Hydrazines in electrochemistry

The challenge of oxidative nitrogen transfer is fascinating because nature does not know how to do it, at least not when it comes to oxidative C-N bond formation. I already commented on this feature of biosynthesis in the past and there is no need to belabor the point. The arsenal of synthetic tricks we have is astounding. The trouble is, of course, that generation of nitrogen oxidants can require rough conditions that might adversely affect other “spinach” that hangs off your molecule. We worked on this problem in the past and found electrosynthesis to be full of options. Here is an old pic of one of our reactions along with the reactor we used. I am only indicating the process taking place at the anodic compartment, in which we oxidized the hydrazine-containing starting material. The cathodic compartment separated by a frit you see, is colorless. It is actually possible to see hydrogen bubbles on this picture – they come as a result of proton reduction (protons are produced during oxidation). I am also attaching a link to the JACS paper where we demonstrated how anodic electrochemistry helped us solve some challenging problems of oxidative nitrogen transfer. Image


When I visited the Dallas ACS meeting a couple of weeks ago, I heard Phil Baran speak about his lab’s use of electrochemistry in natural product total synthesis. I saw his JACS communication earlier today and enjoyed reading this work because it brought back many fond memories of hydrazine chemistry. As was the case in our oxidative approach to aziridines, the beauty of electrochemistry in Phil’s case is in offering a glimpse of synthetic opportunity by judiciously choosing the right window of applied anodic potential at which the amine can be selectively oxidized. In this particular case, electrooxidation leads to the formation of a hydrazine-containing natural product dixiamycin B. Any chemical oxidants Phil’s lab tried, failed in this oxidation reaction. I was not surprised that carbon was the best electrode material in this case. It is almost certain that the “flat-ish” substrate you see interacts quite well with the anode surface. We could not use carbon in our aziridine chemistry, though. Platinum was the key to us as graphite led to strong background currents corresponding to alkene oxidation.



Really bad ideas

It’s tough to be a graduate student. If you are a Professor, you can sit in your ivory tower and think about all manner of nutty ideas and, as long as none of them violate any laws of thermodynamics, they will be eventually reduced to practice (and improved!) by our capable graduate students and postdocs. But the devil is in the detail and all those brave souls are left figuring out how to lower the kinetic barriers of reactions we contemplate. There are reactions (unfortunately, a lot), in which there are just too many energetically similar pathways, which is why we get in trouble with by-products… Apart from this insignificant detail (I am being sarcastic), chemistry is deceptively simple: any idea about an isolable endpoint of synthesis that is not uphill in energy, is worth the risk. Needless to say, you can design special conditions and isolate uphill intermediates (e.g. carbocations), but this would amount to imposing a kinetic barrier of some sort. Now, are there ridiculous (but seemingly plausible) ideas out there that can throw us for a loop unless we sit down and think about them for a second? Here’s one of the problems I like to discuss with my colleague, Professor Jik Chin. Consider the following generalized process:



Imagine that you want to develop a catalyst that would run this reaction. Can such catalyst exist? No, it can’t. The way this reaction is written is sheer nonsense. For this conversion to have a chance to work in the forward direction, the Gibbs free energy change must be less than zero. In the example above we clearly have no entropy change and enthalpy does not change either. In addition to the violation of the Second Law of thermodynamics, there is a problem with the principle of microscopic reversibility here as any catalyst that works in the forward direction should be capable of catalyzing the opposite process. Of course, stoichiometric reactions can be designed and there are many solutions for this “R into S” type of problem. Enzymes can do this too (and catalytically!), but those reactions are coupled processes, which means that there is something else that goes on with either your product or your starting material. Hence, the energy of the product is not the same as the energy of the starting material. You can break microscopic reversibility with photochemistry, but if you are interested in thermal activation, any catalyst that you think might promote the aforementioned process, will necessarily have to violate microscopic reversibility and the Second Law. Back to my starting point: unless we propose thermodynamically ludicrous ideas, being a Professor is the best job out there. The way George Olah would say, “Hey – I am doing my hobby and the University even pays me for it!”

Uphill battles in amide couplings

Earlier today, our Encycle team had a discussion regarding some of the issues pertaining to N-Me amino acid coupling reactions. Overall, we typically have no trouble introducing N-Me groups into peptides. All we need is an appropriately protected N-Me building block for the solid-phase Fmoc chemistry and off we go. The trouble is, sometimes this coupling fails miserably if hindered amino acids are brought together. There is an ingeneous solution to the problem and it offers a workaround. The reaction was developed by Professor Schafmeister of Temple University and it involves amino acid fluorides as electrophiles. A few words about them: in brief, acid fluorides are remarkably stable to aqueous hydrolysis. In contrast to their chloride congeners, fluorides also resist racemization. One of the classic ways to prepare them is through the use of DAST (there are better alternatives these days). Kaduk’s way cited below is as simple as it gets – just mix an Fmoc-protected amino acid with DAST in dichloromethane and get your acid fluoride product after aqueous work-up. The product can be crystallized from dichloromethane/hexanes, which makes for a rather practical method.



