Uncommon coupling partners

Every now and then we have a seminar that I miss because I consider it to lie outside my area of expertise. While this might help save time, I later regret not attending those “out of my comfort zone” kinds of talks because I know for a fact that one tends to learn the most out of people who work in unrelated areas. The reason is simple: those folks do not have any of my default assumptions and tend to ask great questions. I can speak from a personal experience as it is all too often that, when I visit other places and meet people who work in areas that are closely related to my lab’s interests, I refrain from asking about certain things because “well, they probably thought of THAT”. This is a mistake, and the only way to rectify it is to attend lectures that are not directly related to what one does. Needless to say, you also learn a lot just by listening to such talks. Today was no exception. I really enjoyed hearing Barney Grubbs of Stony Brooke University (http://www.chem.sunysb.edu/faculty/grubbs.shtml) speak about his lab’s work in the area of materials chemistry. One of the reactions caught my eye. You can read about it in the link below. In order to make the tellurium-containing molecule shown, Barney used an interesting coupling partner – a tertiary alcohol – in place of our “usual suspects” such as organotin or organoboron reagents. I don’t think I saw a transmetallation accomplished in this fashion too many times before! You can think of a mechanism… I think it is quite interesting.



On shineboxes

Have you noticed how political correctness has made its imprint on the scientific discourse that is being shaped up at conferences? The days of hearing offensive remarks for the sake of scientific truth are more or less behind us, yet there is something to be said in defense of raw and unfiltered emotion that used to be omnipresent at scientific meetings. Maybe the feel-good atmosphere we experience these days is because the stakes are higher and people are thinking a lot more about their image and reputation? We used to say that arguments and politics in science get nasty because the stakes are low. This is true of the older days, but maybe not anymore? The way things used to unfold is almost inconceivable to those who embark on a career in science nowadays. And I am not even talking about one’s behavior at a conference. When I was a postdoc we used to have a special term when a confrontation between two people was taking place. That “blissful” moment, when one of the parties to an argument was being attacked, was compared to him/her being asked to bring out the “shinebox”. The video below explains this analogy. Here you see the immortal “Billy Batts” scene from Scorsese’s “Goodfellas” (I apologize for the coarse language, but this is Scorsese, not me). What you see is an analogy to how heated arguments used to develop. I love DeNiro’s role in this scene when he says “Insulted him a little bit…” at 3:08-3:13. DeNiro corresponds to a peacemaker (albeit a temporary one!). Notably, there is often someone like that in a scientific argument as well. This sort of stuff is not happening in science anymore, though, because we are more civilized. Are we not?


Attention to detail

I am on a high-speed train from Xuzhou to Beijing, which means that my 3-day trip to China is coming to an end. You might ask: “Is it worth the trouble to spend all this time on an airplane, only to be 12 time zones away from home for a few days?”. I would say these trips are always worth it, particularly when there is a chance to see old friends and learn new things. I want to talk about a lecture by Professor Laszlo Kurti of the UT Southwestern Medical Center in Dallas. Laszlo is familiar to many people thanks to some of the nice books he published together with E. J. Corey. I particularly enjoy their book on the named reactions and mechanisms thereof. Laszlo’s recent paper in Science described metal-catalyzed synthesis of NH aziridines, which are exciting synthetic targets. Despite my long-standing interest in this chemistry, I want to talk about another one of his lab’s contributions I enjoyed hearing about. Besides its synthetic value, there are compelling pedagogical reasons to think about this chemistry.

From time to time I refer to the significance of mechanism and attention to experimentally determined reaction parameters that are germane to our craft. Take a look at the reaction sketched below. This is a remarkably efficient route to NOBIN-type ligands that was inspired by the Bertolli indole synthesis. This reaction, developed in the Kurti lab, teaches the significance of precision when it comes to measuring the amounts of arylmagnesium reagents. I encourage you to read about the exact mechanistic details using the link provided, but I am just going to say that failure to employ precisely 3 equivalents of the Grignard reagent leads to abysmal failure in this process. You might think that the use of 2 equivalents might simply lead to lower conversion, but it is more dramatic than that, according to Laszlo: failure to aromatize with the third equivalent leads to a mess. In other words, each equivalent of the organometallic species here is assigned its unique functional role. This also implies that the experimentalist running this process must titrate his/her Grignard reagent prior to use, which I am sure is not something that is done by some less careful practitioners of synthesis. All in all, attention to detail is what chemistry is all about. I tend to prohibit students who start doing research in the lab from running any experiments, no matter how trivial they might appear, prior to ensuring that the students demonstrate complete understanding of the mechanisms involved. Laszlo’s nice work is a testament to why this is important.



