlo is familiar to many people thanks to some of the nice books he published together with E. J. Corey. I particularly enjoy their book on the named reactions and mechanisms thereof. Laszlo’s recent paper in Science described metal-catalyzed synthesis of NH aziridines, which are exciting synthetic targets. Despite my long-standing interest in this chemistry, I want to talk about another one of his lab’s contributions I enjoyed hearing about. Besides its synthetic value, there are compelling pedagogical reasons to think about this chemistry.

From time to time I refer to the significance of mechanism and attention to experimentally determined reaction parameters that are germane to our craft. Take a look at the reaction sketched below. This is a remarkably efficient route to NOBIN-type ligands that was inspired by the Bertolli indole synthesis. This reaction, developed in the Kurti lab, teaches the significance of precision when it comes to measuring the amounts of arylmagnesium reagents. I encourage you to read about the exact mechanistic details using the link provided, but I am just going to say that failure to employ precisely 3 equivalents of the Grignard reagent leads to abysmal failure in this process. You might think that the use of 2 equivalents might simply lead to lower conversion, but it is more dramatic than that, according to Laszlo: failure to aromatize with the third equivalent leads to a mess. In other words, each equivalent of the organometallic species here is assigned its unique functional role. This also implies that the experimentalist running this process must titrate his/her Grignard reagent prior to use, which I am sure is not something that is done by some less careful practitioners of synthesis. All in all, attention to detail is what chemistry is all about. I tend to prohibit students who start doing research in the lab from running any experiments, no matter how trivial they might appear, prior to ensuring that the students demonstrate complete understanding of the mechanisms involved. Laszlo’s nice work is a testament to why this is important.

http://pubs.acs.org/doi/abs/10.1021/ja400897u