Rabbit ears

I want to talk about the so-called “rabbit ears”, which is one of the most enduring concepts in organic chemistry. There have been several exciting discussions related to this topic at the American Peptide Society meeting this week.

By way of background, Professors Ron Raines and Dek Woolfson published a thought-provoking paper back in 2010, in which they analyzed the pdb (protein database) and came up with a conclusion that nearby amino acid residues in proteins display n-pi* interaction. I discussed this back in 2013 (https://amphoteros.com/2013/11/27/neighbourly-ties/). According to the Raines/Woolfson analysis, the molecular orbital-based view of the amide oxygen is more adequately described not as A (below), but as B, in which there is a p-like molecular orbital perpendicular to the C-O vector. The authors stated: “Contrary to the expectations of valence shell electron pair repulsion (VSEPR) theory, the two lone pairs of divalent oxygen do not occupy equivalent orbitals that resemble rabbit ears”.

While “B” adequately explains the interaction between adjacent amides seen by Raines and Woolfson, it does not (in my view) provide grounds for saying that the good old rabbit ears concept has no merit. However, this is exactly what some people tend to conclude from their work. What might be done in defense of the poor old rabbit ears? I suppose if there were a study clearly demonstrating the 120o (or so) angle formed upon Lewis acid coordination to oxygen, it would be convincing enough. There is indeed a paper that shows that: Corey’s 1992 report in Tetrahedron Letters exemplifies the 120o B-O-C angle both in X-ray and in solution. I am somewhat relieved that the good old VSEPR model is alive and well.



Killing bugs with cyclic peptides: a unique mechanism

I have been in Orlando, Florida, since last Friday, running the American Peptide Symposium together with Dr. Ved Srivastava of the GSK. It has been quite a ride with Ved. Finally, after 2 years of preparation, we can now sit back and enjoy hearing the kind of science we wanted to share with the community (http://aps2015.org). Lars Sahl has been awesome, making sure our Facebook page is constantly updated with contact. Check it out:


The symposium got a great start with a talk by Professor Richard Lerner, whom I had a privilege to introduce last Saturday. In his opening lecture, Richard described his decades-long work in the area of phage display. Our regular program started Sunday morning with a lecture by Professor Masayuki Inoue of the University of Tokyo. I want to use this opportunity to point out a fascinating, although rare, mode of action of some natural products. I refer to those molecules that interact with a small molecule rather than engaging some complex biomolecule. In Masayuki’s case, lysocin E was shown to interact with menaquinone in the bacterial membrane.

Apart from the notable fact that lysocin E appears to represent a new class of antibiotic, it is really exciting that there is evidence for direct interaction with menaquinone. The robust in vivo effects in mammals described by the Tokyo team were interesting. I would also point out that menaquinone is a sole coenzyme used in the respiratory chain in S. aureus. This structure differs (thankfully) from ubiqunone used for these purposes by the eukaryotic cells. Masauki’s results demonstrate that menaquinone, but not ubiquinone, bind to lysocin E, which explains the selective toxicity of lysocin E against S. aureus.


Kondrat’eva reaction

There is some really nice cycloaddition chemistry coming out of Prof. Rob Britton’s lab at SFU. I just heard Rob speak at the symposium dedicated to the memory of Alan Katritzy. Alan’s passing was a big loss to the community, which is evidenced by the interest his chemistry keeps generating. The chair of our Department, Prof. Rob Batey, together with Prof. Vic Snieckus of Queens University, put together a nice group of speakers to commemorate Alan’s contributions to the science of heterocyclic chemistry. All of this took place in Ottawa, as part of the annual CSC meeting.


Now back to the [4+2] chemistry, which is appropriately (according to Rob Britton), referred to as the Kondrat’eva reaction. It is an interesting process, mainly due to the rare display of cycloaddition behaviour on behalf of the oxazole nucleus. Rob is running these reactions in flow, which makes sense given the volatility of alkene starting materials he uses. The reaction is a wonderful means to put together substituted pyridine rings. If you look at the ones made by Rob, you will see that it is far from obvious how to make them by any other means. In the hands of the SFU team, this chemistry was applied towards the synthesis of bioactive molecules.


Being doomed

I just came back from upstate New York, where I participated in the Northeast Regional Meeting of the ACS. The symposium I engaged in was superbly organized by Professor Anna Larsen of Ithaca College. This meeting gave me a chance to take a picturesque car ride from Toronto through the bucolic settings of upstate New York. These kinds of events are special because the audience is inevitably small, yet there is ample opportunity to see old friends and socialize with people you have not met. Peter Wipf (Pittsburgh), Scott Miller (Yale), Vladimir Gevorgyan (UIC), Amy Howell (Connecticut) and Alison Frontier (Rochester) made for a nice getaway from the daily routine.

I want to comment on something I wrote in my notes during the talk by Vladimir Gevorgyan. He made an interesting statement that an allene ketone of the type shown below (A) needs very “little” in order to get transformed into a furan. It appears that almost any metal catalyst is capable of inducing this transformation. Depending on the catalyst, the corresponding reaction might proceed by a unique mechanism, but the result in the same. I was really glad to learn about this phenomenon as it reminded me of my long-standing fascination with the “doomed” status of some molecules. This brings to mind the fundamental studies by Paul Schleyer. Back in the 1950s, he worked on the synthesis of adamantane and published an influential single-author JACS paper in which he described the transformation of the tricyclic hydrocarbon shown below into adamantane (see B). This work was followed by a number of papers from Paul’s lab, all pointing out different structures that somehow converged onto the adamantane nucleus when subjected to strong acid. The paths were different, but they had something in common: the involvement of cationic intermediates. Regardless of the specific chemistry, there are similar features in all transformations of what I call doomed molecules. The occurrence of reactions that bring a variety of structures to the same outcome is an interesting phenomenon and our appreciation of such pathways might be a sharpening stone against papers that are presumably innovative, yet correspond to inevitable outcomes driven by some strong forces.



