Professor Sigi Waldvogel picked me up from the Frankfurt airport yesterday and we went straight to his lab’s barbeque, which was an awesome way to meet the students and sample some local delicacies, including the delicious federweisser, the likes of which I have never tasted before. This is the so-called “young wine” that can be bought locally and can certainly not be transported very far because it is still brewing. There is no tight cover on the bottle, as you can see – just a bit of foil (otherwise there would be an explosion due to CO2). This stuff, along with beer and sausages, made for a memorable evening.

Earlier today, I had a great time visiting the University of Mainz. I already blogged about one of Sigi’s great Angewandte papers in the past. He continues to trail blaze in the area of electroorganic synthesis and I hope we will find ways to collaborate, particularly given Sigi’s experience with boron-doped diamond as electrode material. I will post something on that in the future.

I also had a pleasure of meeting Professor Till Opatz, who is running a very innovative program in natural products chemistry. Amongst many interesting vignettes he shared with me was a paper that I completely missed several years ago. I am now glad that I have discovered this work as it serves an important lesson in compound characterization. Below is what I am talking about. The nucleophilic attack at the I(+)-activated alkyne was reported some years ago by Larock and colleagues. These authors postulated the regiochemistry shown in the top box. As it turns out, the reaction outcome is different, which was Till’s discovery. I know for sure that there are people in my lab who will be interested in reading this work. The clarification made by Till’s group goes to show that it is prudent to exercise utmost care in structural assignment and to consider all possible outcomes that fit the data. And how many gold-catalyzed reactions might be revisited, ladies and gentlemen? I don’t know. Just saying.

http://pubs.acs.org/doi/abs/10.1021/jo3017378

Everyone thinks that they know what “Catch-22” means. This term is used in various contexts and it is good to remember its origins. “Catch-22” comes from a novel by Joseph Heller that bears the same name:

The story is set in Italy in World War II and describes a military bombardier, Yossarian, who keeps getting more and more dangerous bombing raids assigned to him. Catch-22 is a sinister air force rule that stipulates that one is suspected to be insane if he willingly continues to take part in perilous combat missions, however, if he makes a request to be removed from his bombing duties, he is proven to be sane, which means that he is ineligible to be relieved and must be able to cope with more assignments. This book is a masterpiece and I encourage you to read it, if you have not done so already. And no, I do not think there is any analogy whatsoever to how we treat graduate students with our never-ending lists of projects and requests…

I am on my way to Europe for a week, which means that I will have less of a chance to update my blog. I will be on vacation with my wife, attending a wedding in Serbia, which will be followed by a couple of lectures in Germany – at Sanofi-Aventis and at the University of Mainz. There are many things one needs to do before going on vacation. There is always a ton of emails to write and several loose ends to tie up (crap, I just remembered about another one…). Lab safety is the item of substance that never leaves one’s mind before leaving town. Of particular concern is anything that is remotely dangerous and, in this regard, I have to admit that there are chemicals I admire much less than others. One of them is sodium azide and I just want to remind everyone not to use dichloromethane when dealing with this reagent. You would be surprised how many times I have encountered students in my lab who accidentally forgot this and turned to dichloromethane in conjunction with sodium azide. We all know how bad this combo is, yet somehow we forget. Why? Because we are the creatures of habit and dichloromethane is one of our trusted old friends in reaction work-up. Below is what might happen, though. I am also providing you a link to a paper that describes the explosion caused by diazidomethane. I am providing this link so that you do not think that my warning is purely anecdotal…

http://pubs.acs.org/doi/abs/10.1021/op8000977

This will be a short post. Some time ago, with a blessing from Professor de Meijere of the University of Göttingen, I agreed to serve as the guest editor for a special issue of Chemical Reviews dedicated to the impact of small ring heterocycles in synthesis. My sincere thanks go out to the following contributors, without whom none of this would be possible:

Prof. Hiroaki Ohno (Osaka, Japan)

Prof. Eric Rivard (Alberta, Canada)

Prof. Renzo Luisi (Bari, Italy)

Prof. Tom Lectka (Baltimore, USA)

Prof. Sven Mangelinckx (Belgium)

Prof. Tehshik Yoon (Madison, USA)

Prof. Pauline Chiu (Hong Kong, China)

Prof. Bob Coates (Cornell, USA)

Prof. Aby Doyle (Princeton, USA)

Prof. Yian Shi (Colorado, USA)

Prof. Erick Carreira (Zurich, Switzerland)

And, of course, I want to thank my students Ben Rotstein, Serge Zaretsky, and Vishal Rai, who contributed to writing our own contribution to this issue.

http://pubs.acs.org/toc/chreay/114/16

I am also really grateful to Prof. Guy Bertrand who made it all go very smoothly. I hope that you will have fun reading all of the papers in this collection. I know I will!

