Some years ago (circa 1995), I learned about the magic of arsenic trichloride. I think it was Karl Christe (when he was still at the Edwards Air Force Base in California), who told me about this wonderfully “benign” material. At that time, I was desperately trying to dissolve a polycyclic aromatic molecule. Apparently, when nothing else works, arsenic trichloride is supposed to solve all your problems, particularly when it comes to dissolving polyaromatics. For many years I have been trying to find the original source describing this wisdom and, as luck would have it, accidentally came across the paper I have been looking for. Here it is, so put it to test if you are brave enough. According to the authors of this old work, arsenic chloride is cheaper than deuterated chloroform. I am not sure about that, but I know several people who swear by the unique properties of this liquid. You might ask: “So did you give it a shot?”. Nope, I did not. I am not that brave after all!

http://www.sciencedirect.com/science/article/pii/S0040403900721101

For as long as I can remember, I have been told that silicone grease on glass joints is a bad idea. I remember taking this advice to heart because the alternative was to see an IR-like mess in the aliphatic region of my proton NMRs. The benefits of cleaner spectra outweighed an occasional frozen glass joint, although now that I think about it, Teflon tape on the inside had similar lubricating effect (and turned into my preferred way of avoiding frozen joints during grad school). Later on, I would tell this same story about grease to several generations of my doctoral students. The silicone nightmare is part of our synthetic folklore and efforts to avoid it represent a broadly accepted laboratory practice. However, we have a bit of a dilemma here, especially if we look at the review article quoted below. The title has “grease” and “serendipity” in it, so you can see where the paper is headed. We are conditioned not to use grease in reaction setup because we do not want to see garbage in NMR spectra. But it is possible to make things a bit too sterile, isn’t it? Otherwise certain serendipitous findings, such as the nickel example on display, will never be made. I am not saying that this particular carbene complex is noteworthy as a catalyst precursor, but who knows? There may very well be a niche for “OSiOSiO” bridges out there. They are interesting and largely underexplored. Unless generated unintentionally, that is… The “OSiOSiO”-based ligand was observed during an attempt to run what many would consider a fairly standard inorganic prep to make nickel-carbene complexes. I do think that the wording “greased Schlenk” might be a bit much, but I am here to faithfully reproduce what I see, ladies and gentlemen. I note that this review by Saito is not his first paper on the subject (this is more of a “Grease 2.0”). I salute you, Professor Saito, and I am glad that grease is developing a faithful following.

http://www.sciencedirect.com/science/article/pii/S0010854515002349

There are nuances in terminology, culture, and default assumptions among different branches of science. What appears natural in one area often goes against the grain and intuition in another, particularly when it is difficult to put forth well justified arguments at a molecular level.

In the past, I commented on the peculiar properties of PEG (polyethylene glycol). In my discussions with colleagues in protein crystallography, I have always found it odd to hear references to PEG as the “dehydrating agent”. It is especially uncomfortable when PEG is administered in an aqueous buffer to a vessel containing protein crystals. But our biological colleagues have no trouble with this concept at all. Below is a reference to the propensity of PEG to exert “extreme dehydration” on protein crystals. I used this paper in my talk (IRTG conference here in Toronto) earlier this week. While no one has issues with heterogeneous molecular sieves as water mops, many a chemist cringe at the thought of dehydration in water, given the homogeneous nature of one of the parties to the interaction. While this sounds like an oxymoron, dehydration of this sort is something protein crystallographers are rather comfortable with. In the paper below, PEG-driven dehydration is called upon to drastically alter the quality of protein crystals.

http://scripts.iucr.org/cgi-bin/paper?S1744309111048706

During a recent trip to the ISACS Conference in Irvine, CA (organized by my friend Vy Dong), I came across what I think is the craziest synthetic sequence I have had a pleasure of seeing in some time. This work is now more than a year old, yet it was still very invigorating to hear Seth Herzon describe it in detail. The reaction sequence depicted below is the pivotal cascade in Herzon’s synthesis of (+)-batzelladine B. In this process, deprotonation of the acetylene intermediate with n-butyllithium followed by the addition of lithium benzyl octanoate triggers 1,2-addition to the β-ketoester, retro-aldol ring-opening, and proton transfer to afford the enolyne intermediate. Subsequent to that, isomerization to the acylallene takes place, which is followed by Michael addition and neutralization of the resulting enolate. The role of DMPU is notable: this additive was found to be necessary to promote the retro-aldol ring- opening. This sequence takes the top prize in how chemoselectivity is achieved in an environment with multiple basic sites.

