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.



The enduring concept of isolobal relationships

A couple of weeks ago, I heard one of the most interesting lectures of the past year. Prof. Alcarazo, now at the University of Göttingen, was visiting our department as the external examiner of one of Doug Stephan’s PhD students. From his talk, I learned about the surprising reactivity of thiourea, known in all sorts of roles – from heterocycle synthesis to asymmetric catalysis. The novel reactivity shown in Figure has its origins in Roald Hoffman’s teachings on the power of isolobal relationships in chemistry. Alcarazo and his students have extended this enduring concept to the “sulfur version” of hypervalent iodine reagents. As it turns out, a lot of reactions known in organoiodine chemistry can now be carried out using significantly more user-friendly organosulfur compounds, many of which are accessible from thiourea derivatives using a couple of trivial transformations. By way of an example, I am showing the cyanation of N-methyl indole.



Inspirational chemistry

Every once in a while, we all want to read something inspirational. Alas, we like different things and our choices reflect personal preferences, dogmas, and current fads. There are people who somehow get existential meaning out of “transition metal-free X”, with X being pretty much anything… Some other folks get a kick out of site-specific modification of amino acids in proteins… How about science coming out of places that have no business producing anything meaningful because they are entrenched in conflict and corruption? I like that. Below is a paper co-authored by a team of scientists from Enamine in Kiev, Ukraine. The fact that these individuals are able to produce science of this caliber under the conditions they are currently in, is quite admirable. The Org. Lett. paper describes a very counterintuitive participation of CF3 diazomethane in reactions with nucleophiles. Effectively, nucleophilic additions of certain nucleophiles appears to result in the attack at nitrogen, which goes counter to everything we know about diazomethane chemistry. As a result, a series of interesting transformations are enabled and I would call it a method par excellence for producing heterocycles of medicinal importance. I am at a loss as to why this transformation of diazo functionality has remained veiled through all these years…



At long last – an HDAC structure with a cyclic peptide inhibitor

Not too long ago, Christianson and colleagues published a notable paper in Nature Chemical Biology. It describes the molecular basis of catalysis and inhibition of histone deacetylase 6 (HDAC 6) and uses several small-to-medium sized probes to investigate this enzyme. Naturally, my attention was focused on the exciting co-crystal structure of HDAC 6 and HC toxin, which is well-known covalent cyclic peptide inhibitor. HDAC 6 comprises two tandem catalytic domains. One of them is specific for substrates bearing C-terminal acetyllysine residues. Now that we finally have a molecular-level view of a cyclic peptide inhibitor/HDAC interaction, this paper should encourage a new wave of attempts to design selective and potent inhibitors of HDACs. I am not sure I agree with the authors regarding their claim that the cis/trans/cis/trans geometry of the four amide bonds in the HDAC-bound HC toxin is particularly remarkable. I cannot think of anything else that is reasonable, particularly if proline is one of the residues. In fact, there are a number of crystallographically characterized cyclic tetrapeptides that feature exactly this arrangement. There is, nonetheless, an interesting clue regarding achieving selective HDAC inhibition using cyclic peptides: despite the presence of the strictly conserved cysteine 584 residue, HC toxin binding is dominated by zinc interacting with the gem-diol, leaving the epoxide intact. The thiol side chain of cysteine 584 is still well positioned for nucleophilic attack at one of the epoxide carbons, but the authors suggest that inhibitor binding to other HDACs would result in an even closer contact between the nucleophilic SH and the epoxide electrophile, leading to covalent bond formation. This offers an interesting bis(electrophile) selectivity filter.




Reactivity and selectivity

On a recent trip to Munich, I got acquainted with the research of Professor Hendrik Zipse. His mechanistic understanding of catalysis of alcohol silylation is both deep and educational. It serves as an instructive reminder of the reactivity/selectivity principle, which is something chemists relate to on an intuitive level. Not too long ago, Zipse and co-workers published a series of papers aimed at understanding the fundamental underpinnings of Corey’s classical silylation of alcohols. Zipse reminds us that DMF was the prescribed solvent in the original system. In this process, imidazole was used to mop up HCl, making TBS transfer one of the most familiar processes in organic chemistry. The question is whether or not the role of all components is crystal clear. It is now, but only after Zipse’s kinetic analysis. In brief, DMF is not your innocent by-stander. Its role is to form the active silylating argent, which is the Lewis acid/base pair shown below. Due to the high activity of this adduct, reactions in DMF (the original solvent from Corey’s 1972 paper) do not show impressive selectivity among primary, secondary, and tertiary alcohols. This is a very important finding. In contrast, if one stays away from DMF/imidazole mixture and runs silylations in dichloromethane along with DMAP and triethylamine, the selectivity is excellent. Improved reaction profile correlates with lower activity of the DMAP-derived active silyl transfer agent.