Do not underwrap your hydrogen bonds

It is hard to wrap one’s head around the concept of underwrapping (no pun intended) but it is not so intimidating (underwrap = expose to solvent). Ariel Fernandez uses it to describe peptide structures. He applies a variety of metrics to arrange the corresponding peptide molecules on the spectrum of toxicity (and many other properties such as cell permeability). In his Nature Biotechnology commentary several years ago, Ariel has made some compelling arguments pointing to a correlation between properties such as toxicity of a peptide and the extent of hydrogen bond accessibility. There are many other properties described in this work as well.

For instance, the worst wrapper of hydrogen bonds in the entire protein database is the peptide toxin isolated from green mamba venom.


Given the amount of current interest in macrocycles made out of amino acids, people should pay special attention to how hydrogen bonds are “shielded”… A molecule must also keep its hydrogen bonds dry if it wants to cross the cell membrane. This is another lesson emerging from Ariel’s work.

On how far and how fast things go

I fell prey to the dictum I preach in my classes… I often say something along the lines of: “Chemistry is more or less about how far a system can go and how fast it can do it. In our craft we ought to control both”. Of course, I refer to the thermodynamic / kinetic control. I wonder how many students have heard me say it over the years and got fed up hearing it…


The image above is not an exoplanet or our Earth’s moon viewed from some haystack. It is a photo of an exciting macrocycle which has, as you can see, crystallized. The crystals emerged as a result of a painful process that involved me setting up 1056 experiments.  What you see is an expanded view of our typical 3mm-in-diameter well. The most frustrating thing is that these crystals, albeit needle-like and imperfect, vanished within 24 hours. It is interesting that the crystals formed fast (kinetics were favorable), but eventually disappeared due to their instability. Fortunately, we do have the Le Chatelier principle in our disposal and my next steps will be to repeat the experiment and preclude the reverse from happening. Since this is a vapour diffusion-type method (with water ruling the gas phase), I will need to carefully play tricks with the other reservoir. This is a very precious molecule, though. All 0.02mgs of it. Stay tuned.

A bottle of wine and some memories…

Here is a lovely bottle of wine I had not long ago together with my good friend and colleague Mark Lautens. The bottle is from 1986 and has waited for us in Mark’s impressive wine cellar. I was not even an undergrad at that time! Gorbachev was still in power, I lived in the Soviet Union, and my generation had no clue what awaited us in about 4 years. I knew I wanted to be a chemistry teacher but I was not really sure I would get into the University.


Anyways, we always have fun when we visit Mark’s place. It is too bad Jovana (my lovely wife) was on call that night and could not join us…

Speaking of Mark Lautens – here is a really cool paper from his lab from a while back. The reason this work is special for me is that it deals with amphoteric reactivity. In this particular case, Stéphane Ouellet (one of Mark’s PhD students at the time) showed how vinyl epoxides behave as amphoteric reagents.;2-W/abstract


I love the tautomerization event that creates the nucleophile capable of aldol chemistry!

Methylene taken away: norcysteine

Today I want to talk about norcysteine, an unnatural analog of cysteine that has the methylene group “taken away”. That’s right.


You look at norcysteine and you go “How in the world is this stable?”. But apparently it is stable… Jean Rivier of the Salk Institute in La Jolla has done really nice work that demonstrates some of the unusual properties of this amino acid. Here is a representative paper:

You might imagine that the corresponding SS bonds would be really different (shorter or longer SS bond?) from typical Cys-Cys connections. The thing for me is that the aldehyde oxidation state of the alpha-carbon might not mesh well with a reasonable expectation for configurational stability of this particular amino acid. However, norcysteine-containing peptides are configurationally stable at the alpha methine position. One can imagine a ton of applications for this molecule. I doubt we will see a variant of the native chemical ligation, but who knows?

