Here’s a synthetic post, dedicated to the talented folks in total synthesis who have a lot of really cool tricks up their sleeves. I am going to talk about just one (or two) steps in Tohru Fukuyama’s fairly recent lyconadine synthesis. The sequence goes through one of my favorite processes – a microscopic reverse of an electrocyclization… I mentioned a similar reaction in the past when I referred to our own work in electrocyclic ring-opening of bromoaziridines. Take a look at a clever use of electrocyclization (its microscopic reverse, that is) in efforts to create a complex 7-memebred ring. First of all, please note the dibromocyclopropane preparation. Wait – before we go any further: do you know whose process this is? If you are thinking of Prof. Makosza from Poland, you are correct as he is the man! I already commented on his vicarious aromatic substitution mechanism. The phase transfer-catalyzed dibromocyclopropanation hails from his lab as well. The yield here is not great, presumably since we are dealing with a fairly challenging substrate… Then comes the key step, which is carried out in pyridine at reflux. A ton of fun, no doubt, but the result is impressive – the ring system is set up and the benzyl group is gone… There is an elimination pathway that competes, but these are minor details. It is still an elegant sequence. I think one nice lesson here is to always remember the principle of microscopic reversibility, which is not simple when thinking about retrosynthesis, in my view!

http://pubs.acs.org/doi/abs/10.1021/ja312065m

We have finished our grant proposal and managed to submit it on time. As I mentioned yesterday, this grant deals with the chemistry of boron-containing heterocycles and their biological properties as serine protease inhibitors. A preliminary account of our borocycle chemistry driven by boryl isocyanides, appeared earlier this summer (see my July 21 post). Besides what I think is an interesting structure-driven means to optimizing the cellular permeability and activity of these molecules, we have an approach to place boron in heterocycles using simple condensation reactions. As I was thinking about condensation chemistry, I recalled to mind some of my favorite papers from the past. A lot has been said about enamines in recent years, and for a good reason. Originally developed by Stork, enamines are the engine of many innovative synthetic approaches, including organocatalysis. Yet, if you think about the parent “NH2” enamine, it has remained a curiosity due to its highly unstable nature. Back in 2001, Novak and colleagues published a thought-provoking paper that trapped these species in a radical-mediated polymerization. This publication has always been one of my all-time favorite papers. The way to generate the parent enamine shown below is not through condensation (can’t really use thermodynamically controlled reactions). Instead, the authors used transition metal-catalyzed isomerization. Afterwards, they cleverly co-polymerized the enamine under radical  conditions before it had a chance to undergo tautomerization. To me, this is super cool.

http://pubs.acs.org/doi/pdf/10.1021/ja011609i

P.S. I am sure my lab might notice the wording “simple enamines” in the paper title…

Right now I am in the middle of grant writing with my student Adam Zajdlik… The deadline is tomorrow and we are trying to get the last remaining items in order. This is a joint grant with Dr. Aaron Schimmer of the Princess Margaret Hospital here in Toronto. Our idea is to use boron-containing heterocycles as proteasome inhibitors. Adam has become quite a pro at making them. Plus we now have Victoria Corless in our team, which will provide further momentum to the effort. Due to this deadline I am not going to post my usual scientific blurb, but I am going to give you what I promised on Friday… Please bookmark the website that has a bit more information about the American Peptide Conference in 2015:

http://aps2015.org

Had anyone told me 5 years ago that my lab would be heavily engaged in peptide chemistry, I would not believe a word… Fast forward to 2013 and here I am, together with my man Ved Srivastava of GlaxoSmithKline, organizing the next American Peptide Symposium. What a turnaround.

Here is an early-bird invitation to everyone who is interested in peptide science. Come to Orlando in June, 2015! We will have a splendid conference prepared for you. Our logo is below and a link to the website is forthcoming. So, bring your significant others and have some fun in Orlando with us. Besides the scientific program, Ved and I will work hard to ensure that entertainment is taken care of. I will bet that there will be some nice Cuban food, cigars, and so on. This past APS meeting was held on the Big Island of Hawaii and it was awesome (kudos to Marcey Waters and David Lawrence). The only downside was that it was a bit too far and many people could not make it (especially industry folks who just could not convince their upper management that there is science in Hawaii). Orlando, on the other hand, is strategically placed to embrace both the European and American contingents.

