Reaction selectivity comes in many different forms (regio-, chemo, stereo-, you name it). Factors that affect various types of selectivity are, should we say, complicated… Temperature is the oldest and most reliable way of achieving selectivity because of a direct relationship between it and the kinetic barrier of a given reaction. Here is a paper in JACS that came out quite a few years ago. In it, Chang and colleagues prepare a library of substituted triazines using nucleophilic aromatic substitution. The point of the paper is not the chemistry used by the authors. Indeed, the cornerstone of the process has been worked out in other labs before this paper. In Chang’s example, it is all about how they ran their synthesis. The authors achieved high levels of selectivity by sequentially ramping up temperature. In my view, this is quite remarkable. For the life of me, I cannot think of another example that approaches this one in terms of simplicity and clarity of execution of three distinct operations! Check it out: 0 ^oC, 60 ^oC, 120 ^oC… If you read the experimental section, you will note that base is added only in the last two iterations (the 0 ^oC step does not involve added DIPEA). You have to admit that a system that allows this type of control is special. The flip side (there is always one, isn’t there?) is that this kind of aromatic substitution has been beaten to death in library development, making the resulting class of compounds over-represented in many collections. However, this should not take anything away from the value of the present process. It would be good to have more examples of this kind of reactions as they would allow one to take a common scaffold and sequentially decorate it like a Christmas tree with all sorts of appendages using… temperature as the enabling parameter.

http://pubs.acs.org/doi/abs/10.1021/ja026720i

Last night my second year PhD student Adam Zajdlik came back from Sherbrooke, where he attended the QOMSBOC meeting (Québec-Ontario Minisymposium in Synthetic and Biological Chemistry). This is an annual event that gathers together students, postdocs and faculty in either Québec or Ontario (alternating years). This year it was Québec’s turn and from what I hear Guillaume Bélanger did a great job organizing the conference. The format is such that it is mainly students who give talks and posters. Two invited academic faculty members and one industrial lecturer are also included in the program. I organized one of these conferences in Toronto back in 2008. It was a blast working with the students on the logistics of the conference.

Adam gave a talk and received one of the prizes for his oral presentation, which made us all very happy. I also commend him for waking up early on Sunday to deliver his talk (at 8:30am). I recall the amount of alcohol consumed by the participants at our own event back in 2008. I was happy to see people walk the next morning, let alone think about science! Adam and I salute all of those students who had the strength to get up and show up in the early Sunday hours. In terms of chemistry, Adam is continuing his inroads in the area of boron-containing bioactive molecules. We remain committed to exploring the potential of boron. Boromorpholinone is one of Adam’s favorite scaffolds. On particular boromorpholinone he developed is a nanomolar inhibitor of proteasome 20S (this finding comes from our joint with Professor Aaron Schimmer). We are still debating on the mode of action of our compound and are currently leaning towards in cellulo linearization. A view is shown above. This covalent docking result was obtained using Glide and we will be trying to get a co-crystal now. You can see that, due to its oxophilicity, boron binds to the hydroxyl group of Thr1 (boron is green). This finding has enabled us to start a collaboration with Professor Ben Cravatt of Scripps (http://www.scripps.edu/cravatt/). I hope to disclose the details of this work one day soon, when the paper is ready. Suffice is to say that there are some really interesting leads Ben and his student Micah have been getting.

Again, congrats to Adam!

This is an odd question, isn’t it? The answer largely depends on who’s answering. A natural products chemist will have a vastly different opinion from someone who is more interested in small molecule probes. Some people might even be taken aback by the “should” in this question. Many of us are guided by sheer curiosity, rather than by the inherent value embedded in the function of molecules we make. Still, though, it is fun to make molecules that are both novel and useful. Some really nice strides have been made in employing well-known heterocycles to solve well-recognized problems of modern biology. As an example, please consider the isoxazole core shown below.

http://pubs.acs.org/doi/abs/10.1021/jm301588r

Drs. Stuart Conway and Paul Brennan of Oxford University have developed several potent inhibitors of the so-called bromodomains, whose main function consists of recognizing (or “reading”) the acetylated lysine side chains off histone proteins. The isoxazole scaffold is a clever mimic of the N-acetyl group found in N-acetyllysine. By interacting with the acetyllysine binding site, isoxazole-containing small molecules outcompete natural peptide-based partners of bromodomains, resulting in interesting downstream events. This is because “readers” such as bromodomains are involved in many epigenetic signalling pathways.

