Ugly cousins: mystery molecules popping up everywhere

Let me share a frustration I never thought was possible: you look at a co-crystal structure of a protein with a small molecule bound to it and you have no idea what this small molecule is. That’s right. I have to admit that this is a fairly awkward feeling for someone who has a lab that makes small molecules. My students rely on X-ray crystallography for structure determination in our day-to-day endeavours. However, we use direct methods in organic chemistry and, sure enough, when you have a molecule whose structure is solved at 0.6 Angstrom resolution, life is good and you can rely 100% on the data when it tells you what a given molecule is. Protein structures are way more complex, yet rely on a MODEL when you try to solve the structure. If you have a 2.4 Angstrom resolution structure and you see electron density corresponding to a small molecule bound to the protein, good luck finding out what this molecule is unless you already know it or suspect what it might be! Isn’t it frustrating?

A case in point is shown below, which is our day to day struggle at the moment… Right in the center of the picture you see a banana-like electron density which is not part of the protein. You do see a (presumed) structure and it is shown as a model. But don’t be fooled, this is far from reality. We know that it ain’t real since anomalous scattering tells us that there are no S atoms, despite the SO3- group clearly modelled in the structure shown. We are trying to find out what the density belongs to and are still in the dark. I never thought (perhaps naively) that this could be the case, but it is true… Protein crystallography is for proteins and small molecules appear to be the proteins’ ugly cousins! We are trying to use all sorts of tools, including non-denaturing MS but we can’t seem to zero in on the right structure (yet). Stay tuned. Incidentally, this is a protein I crystallized with Elena not long ago. I can’t disclose the name of it yet, sorry.


I love this sabbatical!

Cascade starts from a Mitsunobu…

Here is a very neat result from Jon Ellman’s lab at Yale. As part of a study documented in Org. Lett. (, an interesting observation was made: the intended nitrogen-driven Mitsunobu process did not take place. Instead, a cyclopropane has been formed:


Building on this observation, Andrade’s lab showed a really cool cascade process that ultimately enabled a short synthesis of (-) melotenine A ( I think the mechanism is really interesting. Cascade reactions rule!


On early mornings without coffee (but with boron)

Yesterday morning I was doodling on a piece of paper, thinking about Zhi’s synthesis of alpha boryl aldehydes. These molecules offer a nice entry into boron-containing intermediates (I blogged about them in July). Of course, “B” stands for “boron”…

It was early in the a.m., I did not have my coffee yet, and I somehow typed bromine (Br) instead of boron (B)… But then it occurred to me: “crap, there is something weirdly familiar here!”. I started digging into our old papers and I found one by my former PhD student Larissa Krasnova from 2006. She developed this nice hydrazone formation:

If you compare her work to our boryl aldehyde synthesis, there is an interesting parallel in terms of what migrates and what is around the migrating group… Mechanisms are different, but still:


Whenever there are interesting ways of comparing the incomparable, I always go back to the lessons taught to us by Roald Hoffmann of Cornell. I refer to isolobal relationships, of course.

In our case there is no isolobal relationship, just a lack of caffeine, but still… Interesting.

Joanne and Sonia – great job!

There is no doubt that one of my favourite experiences is when we get to train undergraduate students in our lab. This Summer we hosted Joanne Tan and Sonia Zaichuk. Joanne is an undergrad from McMaster, whereas Sonia is from U of T. Yesterday we had a Summer poster session sponsored by AstraZeneca (an annual event when our students present their results) and… both Sonia and Joanne were among the prize winners!

The whole lab was really proud of them. I personally derive the biggest satisfaction from the following: typically I get to see and correct students’ posters but now that I am on sabbatical I suppose people think I do not have time. So… I did not see the posters! It is really cool that the ladies (under the guidance from Ben Chung and Serge Zaretsky, their immediate advisors) displayed a really high caliber of scholarship and presented their work in the best possible way. Kudos to them as well as to Serge and Ben!! 



Searching for new amphoteric molecules

Ever since my lab identified aziridine aldehyde dimers in 2006 and termed them “kinetically amphoteric molecules”, we have been searching for new examples of this privileged, yet strange, class of compounds. Of course, we have also paid close attention to other researchers’ efforts in uncovering cases of amphoteric reactivity!

I have been really intrigued by Professor Sun’s oxetane aldehydes. Here is an example of an efficient [6+2] cyclization with siloxy alkynes giving rise to the first intermolecular synthesis of eight-membered lactones.

There are two pathways (a and b) that are being considered by the authors:


Drawing on their initial discovery, Sun and co-workers later expanded the utility of oxetane aldehydes to multicomponent reactions. Thus, the oxetane ring was shown to be a superb directing group that played a crucial role in achieving both high yields and high enantioselectivities in amphoteric molecule-driven multicomponent reactions. I will continue paying attention to advances in this area…

Let’s double our failure rates…

Below is one of my favourite quotations and I hope you like it. I think that my recent experience with getting macrocycle crystals together with my students underscores the notion that, at some point, we just need to drastically increase the number of experiments we can run and analyze. Effectively, what Elena and I have been doing with protein crystal structures, can (and should) be applied to other molecules which are tricky to crystallize. We have shown that the SGC platform is adaptable to other scenarios and I will continue our work along these lines of screening. Dr. Paul Reider (Merck) told me once that at least 10% of a researcher’s work should be aimed at science that is not hypothesis-driven but is Edisonian. I concur: this is what we should do more of. Nature is just too complicated.


A happy day in the macrocycle universe!

This is a happy day for us because one of the architecturally complex macrocycles we have been working on succumbed to crystallization and diffracted really well. I am showing the main parties to this feat: Joanne Tan (an undergraduate student from McMaster who has been doing a great job with us over the past 3 months as part of her NSERC-funded Summer research position), Jen Hickey (Jen is working with Encycle) and Serge Zaretsky (my PhD student). Hats off to these guys for making the molecule. Importantly, we were able to show that we can employ protein crystallization conditions in order to get perfect (you can see) crystals of significantly smaller molecules (in this case – medium-sized macrocycles). I am amazed by the power of this method as we only needed 2 mgs to screen 96 crystallization conditions! If you do the math, crystals in the two wells that you see below (each well is 3 mm in diameter) came from 0.02 mgs of material in each case. Powerful stuff. Alan Lough has solved this structure (and we are working on another one with Aiping Dong from SGC, who is very excited about the project).

Sorry that I cannot show you the structure in full – I don’t want to jeopardize the publication. You will see why. One of these days.

Cross-fertilization between biology and chemistry is in action!