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.
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).
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.
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.