On projected veracity and stupid statements

Projected veracity is a fascinating phenomenon that assumes truthfulness of one’s judgment on the basis of a notable prior accomplishment.

Today I came across the following piece, which documents offensive statements made by Dr. Tim Hunt, one of the winners of the 2001 Nobel Prize for Physiology or Medicine. He talks about the need to separate women from men in research labs. I don’t want to retell this story because it is stupid, offensive, and not worth the energy I have to expend typing letters. The Royal Society is distancing itself from Dr. Hunt. He himself is regretting what he had said, and so on:


But, ladies and gentlemen, I see a bigger problem here. My issue is with something no one ever mentions, namely: it is preposterous that Nobel Laureates are considered oracles. Many of them are allowed to share their wisdom on things they have no expertise in. I am tired when the general public assigns immense value to everything that comes out of their mouths. Just because a small committee in Sweden decided to award a Nobel Prize to someone for a notable and well-deserved scientific accomplishment, does not mean that whatever comes out of his/her mouth is worth listening to or getting worked up about.

But, alas, I suppose this is how it is with our illiterate society: whenever there is an issue, people rush to seek an opinion of a Nobel Laureate as if it is worth anything beyond some fairly narrow domain of knowledge.

Some people would say about Dr. Hunt: “Boy, this is so bad… After all, he is the winner of the Nobel Prize…”. So? Just pause and think about it. There is nothing that tells me that an opinion of a Nobel Laureate other than his/her science is worth listening to. Just consider how many really odd scientists are out there. Scientists are weird: we have awkward social skills that often border on the Aspergers’ syndrome. Just because someone is exceptional in one thing does not mean he/she is a well-rounded, reasonable person. And – make no mistake about it: although the opinion of a Nobel Laureate outside of his/her area of expertise is only marginally interesting, the view that women are somehow less suited for science is unacceptable for any individual to have, whether they are a Nobel Laureate or not.

The power of rational design

Griselimycin (GM) is a cyclic peptide from one of the Streptomyces strains. The molecule has been known since the 1960s. A research program, initiated at Rhône-Poulenc in those early days, was shelved in the 1970s due to the short plasma elimination half-life of GM upon oral administration. Now Rolf Müller of the Helmholtz Institute for Pharmaceutical Research in Saarland and researchers at Sanofi-Pasteur report in Science on the derivatives of GM with excellent anti-tuberculosis potential. Surface plasmon resonance has revealed DnaN (the sliding clamp of DNA polymerase) to be the target of this molecule. What’s most interesting is the effect of proline alkylation on the stability of GM. Apparently, proline-8 was identified as the locus of metabolic liability, which triggered the search for more stable versions of GM. Simple structural modifications led to metabolically stable compounds with increased lipophilicity and oral bioavailability of up to 89%. A crystal structure of the cyclohexyl GM-DnaN complex was determined, showing that one of the peptide-binding pockets of DnaN had been occupied by the cyclic part of the ligand. I continue to marvel at how some minute structural changes lead to profound consequences in the activity of cyclic peptides. And please don’t tell me that biological methods (phage display, you name it) are better than rational design based on logical arguments. This paper is a great example of the synthetic approach.



Missing out on discoveries

Scientists make discoveries all the time. Research findings differ in terms of significance, breadth, and downstream potential, but they do happen on a daily basis to everyone who is passionate about research. Any undergraduate student who is just getting into the “research groove” is a good example. The fact that the majority of his/her discoveries early on are not going to impress the community-at-large is not important. What is critical is to get into the habit of noticing interesting things, even if they are not earth-shattering. Upon training, one gets to appreciate the finer details, which inevitably leads to significant findings.

Now let’s consider someone who has just made a truly thought-provoking discovery. Here is a question that interests me: how often have others passed by that observation and did not even think twice about its significance? One can probably say that the predecessors might not have had the right tools, which would explain why the discovery had eluded them. I think this is very understandable. But then there is another possibility: people might have had all the tools in the world to make the discovery, yet they really did not care about it as their primary objective was in a totally different field. This could happen if we consider different areas that are driven by unrelated objectives. Take, for instance, polymer chemistry on one hand and synthetic methodology that targets small molecules on the other. Here is one of the cases from my “vault” of papers from 20 years ago. Below you see a link to the classic paper by Leigh and co-workers in Angewandte. It details the first crystallographic characterization of the smallest known catenane. If you consider the reaction that leads to the synthesis of this molecule, I am sure you will agree that things cannot get much simpler. In fact, the authors themselves state that the reaction involves “chromatography-free purification procedure simple enough to be performed in a well- equipped high school or undergraduate laboratory”. Now just think about the number of times polymer chemists studying amide materials made this catenane prior to 1995. There is substantial peer-reviewed and patent literature that documents formation of insoluble white powders during polycondensation. According to those reports, the precipitates are to be discarded upon work-up… I am sure there are many examples like this in other areas. It is indeed rather easy to pass by something exciting and not even notice it.