Old (and new) stomping grounds

I feel that ever since I started my position here in Toronto in 1998, we have consistently encountered more or less the same core challenge (despite covering a wide palette of research areas). I refer to our never-ending pursuit of molecules we a priori attribute some value to. It all started with our interest in fluorinated BINOLs, which were initially really hard to make, but then my students mastered this class of compounds and developed some really nice applications. I also recall how we started with aziridines. It was Shadi Dalili (now teaching at UT Scarborough), who started working with cyclohexene imine. Iain Watson joined the project shortly thereafter and really taught us how to handle these sorts of material. Nowadays we deal with macrocycles, which are really tough both synthetically and from the standpoint of NMR characterization. But we are learning and are making progress. Still, it is always one kind of central molecule (or scaffold) we get transfixed by and put a ton of effort before learning how to deal with it. I tip my hat off to my students who keep passing this torch of hard-target search for things that are tough to make.

On the subject of the old stomping grounds… An old friend, Cathy Crudden (Professor at Queens U.:, came by today with her student Lacey Reid. Cathy met me at MaRS where I currently work (my SGC sabbatical…), we had a nice lunch (next one on me, Cathy!) and chatted about some heavily fluorinated biaryls. This discussion brought to memory my lab’s first inroads into fluorinated BINOLs. We eventually mastered them and I just want to share what was the origin. Here is it:


You see – we first wondered about the relative reactivity of benzyne vs tetrafluorobenzyne. The latter turned out to be way more stable and, consequently, less reactive. But it has been useful for us. We employed it in order to run Diels-Alder reactions with 3-methoxythiophene, which then led us to fluorinated BINOLs. I still see my man Subramanian Pandiaraju (my first PDF), who spearheaded this effort (he is now with Ontario Institute of Cancer Research) and we reminisce of the old days. Fundamental reactivity has always been central to us. At the end of the day, what we really care about is how molecules react with each other.

Boron therapeutics at Anacor

I gave a talk at Anacor Pharmaceuticals today, a company located in the Palo Alto area (which is pretty much in the Silicon Valley), not far away from San Francisco. Dr. Vincent Hernandez was my host. Anacor has been in existence for about a decade and, over the years, managed to convince both academic and drug discovery worlds of the virtues of boron-containing therapeutics. In many of Anacor’s studies, success boils down to clever use of the so-called benzoxaborole, a heterocycle equipped with an electrophilic boron centre. Then magic happens:

Here is a representative molecule developed at Anacor and its genesis, the benzoboroxazole nucleus. The pinkish tetrahedral atom you see in the crystal structure is boron, caught in the act of inhibiting bacterial leucyl-tRNA synthetase. The formation of this adduct with the sugar diol accounts for the observed activity of these molecules against Gram-negative bacteria.Image


We are keen to collaborate with Anacor and apply the novel heterocycles I blogged about towards structure – driven antibacterial discovery. Adam and Victoria (she is about to start officially in a couple of weeks, very excited about this!) have been working on some novel boron heterocycles. I think people will like them.


Flexible poses of macrocycles

Earlier today I set up 1056 crystallizations of the macrocycles my students Joanne and Serge gave me. We are keeping our fingers crossed that we will get something cool in these experiments…

As long as we are on the subject of macrocycles, I have to admit that they are really in the league of their own in terms of the insane conformational space they sample. There is no wonder researchers are having a tough time modelling them in the context of biological receptors. People only say macrocycles are rigid – they are certainly not! Here is a very cool case that shows how difficult it is to navigate through the conformational space of a macrocycle. Elena showed me this paper by Waugh and colleagues:

This work describes a macrocyclic SH2 domain inhibitor shown below:


Here is a quote from the paper: “The sodium salt of S1s was dissolved in water and added to the highly pure Grb2 SH2 domain at 1.5:1 ligand to protein molar ratio. The complex was heated at 50 C for 10 min … before crystallization experiments were set up”. Are you kidding me? If you do not cook this thing up together with its target protein, it just won’t find the right pose. Big-time food for though here…

I am in San Francisco now (in Palo Alto to be exact). Tomorrow I am at Anacor and I will blog about my visit.

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.