http://www.nature.com/nature/journal/v525/n7570/abs/nature14902.html

I came from Hong Kong about a week ago, where I gave a talk at the Hong Kong Institute of Science and Technology (HKUST). During this trip, Professor Jianwei Sun was my host and he managed to put together a superb visit. It is too bad that I was not able to stay longer: due to my teaching commitments I ended up going 12 times zones away for only 3 days. As usual, I got exposed to some really inspiring science. In the past, I mentioned Jianwei’s imaginative research, so today I want to talk about a paper from one of his colleagues, Professor Rongbiao Tong. I was really interested to hear about his approach to the cephalosporamide family of natural products. To me, the coolest aspect of Tong’s method lies in his handling of phenol’s aromatic framework. Below I am summarizing the key transformations of the phenol skeleton in Tong’s synthesis. The sequence starts by dearomatization with PhI(OAc)₂, followed by desilylation. If you track the rest of the steps in Tong’s Org. Lett. paper, you will learn how tosic acid-promoted oxa-Michael cyclization ultimately leads to the formation of the tricyclic ether core indicated below. It is fun to think about the origins of the blue string of carbon atoms in the product. The fact that all of them originate from the aromatic scaffold of a para-substituted phenol derivative is pretty remarkable.

http://pubs.acs.org/doi/full/10.1021/ol402913m?src=recsys

Click chemistry has been a major force behind the development of innovative technologies in materials science and chemical biology. The general accessibility and ease of protocols has been a welcome bonus point, especially for those who are not trained in chemistry. If one can figure out how to place an alkyne and azide components where they need to be, this kit-like approach to building molecules from simple blocks can be tremendously enabling: all you need is to add a copper catalyst. There are also copper-free protocols for running triazole synthesis. These surrogates often hinge on the idea of strain relief (Caroline Bertozzi has been one of the pioneers in this area).

When I attended the 2016 Gordon Conference on Peptide Chemistry and Biology a couple of weeks ago (this meeting was superbly organized by Phil Dawson), I got to hear a thought-provoking talk by Jim Heath of Caltech. He uses click chemistry in order to discover macrocyclic ligands for epitope targeting. Because the presence of copper adversely affects biology, Heath uses the copper-free protocol. However (get this), he is not using any strained alkynes… When I heard it, I got really curious about the underlying reasons for how might a pair of molecules react in a [3+2] fashion at room temperature without any “extra help”. I asked Jim this question and found out that there are, in fact, no miracles here: his yield is abysmally low. While I appreciate that this is not a preparative reaction, I really wonder: why would one want to use the azide/alkyne cycloaddition here to begin with? I would hazard to guess that this constitutes the least interesting of all processes that could be run in the Heath format. Personally, I would be much more interested in looking at some of the pillars of chemistry (amide bond formation?) under his conditions. Sometimes truly interesting things might arise from more conventional processes, and it might also be easier to put together the starting materials. But this is just my view.

http://onlinelibrary.wiley.com/doi/10.1002/anie.201505243/full

There are a lot of nitrogen sources in chemical synthesis and they come in great variety, serving the insatiable appetite of reductions, oxidations, and redox neutral transformations. It is good to see how bond-breaking and making events are orchestrated around the needs of some reagent that contains the “active” form of nitrogen. I particularly like reading about cases wherein nitrogen transfer stems from nitrogen-heteroatom bond breaking. In these instances, I turn a blind eye on low atom economy. Who cares? All I want to see is “molecular gymnastics”. Below is an instructive recent transformation, whose sequence I abbreviate for clarity’s sake. My appreciation of this synthesis of a fused pyridine ring system has to do with how an azo compound undergoes in situ transformation into a diaziridine oxidant, which leads to the eventual scission of the N-N bond during electrophilic aromatic substitution. What we see here is a fairly rare side of azodicarboxylate, which is a common component of redox condensations such as Mitsunobu reaction.

http://pubs.acs.org/doi/abs/10.1021/acs.orglett.6b00456