Cryptic intermediates

Here is an interesting and teachable case that seamlessly merges the elements of biosynthesis and fundamentally important classic organic chemistry. Liu and colleagues report indolenine 1 as the “cryptically conserved” intermediate in the biosynthesis of hapalindole-type alkaloids. It all starts with the magnesium-dependent formation of 3-geranyl 3-isocyanovinyl indolenine from cis-indolyl vinyl isonitrile and geranyl pyrophosphate (this process is enzymatically catalyzed by AmbP1). What ensues is an interesting Cope/aza-Prins cascade, which ultimately leads to divergent pathways to hapalindole-type alkaloids. Besides an intriguing biosynthetic route, this work is important as it opens doors for understanding the molecular basis of the metal dependency of prenyltransferases.

Hapalindole alkaloids have received their fair share of attention in the synthetic community, but only Ang Li et al’s work ( foreshadowed the Cope/aza-Mannich biosynthesis put forth by Liu. While it is nice to read such stories, I am not suggesting that the present case is an exception. The most famous case of “foreshadowing” is perhaps Stork’s classic work on enamines, which had appeared way before type I aldolase mechanism was elucidated.2.jpg

Remodelling the Schmidt reaction pathway

Not long ago, I talked about the power of the Aubé-Schmidt reaction in the synthesis of unusual amide structures. I just saw a JOC report by the Aubé lab that details a rather unusual outcome of this process when TMSN3 is made to react with ketones in the presence of triflic acid (TfOH) promoter. In the course of this reaction, tetrazole formation turns out to be the predominant pathway. This outcomes stands in contrast to established protocols in which one typically expects to see lactams or amides through formal NH insertion into the C-C(O) bond. This mechanistically distinct process hinges on the prior discovery that 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) acts as the catalyst and reduces the number of equivalents of acid needed for good conversion in the Aubé-Schmidt reaction. In the most recent embodiment, the sequence of iminium ion formation / isonitrilium ion formation / ring-expansion, is observed. To sum up, the reaction between azides and carbonyl compounds continues to have an enduring impact on the synthesis of small molecules.


Looks like dementia might be in decline

Here is an important paper that will likely cause a lot of interest and debate. The work published in The New England Journal of Medicine (NEJM) describes the Framington Heart Study, participants of which have been under surveillance for dementia since 1975. This is an extensive analysis of 5205 persons 60 years of age or older. The main conclusion here is that the incidence of dementia has declined over the course of three decades in high-income countries. In the interest of full disclosure, I am not saying that I have read the manuscript carefully. The description of methodology in a typical NEJM paper is above me. However, the conclusions are exhilarating because recent projections have suggested that there would be a significant burden of dementia over the next four decades owing to longer life span and associated higher number of older persons at risk. The actual decrease reported by Sephardi and co-workers (up to 44% per epoch of the surveillance period) is quite interesting. The understanding of the underlying phenomena is clearly incomplete and delineation of possible causes is needed in order to accelerate the beneficial trend. These kinds of findings go against expectations and show that we really do not have a clue when it comes to cataclysmic predictions. At the dawn of the 20th century people thought that horse manure would be the biggest environmental threat. And then cars came around… Incidentally, NEJM has the highest impact factor – higher than Science or Nature – which is kind of remarkable because this is, in fact, a rather specialized medical journal.

Polycycles galore

I don’t want you to think that I have been reading only Diels-Alder literature of late, but I found the recent JACS paper from Michael Doyle’s lab to be quite remarkable. The authors report a mild conversion of diene-tethered diazo compounds to the corresponding [4+2] cycloaddition products. Prior to the Doyle work, diazo compounds were not known to partake in cycloadditions of this kind. When I read stuff like this, I inevitably ask myself: how many times such a reaction happened (unbeknownst to the experimentalist) in the past? You have to agree that people must have studied metal-catalyzed intramolecular cyclopropanation processes in which a diene was evaluated as the carbenoid acceptor. But then maybe no one bothered to evaluate dienes in that capacity. Otherwise, how can one possibly imagine that a room temperature pathway to the Diels-Alder adducts shown below has remained veiled for so long? There is some gold-based catalysis described in this paper as well, but it is the room temperature transformation in chloroform that is surprising.




Going after riboswitches

Non-coding RNA structures called riboswitches are known to regulate gene expression. As opposed to proteins and nucleic acids, riboswitches have remained a largely underdeveloped class of drug targets. A team from Merck recently reported the discovery of ribocil, a compound that selectively modulates bacterial riboflavin riboswitches. The small molecule was identified as part of a phenotypic screen. Ribocin was found to inhibit bacterial cell growth by repressing ribB gene expression. Specifically, this new molecule competitively mimics the natural ligand of a bacterial riboswitch, namely flavin mononucleotide (on the right hand side of the graphic below is a representative riboswitch complexed with flavin mononucleotide). I think it is exciting that small molecules can now target non-coding RNA structural elements. One cannot help but notice structural similarities between ribocin and a number of well known kinase inhibitors, which begs a question about the possibility of repurposing some of those “usual suspects”.