While in China

I have not posted anything for a few days because of my travel to Beijing and, afterwards, to Xuzhou (Jiangsu province). Currently, I am attending the ISOSDD-4 meeting (International Symposium on Organic Synthesis and Drug Discovery). I was invited to attend this conference by an old friend of mine, Professor Guigen Li of Texas Tech, who also has a research outpost in Nanjing (Jiangsu Province). Guigen and I go way back, to our days in the Sharpless lab at Scripps where we were both doing our postdoctoral stints in the late 90’s. Here, by the way, is a link to an important paper by Guigen, Chang, and Sharpless, which constitutes the first disclosure of the asymmetric aminohydroxylation reaction. This was, in fact, Guigen’s discovery, and is one of the many items that come to mind when I look back at those eventful years.


Hans Adolfsson of Stockholm University is another person whom I have not seen for many years. He also hails from our days in the Sharpless lab. Hans is attending this meeting as well and I have been very happy to interact with him too. Hans is now full of extra responsibilities as the Vice Chancellor at Stockholm University. Despite his busy schedule, Hans has a vibrant research lab that has done some excellent work in the area of asymmetric hydrogenation using peptide ligands. One of the curious recent findings in the Adolfsson lab is that of amide reduction into enamines. While there is no clear-cut mechanistic rationale for this process, it is one of the most remarkable paths to enamines I know. If you follow my posts, you know that I always emphasize novel approaches to well-established intermediates in organic chemistry. This, in my mind, always offers fertile grounds to discovery.



An eyesore here, a gem there

If I told you that there are some real eyesores in synthesis, I am sure you will know exactly what I mean. We have all been there. For example, you run a cyclization reaction and note that the best yields you record are for the so-called gem-dimethyl containing substrates. The reason is that you need some help from the Thorpe-Ingold effect that contributes to improved kinetics of cyclization by reducing the number of accessible conformers (plus some other reasons). Or you need a pro-nucleophile with a pKa that is suitable for the weak base you intend to use. Then you use a gem-diester. Again, you are stuck with it at the end, although this case is not as bad as the gem-dimethyl example. At least you have decarboxylation chemistry in your disposal and can “erase” one of the ester groups (if the rest of your molecule tolerates your conditions of choice, of course). At some point you feel dejected as no one asks questions along the lines of “Have you tried your reaction without the two methyl groups?” because everyone knows that you need the Thorpe-Ingold effect. They just give you a look that says “poor you”… It seems that gem-“anything” is bad news.


But not necessarily. For a number of reasons, my lab has been looking at gem-dichloro aldehydes. Is this another one of those “gems”? I recalled to mind a great paper published by Tom Rovis and colleagues several years ago. In it, Tom showed a useful application for a molecule that contains a pair of “gem-offending” chlorines. In this case, what happens is a carbene-mediated transformation that leads to amide bond formation. Very cool stuff.



Small shifts offer big insights

Last week we said our goodbye to Rebecca Courtemanche, who finished up her MSc degree. Rebecca is now in Vancouver and we miss her already because she has been instrumental in our efforts to measure small molecule/protein interactions by NMR. I asked Rebecca to write a blog entry dedicated to some of the research she performed while at the University of Toronto. Here is her post:

“As a chemist, I have an innate curiosity to study molecular interactions in biological settings. Chemical probes are small molecules that interact with protein targets. Understanding these interactions give insight into a protein’s role in a disease and can guide future drug discovery. Interest in chemical probes has significantly grown over the past decade and their importance is addressed in Stephen Frye’s article entitled “The art of the chemical probe”:


When I was given the opportunity to research chemical probes for biologically relevant proteins last Fall I was very excited to ‘nerd-out’ (according to my non-chemist friends). Dr. Peter Brown’s group at the Structural Genomics Consortium, SGC, has been actively pursuing probes for epigenetic proteins. Along the way, we found that 1H-15N HSQC chemical shift mapping has been particularly insightful in distinguishing the strength of interaction between a molecule and a protein as well as the molecule’s binding location. Proteins were expressed and purified such that they were 15N enriched (we used 15N-labelled ammonium formate while growing cells). This way, for a 1H-15N-HSQC experiment, all H-N correlations from the backbone amide groups as well as some side chain H-N correlations can be observed. Together, they provide a map of chemical shifts unique for every protein. When a small molecule is added to the protein, the region of the protein directly involved in binding will undergo a structural rearrangement, thus inducing a change in the region’s magnetic environment. On an HSQC map you see below (the nature of the protein is still confidential), the unbound protein will have a different chemical shift map as compared to the bound protein. The amount of chemical shift movement relative to the concentration of the binding molecule provides a sense of the strength of binding and it is possible to calculate a dissociation constant (Kd).


