Proline: its puckering and a sila- version

For the past two days I have been in La Grande Motte, which is not far from Montpellier in the South of France. The conference was put together by Professors Pascal Dumy and Jean Martinez, to whom we are most grateful for not only arranging a great program, but also for giving us an excuse to visit this part of the world in the Fall:

There have been some memorable talks thus far and I have learned many new things, particularly about proline. This molecule continues to amaze a whole lot of people, including myself. Professor Helma Wennemers of ETH-Zurich presented her research aimed at understanding collagen. I was impressed with the molecular-level details of this material that has been obtained by Helma’s lab. Collagen is a polymer that consists of proline, hydroxyproline, and glycine. Helma described the significance of how the proline ring puckers and the prevalence of n-to-pi* interactions that exist in this material (


In the past, I mentioned these important interactions on my blog and talked about the work of Ron Raines (who is also here, by the way). In her crystallographic analysis of oligoprolines, Helma has now obtained evidence for the n-to-pi* interactions between the adjacent proline residues. Given the importance of proline in my own lab’s macrocyclization reactions, I am surprised that we have not considered the relevance of puckering on macrocycle conformation. Another proline-related vignette came from the lab of one of this conference organizers, Professor Martinez. Dr. Florine Cavelier, who belongs to the Martinez lab at the IBMM Institute in Montpellier, presented her work where silaproline was featured prominently. Prior to this conference, I had not been aware of the significance of this unnatural amino acid and I am glad that I had a chance to see its unique influence on peptide materials. By the way, the synthesis is rather simple and scalable:



Some razzle-dazzle

There are many atom transfer reactions that generate three-membered heterocycles from multiple bonds. Yet, if you really think about it, there are not too many diverse mechanisms that describe these reactions. Or, more precisely, a few well-established mechanisms describe the vast majority of known processes. For instance, oxene and nitrene-like species (typically associated with a metal) is what we expect to see in epoxidation and aziridination reactions. I keep my eyes peeled for rare cases where I see some razzle-dazzle (to use the term Jon Soderquist uses to describe some interesting bond movements). You look at such reactions while sifting through TOCs and you go “wait a second, what happened here?”. Take, for instance, a really neat example described by a group from Merck several years ago. In this sequence, a cycloaddition initially generates a 5-membered ring adduct that later rearranges into an aziridine-containing structure. The most interesting features of this reaction, in my view, are the net transfer of oxygen to the alkyne carbon (generating the ketone you see) and the arrows themselves. If you think about it, it is not entirely obvious how something like this can be described using frontier molecular orbitals. I need to think about it (and maybe ask Dean Tantillo of UC Davis)…



Light in synthesis

Low quantum yield is just one of many troubles with conventional photochemical reactions such as isomerization of double bonds. In addition, scalability has been quoted as an obstacle that precludes many classic photochemical reactions from entering the mainstream of synthesis. However, when they work, these reactions can be marvelous. I tip my hat off to Mulzer and co-workers who used photochemistry at a late stage of their synthesis of 17-deoxyprovidencin. The key to success here is that the absorption maximum of the Z isomer (below) lies at 306nm, whereas the E isomer absorbs below 300nm. Irradiation with UV-B light resulted in the desired Z/E isomerization. This example highlights another point, namely the need to use the right gear in these kinds of reactions: Pyrex glass is absolutely critical as it cuts off UV wavelengths below 300 nm. Therefore, once the desired E isomer is formed, it has no chance to go back to the Z form. This is very crafty. In more general terms, I think it would be interesting to look at photochemistry in constrained macrocyclic environments offered by cyclic peptides. There’s got to be a lot of unusual reactions that will pop up there.



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.