Back to the hindered amide workaround developed by Schafmeister. The mechanism involves mixed anhydride formation, which is the central trick here. Once this electrophilic intermediate has been formed, the rest is “downhill history” as nitrogen acylation becomes an intramolecular process. Even exceptionally hindered amides can be made using this procedure. Connoisseurs of multicomponent reaction might notice a similarity with Ugi’s mixed anhydride. We are attempting to run the Schafmeister process this week (wish us luck, we have a tough substrate that failed with everything else).



Some rare natural products

There are elements in the periodic table that, despite their abundance on earth, appear extremely infrequently in natural products. Fluorine is a good example: there are only a handful of natural products that contain monofluoroalkyl substituents and there are none with CF2 and CF3 groups. The rarity of the latter two tends to surprise students when they hear it for the first time. I suppose this has to do with the omnipresence of CF2 and CF3 substituents in therapeutic agents, which is why some people assume that the inspiration for their emergence must have come from some natural product. There is a tendency to forget that if we think about how C-F bonds are biosynthetically introduced into organic compounds, it is almost impossible to place more than one fluorine atom on the same carbon.



Boron is another enigma. There is a lot of it on our planet, yet we rarely see boron in natural products. A marine natural product borophycin is one of those rarities. Earlier today we had Professor Jon Clardy of Harvard Medical School give one of University of Toronto’s annual Gordon lectures (this is a set of three lectures given by one person and the topics vary from talk to talk). While the theme of today’s lecture was not related to boron, I caught myself reminiscing on some of the work Jon had done 20 years ago. He is responsible for a spectacular collection of isolated and characterized natural products, and one of them is borophycin (see above). I am showing the structure of this intriguing compound and a link to Jon’s 1994 paper together with Moore and their colleagues. Isolated from green-blue algae, borophycin is a potent cytotoxin which was characterized by both NMR and X-ray in the 1994 JOC report. I don’t think there is unequivocal evidence supporting or refuting the essential nature of boron to the biological activity of this molecule, but it is a really nice example of a rare boron-containing compound found in nature. By the way, this molecule might also provide a clue as to why boron is NOT (contrary to some popular belief) benign from the standpoint of toxicity. Boron-containing waste is a big problem and it is known that it causes blue algae to grow. Perhaps there is a link there with borophycin, but I am not sure.

Switching places

Whenever I think about heterocycles, I always long for a worhty reaction that does something “outside the box”. While condensation processes continue to serve as a rich resource of ideas on how to put together different substitution patters of nitrogen heterocycles, there are only a few rections that enable one to rearrange heterocyclic scaffolds. Today I will mention a fairly obscure reaction that hails from the old Soviet Union, which is why I am willing to bet that many of you have never heard of it. Chemistry developed behind the “iron curtain” tended to stay there, and there was even a suspicion on behalf of Western chemists that there might be deliberate diversions and misinformation in Soviet journals. I don’t think this was actually ever the case, but there had been many examples where no knowledge about a given reaction practiced by the Soviet chemists existed until it was discovered some years later in the West.

The Kost-Sagitullin rearrangement is one such process. Almost all literature pertaining to this remarkable rearrangement was published in Soviet journals, although there are some good modern reviews in English. I am showing this reaction in the graphic below and providing a reference. The Kost-Sagitullin rearrangement is a great way to convert pyrimidines into pyridines, but you probably realize that there are some limitations pertaining to the substitution pattern of the aromatic ring. The last step is actually quite neat, but I won’t dwell too much on it now. It is up to you to think whether or not this is an electrocyclization or a stepwise process. It is too bad that not much has been done in elucidating the mechanistic underpinnings of this remarkable “nitrogen dance”.


Edinburgh, London, and slow internet

Over the past four days I have been in Edinburgh and then in London, which is why I have not been able to post anything. Stay tuned – I am back to Toronto tomorrow. Incidentally, I can’t say that I am impressed with the hotel internet. When it comes to uploading fairly large graphics I like to use on my blog, things often fall apart. Somehow this have been particularly problematic on this trip (there are other reasons too…). This reminds me: those of you who regularly submit papers to scientific journals and have to wait for several days to hear a response – try to see if you tend to upload ridiculously large SI files. If you are a journal editor, you know that it is a nightmare to download some of the NMR graphics people put together these days. My advice: use low resolution graphics. I am definitely on the receiving end of this in my capacity as one of the Associate Editors for Organic and Biomolecular Chemistry. I can’t deal with large SI files while travelling and staying in hotels with slow internet. This, of course, creates needless delays for the authors. The best way to go is to export your giant .pdf file into a .jpg and then convert it back into a .pdf. This seemingly senseless process will give you a much smaller .pdf file. I learned this from Adam, one of my graduate students.