I will also start spilling the beans about some special features we have in store for your amusement… As part of the conference, we are preparing a cool new 2-hour section called “rapid-fire”. At the beginning of the conference, the attendees will be given a chance to email the organizing committee two slides with their latest results. Of course, you need to consider the pros and cons of this disclosure. We will then select speakers and give them 5 minutes each in the rapid-fire section. 2 slides, that’s it! This is going to be a new mechanism to give floor to young researchers such as students and postdocs who may have a cool result, but perhaps not enough material for a full-scale oral presentation. This lack of a full story is often the reason for one’s reluctance to submit an abstract for a talk. The rapid-fire section will not have a pre-announced program. We plan to call the chosen speakers from the audience during the allotted time. These are our plans and we’ll see how they materialize. We certainly hope they do!

We fight entropy every day but it costs us in enthalpic terms… Whenever I notice papers where order emerges from chaos, I pay attention. Here is a really fabulous example from the lab of Michael Rubin (Kansas University). This is coming from another one of the talks I heard while attending the Heterocycles conference in the south of Russia last week. Take a look at what’s happening – it is a neat trick: you start with a racemate, you don’t make your life any easier at the next step when you create an awful mixture of diastereomers while installing the amide bond. However, the subsequent step clears it all up as the base does two things: it eliminates HBr and creates the ring system. The coolest thing is that all the unwanted diastereomers converge onto a simple symmetrical sub-structure that is ready to undergo addition. The addition step is not as trivial as one might think because you do not have a typical conjugated olefin. Strain drives it, though (all 52 kcal/mol of it). Michael presented some compelling evidence showing favourable orbital overlap during the addition step (what is it, by the way, endo addition? exo? trig? dig? what? not so straightforward…). Diastereoselectivity is high and is governed by the conformational preferences dictated by the chiral amide. I think all students will appreciate examples of this sort: you have an awful-looking TLC that goes clean towards the end!

http://pubs.acs.org/doi/abs/10.1021/ja900634m

I think one of the most important things scientists need to do is know how to rest well. Going to the gym is hugely important, yet not always possible. I think that the best thing I have ever done in my career was to adopt something Prof. Ian Manners (now at Bristol) taught me several years ago, namely not to go to office on Wednesdays. Just work from home, he said. This simple change has made a world of difference because it has turned into a mechanism to work on manuscripts, grants, and to read at home. I feel the need for this extra time now that I am on sabbatical and actually do go to work on Wednesdays! What an irony. I really miss my Wednesdays off and there is definitely a feeling of being overwhelmed with all the stuff such as administrative responsibilities, writing reference letters, and so on.

So, if you read this, trust me because this is well tested: if you become a Prof. (which, sadly, will mean that you will spend way less time on thinking about research compared to your time as a postdoc or as a graduate student): skip work once a week. When I was in Russia last week, I talked to Valery Fokin, my old friend (now a Professor at Scripps), who told me that he has now also adopted this method. Valery does it even better, I have to say: he does not open email at all on Wednesdays. When I am back from my sabbatical in January, I will give this a shot, there is no question about that.

It took me a while to find this method (thank you, Ian Manners!) and it works… You know what Churchill said: “We always come to the right decision, having tried everything else first”.

Here is a shout out to my PhD student Sean Liew, whose paper recently came out in J. Org. Chem. Sean has been with us for about 2 years and, among other things, developed a great way to make vicinal diamines. One of the key control elements in this chemistry is attributed to the dimeric nature of aziridine aldehydes we have been working on. Below you see the transformation I refer to as well as Sean himself. Plus, I am showing a model Sean developed that accurately predicts the observed selectivity. The central feature of this chemistry is the hemiaminal that keeps the two monomers glued to each other for the duration of the transformation. The way the process operates is like this: the dimer partially dissociates, which allows it to interact with the incoming nucleophile. The said nucleophile is delivered to the nearby electrophile. In the present embodiment, we have boronate playing the role of the nucleophile and iminium ion acting as the electrophile. Towards the end of the reaction, the aziridine hemiaminal dissociates, releasing the product plus the monomer, which redimerizes. This is how we think about this chemistry. We are now trying to apply Sean’s reaction in a variety of contexts and the prospects are encouraging. Sean and I were asked by the J. Org. Chem. to come up with artwork so that the paper gets featured on the cover of the journal, which is cool. I am happy for Sean, although the deadline for the cover art is upon us. Why don’t I send Sean an annoying reminder email right about now?…

http://pubs.acs.org/doi/abs/10.1021/jo401489q