In the picture above, I am showing a view of the co-crystal structure between BRD4 and its isoxazole-based inhibitor. The structure was solved at SGC-Oxford. The view shows how the isoxazole core interacts with the water framework (red spheres) in the protein structure. I am going to visit Paul in Oxford in about 2 weeks in order to discuss a collaboration that will seek to employ our own molecules in this vein. It will be fun to evaluate something completely new, namely heterocyclic cores that have not been considered before. Back in Russia they say “anything new is a well-forgotten past”. Indeed, some might say that it is not easy to imagine a stable aromatic molecule that has eluded isolation and synthesis. But I disagree… There is ample room for ideas aimed at aromatic scaffolds that have never been contemplated before. Apart from our own efforts, examples that demonstrate a viable approach to this sort of science can be found in a fairly recent report by Pitt and co-workers (see the link below). The title of the paper is outstanding: “Heteroaromatic rings of the future”. There are clearly many new ways of putting together stable aromatic scaffolds that have remained unconquered to this date! I am sure that some of them might be brought to bear on difficult problems of biological probe design.

http://pubs.acs.org/doi/abs/10.1021/jm801513z

Let’s admit it, all scientists have secrets. There is a simple and elegant experiment (or two) we wish we had thought of, or had performed ourselves. For me, the Urey-Miller experiment fits the bill. A two-page Science report published in 1953 shook the world and became an instant classic in the history of science.

In order to test plausible conditions on the early Earth, Miller came up with an ingenious idea: to circulate a mixture of four simple compounds (nitrogen, water, hydrogen, and methane) that were likely present back then, through a chamber where electric discharge was constantly applied through the gaseous mixture. This discharge was designed to simulate the rough primordial times. After several days, mercury chloride was added to the reaction mixture in order to ensure that bacteria did not have a chance to grow, thereby polluting the results. The analysis of the reaction mixture indicated the presence of amino acids such as alpha-alanine, beta-alanine, and glycine. This was a milestone in our understanding of how protein building blocks are formed. You might argue that this experiment does not prove how chirality emerged, which is true. In a way, the Urey-Miller experiment is a “low hanging fruit” that catalyzed our search for the origins of life. There is even a Gordon Conference dedicated to this subject. As you can imagine, there are some interesting, if not eccentric, folks who attend that gathering. Regardless, I wish I had thought of this experiment…

http://www.sciencemag.org/content/117/3046/528.short

Humans have celebrated food since the dawn of civilization. We are what we eat. For centuries, painters have been drawing inspiration from all manner of cooked and uncooked specimens. Here is Jan Davidszoon de Heem’s “Still Life with Fruit and Ham” from 1648.

Today I have my PhD student Ben Chung as a guest on this blog. Ben gave an inspiring talk about chemistry of cooking last week. Here is what he wrote on the subject of heterocycles your mother wants you to eat…

Ben:

“Heterocycles are cyclic compounds with one or more elements other than carbon within their ring structure. One of the earliest examples of heterocycle synthesis in the lab was the isolation of alloxan through uric acid oxidation by Brugnatelli back in 1818. However, humans have been making heterocyclic compounds long before then… by cooking food! Through my adventures in learning about food chemistry and molecular gastronomy, I’ve stumbled upon many interesting molecules that are formed through cooking. These molecules are mainly produced by the Maillard reaction, which describes the reactions that occur between sugars and amino acids upon heating.

Using a generic aldose (1) as an example, the amino group of an amino acid (2) reacts with the aldehyde to generate N-glycosides, which then undergo an Amadori rearrangement to generate an amino-functionalized ketose, known as the Amadori compound (3). The net transformation is N-functionalization of the aldose as well as transfer of the carbonyl oxidation state from the terminal end to the middle of the molecule.

The Amadori compound then undergoes additional transformations, generating a class of compounds known as deoxyosones (e.g., deoxypentosones 4 and 5). The regioselectivity of the enolization determines the type of deoxyosone that’s formed, and deoxyosones are named by the chain length and the carbon number at which deoxygenation has occurred.

It is these deoxyosone intermediates that can be further dehydrated, cyclized, and functionalized by ammonia, hydrogen disulfide or methanethiol (derived from amino acid degradation pathways) to generate a large variety of heterocyclic flavour molecules. An example of 3-deoxypentosone degradation is shown above; analogous pathways can occur for 1-deoxypentosones as well. The structures of a few heterocyclic molecules derived from the Maillard reaction are shown below, as well as the aromas they have.

Of course, the variety of different sugars and amino acids present in any given sample of food means that, following Maillard reaction, it is possible to achieve an almost infinite combination of aromas and flavours. Who would’ve guessed that chefs possessed such mastery over heterocyclic synthesis?”

