What phenol can do for you

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.



Too engineered?

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.


Uncommon nitrogen sources

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.



Exotic enolates

I have been away a lot – first at the Gordon Conference on the Chemistry and Biology of Peptides (Ventura, California) and then at the Royal Society of Chemistry’s Editors Meeting in London, UK. Now I am finally back and have some time to write.

I want to talk about unusual enolates today. The one implicated in Haufe’s anti-selective aldol reaction that was captured in his recent Org. Lett. publication is as good as it gets. There are many people who are interested in the SF5 group these days. There are myriad reasons for this surge and I mentioned some of them in the past, particularly the materials science angle. Haufe’s work suggests that ester enolates that contain an SF5 substituent are subject to some fairly reliable aldol chemistry, which is interesting because this represents a nice way to “plug” SF5 into a chiral, sp3-rich environment. Up until now I have mainly seen the “aromatic” aspects of SF5.

The starting ester used by Haufe is prepared on scale using a really cool reaction between SF5Cl and a ketene. This process has been known since the 70’s, so check it out (reference 16 in Haufe’s Org. Lett.). I should mention that Professor Haufe of the University of Müenster is no stranger to fascinating transformations of organofluorine compounds. He has been at it for a number of years and is currently one of the Regional Editors of the Journal of Fluorine Chemistry.