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.