Here is a good read:

http://pubs.acs.org/doi/abs/10.1021/ar8002078

Let’s face it, using excess of one of two reactants is the essential evil of organic chemistry. While there are understandable thermodynamic arguments to do so (for example, the Le Chatelier principle and the need to drive reversible processes in the desired direction), the use of excess amount of a given chemical in a simple bimolecular reaction is really sub-optimal, especially if it is an irreversible process. When I read papers, I like to pay attention to reaction stoichiometry and I am instinctively drawn to reports that document stoichiometry of 1:1 or close to it. This tells me a lot about the underlying process efficiency (it is green! I hope my student Adam is happy I said that…).

Here is a fairly recent report by Adimurthy et al. This paper is notable for several reasons. It exemplifies proline organocatalysis, but of an unusual type in that the electrophilic component is NOT an aldehyde (which is the usual suspect). Instead, an amide plays the role of an electrophile here, which is cool as we are talking about one of the strongest linkages in chemistry. The reaction is essentially a metathesis because another amide is created. Many examples (if not all) recorded in this work proceed with 1:1 stoichiometry. To me, this speaks to the robust inner workings of this type of activation. I know ammonia is produced, and it is gaseous, and so on, bla bla. I still like this chemistry. This stuff is environmentally benign, which ought to make us all happy. As the Canadian philosopher Marshall MacLuhan (1911-1980) said, “There are no passengers on spaceship earth. We are all crew”. I am being a bit of a sarcastic dweeb now, I know… It’s been a long day.

http://pubs.acs.org/doi/abs/10.1021/ol4002625

My PhD student Jeff St. Denis gave a great Monday Night Seminar tonight. He talked about his efforts to develop practical boron transfer reagents. “Enabling” is one of the keywords we emphasize in our research as we try to look at synthetic methods through the prism of enablement. In brief, it’s all about going after reactions or reagents that make people want to use them because there are no good alternatives. Together with Ved Srivastava, we even resorted to the “enabling” angle as a motto for the 2015 American Peptide Symposium we are putting together (www.aps2015.org).

Now… This might sound like a blasphemy given my stated position on the matter, but it is important to keep in mind that enabling and practical organic transformations, while significant, are not the only game in town when it comes to modern synthetic chemistry. To a large extent, the tough funding situation is behind the push for practical reactions and research motivated by somewhat political motives. However, time and again I am reminded about some really accomplished people who have reached great heights with roots in very basic, fundamental chemistry. And these people are not necessarily in academia.

Take my friend Robert Gnann. Robert hails from Germany, where he did his doctoral training. I met Robert in Los Angeles some 20 years ago and we had a great time there while he was a postdoc with Carl Christie. Throughout the years I have marveled at some of the things Robert had done during his PhD. Take a look at some of the chemistry developed by him and his PhD advisor, Professor Naumann. In this sequence, you take xenon difluoride and exchange its fluoride ligands for a trifluoroacetate and a triflate. When the resulting molecule is exposed to an aromatic compound, electrophilic substitution ensues. What is this? A “xenonoation” of sorts, I suppose… I am showing the Xe-triflate bond in covalent terms, but it is, of course, ionic. I love inert gas transformations and, while this chemistry has no immediate applications, it is intellectually stimulating and exceptionally challenging due to the sheer instability of everything involved in it. In my view, “enabling” is not to be equated with immediate and obvious field of use. It is sad that the dogmas of green chemistry (seriously – recall those 10 commandments, it is almost Marxist the way people show them in talks) have been influencing our thinking a bit too much and “blue sky” research is no longer en vogue.

http://onlinelibrary.wiley.com/doi/10.1002/zaac.19976231127/abstract

By the way, Robert is a big cheese now, he is Momentive’s senior vice president and managing director of silicones in Europe, the Middle East, Africa and India. He has not been doing research for a long time, but the foundation of his training lies in exploring some fascinating inert gas chemistry in the Naumann lab. The inorganic synthesis training he received came with a good dose of attention to “minesweeping techniques” aimed at matter that is shock-sensitive even at -50 C. I bet this training teaches attention to detail because, if there is one wrong step, the game’s over… I am willing to bet that this background has helped Robert navigate the rough waters of global business.

