What can formaldehyde do for you?

Xenobiotic electrophiles are “taken care of” by glutathione, which is part of our primary defence mechanism against various kinds of toxic molecules (this is why you do not want to take too many Tylenol tablets as the metabolite of this drug would quickly chew up your glutathione reserves, making you vulnerable). We do not often think about what happens to glutathione as a result of this chemistry. We probably think that it must be trivial and uninteresting. Certainly, the thiol group must play its key role in glutathione transformations, but I don’t think one tends to worry about the details of glutathione modifications. I was reading the 2007 paper by Kevan Shokat and colleagues in Organic and Biomolecular Chemistry and got reminded about the fascinating effects of formaldehyde, one of the simplest electrophiles, on polyfunctional molecules such as glutathione. Below you see a serendipitous finding made in the Shokat lab as part of a study aimed at non-enzymatic reactions between glutathione and formaldehyde. Not only did the insanely looking bicycle form, it also got co-crystallized with the carbonyl reductase I enzyme (pdb id: 2pfg). If you are interested in heterocyclic chemistry, this example of formaldehyde-driven construction of complex heterocycles should be of interest. I have always been fascinated by the increase in complexity that can be ascribed to the “stitching power” of this seemingly trivial molecule.




Amide enolates – still rather rare, I suppose

I was glad to see a nice amide alkylation reaction as part of a total synthesis of (+)-bermudenynol recently reported in Angewandte by Kim and co-workers from Seoul National University. The natural product, the structure of which is shown below, contains an 8-membered ring. We all know how difficult it is to build these kinds of scaffolds. In fact, the authors failed miserably in their attempts to use the ring-closing metathesis, which is the workhorse of medium ring construction. Instead, they turned to a much riskier proposition, namely an attempt to develop a route to the allyl bromide-based substrate shown below and subject it to amide enolate-induced cyclization. Surprisingly, the reaction worked really well, which is interesting considering how infrequent amide enolate alkylations are. There are other interesting features in this synthesis, but amide alkylation is the centerpiece of the approach. The polyhalogenated structure of (+)-bermudenynol also reminded me of some interesting molecules shown by Prof. Chris Braddock (Imperial College) in his talk here at the University of Toronto a couple of days ago.