Figure 1. 1H-15N HSQC spectrum overlay: blue contours are the unbound protein and the red and green contours represent 1:1 and 1:3 molar ratios of protein to compound, respectively. 

Understanding the binding location on a protein can be achieved if it is known which NH correlations correspond to which amino acid. We are currently assigning our proteins by 3D NMR techniques using doubly labeled protein (C-13 and N-15). For more information pertaining to protein NMR theory see http://www.protein-nmr.org.uk/.”

Trouble at the periphery

Amino acid side chains participate in a number of reactions that result in peptide modification. Some of these reactions are of fundamental significance and play an important role in folding processes. Disulfide formation by oxidation of two proximal cysteine residues is one such case. Apart from its relevance in protein biochemistry, this reversible process also ensures structural integrity of fairly small cyclic peptide systems. Ziconotide is an example of a disulphide-rich analgesic agent derived from a conotoxin.

There are also amino acid reactions one would want to avoid. Today I want to talk about threonine. I always viewed this amino acid with caution (and serine too). If you pay close attention, you will note that threonine looks like the product of an aldol reaction, in which the amide functionality acts as the enolate component, whereas acetaldehyde corresponds to the aldehyde partner. Whenever you see an adol process, you can be sure that its microscopic reverse is feasible. Writing in Organic Process Research and Development, a group from Astellas report a retro-aldol by-product in their synthesis of a cyclic peptide drug candidate. I think this is an important warning for those who work with serine and threonine containing peptides. Be careful with the base you use!



Curious homologs

I think we all know about the significance of triazoles, which are readily accessible via [3+2] dipolar cycloaddition between organic azides and variously substituted alkynes. These aromatic heterocycles have found a myriad of applications, immortalized in what we now know as the click chemistry. Are there any 6-membered analogs derived from azides? This is the question I asked myself earlier today. These molecules would correspond to 1,2,3-triazines. As it turns out, there is a pretty nice method by which organic azides produce this sort of heterocycle. Below you see an example that involves triphenylphosphine that acts upon the molecule of an azido ketone. The role of triphenylphosphine in this Staudinger-like reaction is to “mop up” an oxygen atom that is produced upon attack of the terminal azide nitrogen at the carbonyl carbon. In this process, the organic azide acts as a nucleophile. The other notable case where an azide partakes in a polar mechanism is the so-called Aube-Schmidt process, although two nitrogen atoms are ultimately extruded as gas in that sequence. In the triazine case below, all nitrogen atoms stay put. It is not easy to see a concerted cycloaddition reaction that would deliver a 1,2,3-triazine from the corresponding azide, which is why I really like the condensation route shown.



From riches to rags?

That’s right, the other way around. Tonight we are talking about “passing the baton” to a weaker link. You are probably wondering what I am talking about. Here is a paper from my vault and the reason I continue to like this old contribution by Grigg and co-workers is that it is different from what we are accustomed to in the area of transition metal catalysis. We are used to seeing a lowly element such as boron, silicon, or tin pass the baton to a world-class metal such as palladium during transmetallation. But the reverse is happening in the Grigg case, which carries a certain unintended justice for the little guy. Earlier today I was discussing indium-mediated allylation reactions with my students and remembered the ChemComm article by Grigg. In the allylation reaction shown below, palladium starts the reaction, but indium is the one that finishes it up. Some might say that this is akin to putting a Lamborghini engine on a VW bug, but you know what: last time I checked, VW actually owns Lamborghini (this is a fact, by the way). I have to admit that this palladium-to-indium business is still a rarity. But it does have its place under the sun.



Handling nitrogen

Here is a great sequence to (-)-lepistine that has been developed by Professor Fukuyama and his students at the University of Tokyo. For many years, Fukuyama has been popularizing the use of the nosyl group. This chemistry has turned into one of the most useful ways to handle nitrogen in complex molecule synthesis. I forgot who told this to me, but common wisdom of synthesis tells us that adding one nitrogen atom to a molecule adds approximately one extra year to a student’s PhD. Just for clarity: I refer to a comparison between two molecules, one of which is one N atom “richer”. I have to admit that there is probably some truth to this statement (students from my lab: please ignore this sentence – otherwise we might be in trouble). Anyways… Back to Professor Fukuyama: the nosyl group is a fabulous way of handling nitrogen in synthesis. In the (-)-lepistine constuction, you see a great demonstration of clipping nosyl groups off, which generates an iminium ion in the same pot. After that, a lovely transannular collapse takes place, leading to the formation of the core of the natural product. Also noteworthy is the bridgehead double bond in the intermediate. All those things that are not supposed to happen in the second year organic chemistry I just taught two months or so ago!