Here’s a sneak preview of what my student Sean Liew has been working on as the cover for J. Org. Chem. December issue (something similar to this will soon appear in print) . Several weeks ago I blogged about Sean’s research and mentioned that he was working on the cover art that was requested by the editorial office. I really think that Sean did a cool job here. Prof. Dale Poulter (the Editor-in-Chief of J. Org. Chem.) concurs. When it’s all done and edited, I think it will be a fun cover that captures the key control elements of reactivity in Sean’s system. Sean’s quite an artist!

Every morning I deal with my editorial duties for Organic and Biomolecular Chemistry, an RSC publication (http://pubs.rsc.org/en/journals/journalissues/ob#!recentarticles&all). There is one particular type of manuscript I reject without even thinking twice about it and certainly without needlessly bugging the already overwhelmed refereeing system. I want to talk about it today because this problem correlates with a continuing issue I have and will always have while training my own students. Here is a dramatic oversimplification of what I saw today (I removed the structural details, the only real thing is the yield):

There was no other information supplied, just a table with similarly low yields. There was also no attempt to discuss the factors affecting the reaction efficiency. So what does this number (28%) mean? What are we to learn from it? I do not have any OBJECTIVE parameters in front of me and I cannot, therefore, trust this chemistry. The removal of subjective factors from research is critical. Here is the main rule I have been fighting hard for in my own lab: have a good handle on the assay yield, selectivity, and conversion. Let me explain this in more detail. In short, selectivity and conversion are the metrics that enable a simple calculation of the assay yield:

I will give an example. If 90% of the starting material is converted in a given reaction, but only 80% of it actually goes on to form the desired product, we have:

Conversion: 90%

Selectivity: 80%

Assay yield: 90% x 80% = 72%

It is called “assay” because conversion and selectivity come from an internal standard-calibrated measurement, or assay (using GC, HPLC, you name it). While every process chemist in industry knows about the significance of an assay yield, academics tend to turn a blind eye on this critical parameter. It is important to know conversion and selectivity, both of which can be obtained by monitoring product formation/starting material disappearance vs an internal standard. Without knowing these metrics, we do not know what a given number means. Say we see a reported 28% isolated yield. What does this number mean? No one knows. But, if you can: a. get a number for conversion (just look at the analytics using an appropriate internal standard) and b. get a number for selectivity (just calculate the amount of the starting material that went into the desired product by measuring its molar amount, using an internal standard), you will get an assay yield which is calculated as conversion x selectivity. If the assay yield is 70% and you get an isolated yield of 28%, you know what to do – improve your isolation skills. If you are reporting an isolated yield is 80%, you know that you are lying. On the other hand, if the assay yield is 25%, then you are doing as good a job as you can while dealing with a tough problem to crack. However, your reaction sucks because the selectivity is likely low (or conversion, or both – regardless, go back to lab). By measuring the assay yield, we confront the clear and present danger of purification inadequacies in our efforts. We might also have a “to do list” in terms of understanding the mechanism and improving the reaction. As John Hartwig puts it, “yield is a relative rates phenomenon”. So – let’s remove subjective factors out of chemistry. Otherwise there will always be people, who will report great isolated yields and say “…well, it worked in my hands” while no one else can repeat their work. There aren’t many luminaries with unique and magical hands in chemistry who have a patented “green thumb” technique that others lack. So – show me the numbers.

Specific covalent inhibitors have long been of great interest to many people, despite the fact that irreversible inhibition has not really been on the very top of pharma companies’ wish lists until recently. I do find this somewhat ironic given the fact that a great many useful medications owe their efficiency to the covalent mode of action. We do not have to go very far for examples – take aspirin for starters…

Today I want to talk about epoxomycin, a molecule that has been associated with the name of Professor Crews (Yale). The company that emerged from this technology, Onyx, was recently bought by Amgen for 10+ billion dollars. Kyprolis is the name of their drug, which is a close cousin of epoxomycin. The difference between the two is just a couple of modifications to improve solubility and other drug-like properties. 10 billion is a lot of value for a fairly simple epoxy peptide, which means that there’s more that meets the eye. Indeed, epoxomycin (an irreversible inhibitor of proteasome 20S) displays a marvelous mechanism of action. The molecular gymnastics that take place during its interaction with the terminal threonine of proteasome 20S are shown below. Obviously, this is not your typical epoxide that reacts by a classic Sn2 mechanism with some active site nucleophile. If you look closely, the interaction has two distinct steps: hydroxyl of Thr1 attacking the carbonyl group followed by amine reacting with the epoxide ring. Thus, the specificity is defined by a multi-center engagement, something that I think is worth emulating in other contexts. Below is a link to the Crews’ seminal paper.

http://pubs.acs.org/doi/abs/10.1021/ja993588m