A week or so ago, Dr. David Price of Pfizer visited our department and gave a great talk on Maraviroc, an HIV antiretroviral drug. While the story David shared with us was unique in many ways, it did have a number of elements in common with other tour-de-force kinds of studies in medicinal chemistry. Invariably, these cases show that good chemistry is only a part of a journey to a successful drug. Chemistry is, nonetheless, a critical component of any drug discovery undertaking. We had some good fun with David, and we do look forward to seeing him again in the near future. While a lot of interesting stories can be mentioned about Maraviroc, I was particularly intrigued by David’s reference to one of the main killers of promising compounds in drug design. I refer to the infamous HERG potassium ion channel. The architecture of this channel offers a cemetery (of sorts) for aromatic compounds. The HERG liability is serious as molecules that plug this channel lead to cardiovascular side effects. David shared with me one of the papers from Pfizer that speaks to this problem:

http://www.sciencedirect.com/science/article/pii/S0960894X06006615

I started digging into this area and, after doing a bit of further research, found another great article that is foundational when it comes to HERG and liabilities associated with it. This 2002 paper by Recanatini describes the HERG pharmacophore, which is similar in its topology to a Bermuda-like triangle, wherein many promising small molecules lie. The term “pharmacophore” is often synonymous with “we do not have a crystal structure, so here is the best model we could get that is based on analysis of a series of molecules”. While it may take some time to finally see a crystal structure for this channel, it seems that if you have the right constellation of three aromatic rings in your molecule coupled with a basic nitrogen, you might be in trouble. I wonder if macrocycles have a free pass here by virtue of their geometry… I doubt it, but who knows? By the way, the Pfizer team did a great job of steering away from this dreadful triangle in their Maraviroc campaign.

http://pubs.acs.org/doi/abs/10.1021/jm0208875

I will dedicate tonight’s post to the silent heroes of organic synthesis, namely some of the excipients we have grown to love. While the term “excipient” is most commonly associated with drug formulation, there is something to be said about an analogy to some key additives that serve their supporting, yet critical, roles in organic synthesis. Without these molecules, you would not see the light of day in many instances where a particularly reactive species needs to be formulated and delivered to a flask near you. In my personal experience (we are going back 15 years for that), urea-hydrogen peroxide was the first combination that taught me to appreciate the supporting role of certain chemicals. In this case – urea, when mixed with hydrogen peroxide, turns into a nice solid material that is commercially available in the form of pellets. I used to buy this stuff from Acros and employed it in reactions where excess water, that comes through the use of aquous hydrogen peroxide solutions, was detrimental to catalysis. Now – how about the iodonium-collidine perchlorate? This is a widely used electrophilic iodinating reagent that benefits from the presence of collidine…

DABSO is a notable recent addition to the list of molecules that deliver valuable and highly reactive species in synthesis. In this compound, developed by Mike Willis of Oxford, the molecule of DABCO is complexed with two molecules of sulfur dioxide. This association enables handling a nasty gas (SO2) in a very straightforward fashion. I am showing just two examples from Mike’s OrgLett paper. The diene case is especially notable as it represents a great way to employ the reversibility of Diels-Alder reaction to protect (and later release) dienes. I have to say: there is something quite special about DABCO in terms of its “supporting” role in many other reagents (Selectfluor comes to mind).

http://pubs.acs.org/doi/abs/10.1021/ol201957n

I want to ruminate on a subject that has been of great interest to me for a number of years. To begin with, I will remind my readers about the difference between causation and association. I talked about this in the past. While this subject might not help you have an engaging conversation at your neighbor’s barbeque, it is absolutely central that we get this distinction right when analyzing data of any type – in chemistry, astronomy, medicine, etc.

