Raising temperature opens new vistas

Boron-containing molecules are among the pillars of chemical reactivity. This is mainly due to the overwhelming embrace of the Suzuki cross-coupling, one of the easiest way to make C-C bonds. Over the years, it has been difficult to find other ways of coaxing boronic acids to participate in C-C bond formation. The paper by Tang and colleagues goes to show that simply raising temperature is a safe bet to discover new boron reactivity. What an irony, considering the sheer volume of research dedicated to getting organoboron compounds to react. Otherwise, how can anyone explain to me that alkenyl boronic acid nucleophiles have hitherto not been matched with alkyl halides? The reaction developed by Tang provides a new electrophilic partner for boronic acids, complementing the iminium ion reactivity captured by Petasis and colleagues 20 years ago. I find the process both interesting and useful. It takes place in toluene and requires about 80 oC to proceed. The success of this reaction is quite remarkable due to the absence of metal catalysts, which is why I tip my hat off to the authors.



Boron in simple and complex amines

Now that the fall semester is finally here, I will hopefully have more time to write my posts. Today is all about Diego Diaz and the cool chemistry we recently published in Angewandte (http://onlinelibrary.wiley.com/doi/10.1002/anie.201605754/abstract). Diego did his undergraduate work with Patrick Gunning and came to do PhD in my lab in the Fall of 2014. He quickly developed a keen interest in placing boron within peptides, gave it all he had, and came up with what I think is the best way to incorporate boron into amino acids and related structures. You might wonder why and I could name a few applications: from cross-coupling all the way to hydrolase inhibition. But I refuse to talk about any of this tonight because the ultimate target of our research endeavors is to understand the basic reactivity of organic molecules. In this regard, Diego’s sigma-loaded iminium ions stand out. We have not only characterized them, but we have also employed them in several reactions, including one of my favorite ways of linking molecules – by way of reductive amination. Below are some of the details. Using two slides from a lecture I gave in Halle (Germany) 10 days ago, I show Diego’s NMR data. With respect and admiration, I also pay a tribute to my late colleague, Professor Adrian Brook. The Organometallics paper you see was Adrian’s last contribution to chemistry. It is fitting that this manuscript details an attempt to make imines from Adrian’s acyl silanes. As we all know, this is not possible with silicon because of the Si-heteroatom bond strength, which triggers migration (Brook rearrangement). In our case, we do not have evidence of migratory processes, which is due to the carefully chosen tetrahedral environment around boron. This is amusing, given the fact that boron, not unlike silicon, loves oxygen.

As “luck” would have it, right about time when Diego’s chemistry entered its high gear, he is moving to Vertex in Montreal, but thankfully only for three months (this is one of those industrial experience shindigs). Let’s see what he will be able to accomplish by Christmas. I hope to be able to disseminate the non-confidential part of it. For now, I am really happy about the facility with which we can “smuggle” boron into the structures of bioactive molecules. Thanks Diego.



Trimethyl lock

As part of an ongoing study, we recently tried to think of reactions wherein an amide linkage gives way to an ester. It is interesting to note that, when it comes to proteases, there is nothing remarkable about N-to-O replacement. It happens all the time and is controlled by the low pKa of the active site hydroxyl, among other factors. Synthetic chemistry is different in that ground state energies dictate that the reverse (O-to-N) is more likely. Indeed, we typically make amides out of esters, not the other way around. Unless there is a way to change the energy landscape of the reaction, that is… In this regard, the fascinating chemistry of trimethyl lock (TML) comes to mind. It is particularly nice to see how basic ideas of conformational control enable some ideas in drug delivery to come to fruition. An instructive example of “immolation” of a boron-containing therapeutic through the use of TML is described in Ron Raines’ recent work. In this paper, the authors describe molecules with boronic acid appendages and their internalization by mammalian cells. As you might have guessed, reversible interaction with sugars is the driver of this process. Boron aside, what attracted me to the paper is that it puts TML, the tool of physical organic chemistry, to good use.