I did not know there are so many black bears here in BC… I can’t say that I saw one, but the stories I heard from Rob Britton earlier today were fabulous. Rob was the host during my visit to SFU, which is located in Burnaby, about a 30-minute ride from Vancouver. Rob’s work in the area of chloroaldehydes has been of particular interest to me. The chemoselectivity of this process is notable, given what’s brewing in the reaction mixture (I refer to NCS and proline co-existance). His lab has put this process to some great use in natural product synthesis.

http://pubs.acs.org/doi/full/10.1021/ol401370b

While there were no bears in sight, our dinner with Rob Britton and Bob Young (a former VP of Chemistry at Merck-Frosst, now a Professor at SFU) in Deep Cove, North Vancouver, was a great conclusion to the scientific part of the trip…

I had a great time at UBC yesterday. Amongst other science stories in my talk I described how we make crystals of peptides at SGC. Somehow this really got the graduate students interested. They peppered me with questions, which was fun.

This visit was a chance for me to see some old friends and meet new people. I would like to say my special thanks to Jen Love, who invited me and organized my visit. Throughout the day, there was a certain “fluorine” theme I could not help but notice. Dave Perrin, who is always passionate about science told me about some of his lab’s work that has convinced the world about how specific activity of radiolabelled trifluoroborates is to be understood. I encouraged you to read this scholarly work:

http://onlinelibrary.wiley.com/doi/10.1002/anie.201208551/abstract

Steve Withers described a great story related to his neuraminidase inhibitors. Although I saw his paper in Science not too long ago, I was thrilled to hear the story from the man himself. Each of the fluorines is critical to the behaviour of this intriguing inhibitor (below) and the work is a testament to the fine balance of relative rates that is possible through the careful selection of substituents.

http://www.sciencemag.org/content/340/6128/71.abstract

Glenn Sammis concluded the triumvirate of fluorine-related vignettes for me and showcased how his lab (in collaboration with J. –F. Paquin) managed to get radical fluorination to go:

http://onlinelibrary.wiley.com/doi/10.1002/anie.201206352/suppinfo

I also had a great time with Marco Ciufolini, Jen Love, and Laurel Schafer. I have followed their work for a number of years and will dedicate a special section some time in the near future. My former student Taka is in Marco’s lab. It was great to see him (good luck with the total synthesis, Taka!).

I started my three-day West Coast trip today. The first stop was at the University of Victoria. I have to say that Victoria is probably the most beautiful place I have been to and I have been to many… The town is right on the Pacific Ocean coast and is a short 15 minute flight from Vancouver. The harbor somehow reminded me of Copenhagen, but it is better.

I gave a talk at the Chemistry Department here, spreading my lab’s gospel of amphoteric reactivity. Most importantly, I got to meet some of the folks whose work I have known for a number of years, and also made some new acquaintances. Fraser Hof’s work in interrogating methyllysine binding domains is really exciting, I can’t wait to read about the latest findings his lab made in recent moths. My graduate student Rebecca Courtemanche hails from Fraser’s lab and I gave Rebecca a big shout out in my talk. Robin Hicks told me about his lab’s research on redox-active ligands based on indigo. Indigo! This is the stuff the jeans are coloured with! Really creative stuff. Who would have thought that this old dye holds so many surprises. I also met Jeremy Wulff, one of UVic’s youngest faculty members. His lab does so many interesting things. I think that his cyclic peptide work geared towards interrogating a protein/protein interface mediated by two beta sheets is very thought-provoking. I am looking forward to seeing some time soon in the literature.

A recent paper in Angewandte by Neil Burford really caught me by surprise, I must say. Neil told me about this piece in detail. We all know that palladium does reductive elimination really well, which is the basis of the vast majority of cross-couplings. But what about reductive elimination from a main group element? I was not aware that this is possible. Yet, Burford’s lab showed that reductive elimination happens in a very curious fashion from antimony compounds. I wonder if main group elements will one day be shown to display this kind of behavior in catalytic reactions…

http://onlinelibrary.wiley.com/doi/10.1002/anie.201210012/abstract

I think all students in sciences rightfully ask questions about their future employment. We live in uncertain times and job prospects are of great concern to our students. I still remember 1997 when I was a PDF at Scripps. My friends all thought I was a complete fool to go into academia. They kept saying: “rather than doing something so crazy, you need to think about what’s more or less guaranteed for life, Andrei”… They referred to jobs at Pfizer, Merck, etc. Of course you know what happened then. The ground rule that governs capitalism is the bottom line. Accordingly, it became profitable for big corporations to outsource production and, later, discovery, to places like China and India. People started losing their jobs in North America and it has been tough here for several years. But guess what? The pendulum eventually swings back. The same laws that governed leakage of jobs to Asia must eventually move to equalize the costs here and there. You might still say that the difference in costs remains large and will continue to stay that way for a while. Well then… I give you widespread corruption in places like China. We are all aware of some serious issues that keep popping up these days, all pointing to fraudulent practices in the pharmaceutical R and D in China. Several big companies are now implicated in scandals and we can foresee a situation when it becomes too risky to do business there. It is always that good old risk/benefit analysis. The jobs may then very well come back to North America. Check out the following high profile report published in Science:

http://www.sciencemag.org/content/341/6145/445.summary

Electrosynthesis is one of my long-time passions, although my lab has not done it recently (but we shall…). I nonetheless pay attention to novel materials that people start to use these days. Here is one: boron-doped diamond. This material has been known to inorganic chemists, but recently the group of Nishiyama in Japan showed that anodic oxidation on the surface of boron-doped diamond leads to very effective formation of methoxy radicals. Learning from this fairly simple case, the authors expanded the method to the synthesis of a natural product, licarin.

http://onlinelibrary.wiley.com/doi/10.1002/anie.201200878/abstract

I am curious if this and other unusual electrode materials will find new applications in selective oxidation.

Keep in mind that there is, of course, reduction accompanying any electrochemical oxidation. Protons typically get reduced to hydrogen gas on platinum. People rarely draw this reaction, though (it is assumed). Another thing to remember is that ANODE is where oxidation takes place, whereas CATHODE is for reduction. That’s a simple rule to keep in mind.

Since we are on the subject of oxidation, let’s increase complexity a bit… Here is Siegfrid Waldvogel’s excellent recent contribution to organic electrosynthesis. A good cumulative exam question, I must say! The increase in 3D complexity achieved in this synthesis is staggering:

http://onlinelibrary.wiley.com/doi/10.1002/anie.201006637/abstract

Many of the molecules studied in our lab at the University of Toronto belong to the amphoteric class (hence, the title of this blog). Amphoteric molecules contain counterintuitive combinations of functional groups that are expected to react with each other, yet don’t do it prematurely due to a good kinetic reason (this is case-dependent). Not long ago I caught myself thinking that we do not put things into proper perspective and rarely trace the origins of the idea to its humble beginnings. To do that, we have to go back to the Greek philosophers and, in particular, Heraclitus, the father of dialectics. Here is his paraphrased quote:

I think we can all name a couple of examples from the literature that use this concept metaphorically. One of my favourite books, Bulgakov’s “Master and Margarita”, hinges on the idea that good and evil can’t live without each other (i.e. they need each other because neither can exist without a contrast). In our case things are much more benign – a nucleophile and electrophile that co-exist… But still…

When asked: “What is the pKa of benzylamine?”, one of my postdoc friends from the old days with Barry Sharpless at Scripps would strike back: “In which solvent?”. This is a great way to buy time, I suppose, while being a bit of a smart ass. I have found this answer to be somewhat irritating but, if you think about it, it is also true that context is everything…

Below you see arginine. No one (in a million years) would suspect arginine to be a hydrophobic amino acid. This label would go against intuition that comes naturally to a chemist. Yet, hydrophobicity is also context-dependent. As a matter of fact, arginine is a residue par excellence in terms of stacking with aromatic groups, thereby plugging all sorts of hydrophobic pockets. Here is a view from a crystal structure Elena and I solved recently. You see how arginine’s guanidine group is perfectly positioned inside one of the aromatic cages that makes this particular protein special. We want to interrogate the pocket, yet it is filled. Arginine – please go away, darn it! We need our fragments there, not you…

Those of us who care about cyclic peptides eventually come to grips with the idea that, despite their relative strength, amide bonds can be fragile when placed within constrained environments. This is the reason why cyclic tripeptides are inherently unstable. The proximity of amide bonds accounts for the transannular reactivity shown below (left). While this sort of reactivity is certainly undesired if one wants to have access to a 9-membered ring composed of amide bonds, it also provides enabling opportunities in synthesis. I can name a couple of examples right here. The first one comes courtesy of Phil Baran (http://pubs.acs.org/doi/abs/10.1021/ja2047232), and showcases how a 9-membered ring collapses in the course of palau’amine synthesis. The second one is a nice example from Dirk Trauner’s lab (http://www.nature.com/nchem/journal/v3/n7/abs/nchem.1072.html). In this case, loline synthesis was shown to proceed through nitrogen attack at the intermediate bromonium ion. These examples prove that powerful reactions can be designed with  transannular reactivity in mind. Unfortunately, these cases further underscore the notion that the majority of medium ring amides are not to be associated with stability…