Now let’s say we all got this distinction under our belts. In other words, we are really interested in causation more than anything else. Here comes the conundrum. The science of logic warns us of the following scenario:

In it, B is only an intermediate cause of the final outcome C, whereas A is the ultimate, all-important cause. A causes B and B causes C. I would bet that close to 99% of our failings in science must come from wild goose chases, in which we try to fix a given system by concentrating on the wrong variable. Here is a simple life example I read in a great book “Being Logical “ by D. Q. McInerny (http://www.amazon.ca/Being-Logical-Guide-Good-Thinking/dp/0812971159). Let’s say you notice that your kitchen stinks and the smell emanates from water accumulating underneath your sink. You are desperately trying to fix it by frequently emptying buckets of water, the problem seems to temporarily go away, but it always comes back… The reason? The flaw in your logic: the ultimate cause is the leaky pipe and you have not thought about it. Once you replace it, life goes back to normal.

Here is a chemistry example: you run a solution phase reaction on some peptide. Let’s say that your goal is to modify its N-terminus. Nothing works… You change a ton of coupling reagents and you get nowhere. This is frustrating, because you think that the issue lies in the low nucleophilicity of the N-terminus. But then, after some time, you find out that the real trouble is that that particular sequence is prone to aggregation, which of course affects reactivity. There is nothing that you can fix with a different coupling reagent, but a simple change of solvent miraculously solves the problem.

This is a simple example and, as you might imagine, there are substantially more complex cases out there. However, I think that the mistake in focusing on an intermediate cause is a clear and present danger in our research endeavors.

A lot has been said about azide/alkyne cycloaddition reaction in recent years. This process (click chemistry) has been applied in a wide range of research fields and the spectrum of use keeps expanding. One particularly widely quoted tenet of this chemistry states that azides and alkynes are orthogonal to polar functionalities, but react with high selectivity with each other under copper catalysis. This is especially useful in the so-called bioorthogonal applications. While this principle is mostly true, it is certainly not universal, which is why it is instructive to see cases that disprove the basic assumption of alkynes’ “innocence”. Today I want to mention just one example. I have always been intrigued by the mechanism of covalent inhibition of Erb kinases that was elucidated by David Uehling and coworkers form GSK some years ago. This paper was published in PNAS and you can check it out below. Granted, the core of this particular line of inhibitors might be described as a fairly special alkyne unit that is perhaps more prone to nucleophilic addition than some others. Nonetheless, one should keep in mind that alkynes are not always orthogonal to nucleophilic species in biological systems.

http://www.pnas.org/content/105/8/2773.abstract

In our fragment-based drug discovery projects, we constantly think about new ways of stitching together heterocycles. It is particularly satisfying if we find a way to make completely new, previously unexplored, chemistry matter. As you might imagine, herein lies a dilemma. On the one hand, we want high ligand efficiency, which goes implies relatively small size. On the other hand, try to plug something completely new (for instance, a 6-membered ring) that is composed of common heteroatoms into SciFinder. Good luck with that. Chances are, your composition of matter has been disclosed in a patent or, worse yet, published in peer-reviewed literature. Challenges notwithstanding, we recently bravely embarked on a journey that has sought the discovery and development of new kinds of small and medium rings. One of our favorite examples is the so-called boromorpholinone, which is obtained by plugging a boron atom into the framework of a well-familiar morpholinone scaffold. You see a model of a representative member of this class of compounds in the graphic below (boron is green). Earlier this year, Aleksandra Holownia (pictured below) joined our efforts as a Summer undergraduate student. Under the direction of my graduate student Adam Zajdlik, Aleksandra not only helped us understand the boromorpholinone area better, but earlier today won one of the AstraZeneca poster awards. I applaud her dedication to this project. As you might imagine, the boron atom in these sorts of rings is not going to be an innocent bystander. There are, in fact, many applications that await these compounds, which is something we are engaged in together with Ben Cravatt at Scripps. Speaking of Adam, he just came back from a one month internship at Anacor in California, where he further learned about the use of boron. Anacor is the pioneer in the deployment of boron-containing molecules in drug design. There are myriad reasons to like boron and I will give you just one: boric acid, the main metabolite of organoboron therapeutics, has LD₅₀ of 2.7 g/kg. This toxicity is comparable to that of table salt. Once again, congratulations, Aleksandra!