A cool new reduction of amides

Beller and co-workers recently published a superb new method for reducing tertiary amides into amines. The reaction is tolerant of a wide range of functionalities including ester, thiomethyl, nitrile, secondary amide, and hydroxyl groups. This post is timely from my perspective because we just had a group meeting discussion about what is new and what is old in the area of reduction technologies. My point at that meeting was that, while there are some incredibly innovative and functional group tolerant methods in contemporary literature, it is important to keep in mind some of the more obscure and less known processes. But old and obscure will be the subject of another post (when we reduce some of our ideas to practice – no pun intended).

Back to Beller’s innovative new chemistry: the most useful aspect here is that no air-sensitive reagents are involved. The reaction uses readily accessible phenylsilane and a rhodium(dppp) catalyst. A fairly extended portion of the paper is dedicated to just one experiment that describes selective reduction of one of cyclosporine A’s tertiary amides (the O-acetylated version of the molecule was used in this process). I am really curious who was brave enough to use 6.5 g of cyclosporine A in this reaction (Sigma Aldrich charges $180 per 25 mg). This has to be connected to the fact that one of the co-authors of this paper is from Novartis (in Basel). Given the continuing interest in cyclosporine A and related compounds, it would be interesting to find out the cellular permeability of the partially reduced version.




The right place at the right time

I am in Ottawa at the moment, attending the 2016 CHRP (Collaborative Health Research Projects) grant review panel. I wish all of the grants I had to read would get funded! The level of science is quite high. Now is our coffee break, so I have some time…

Today is a second post in a row where I mention some kind of azide chemistry. That’s ok because, as someone who has been interested in aziridine chemistry for a while, I can’t let the recent Angewandte paper by Shen and colleagues from Changzhou go without due notice. Below you see a graphical summary. While there is nothing new in intramolecular Diels-Alder reactions, it is always good to see cases in which a particularly unstable dienophile is created. In the present case, the authors show how vinyl azides undergo thermal transformation into azirines, which are then positioned at the right place and time to undergo [4+2] cycloaddition. Good luck making the resulting tricycles by any other means! I think the “latent azirine concept” is quite neat and should find many applications in alkaloid synthesis, among other things. Someone should come up with a quantifiable metric for how rapid complexity increases in a single transformation (maybe it already exists, but I just can’t think of it at the moment). The Shen paper is really impressive in this regard, although (there is always this “although”…) one has to make some fairly obscure starting materials.



Weird amides

I was intrigued by a recent paper from the Stoltz lab. In it, the authors describe their ongoing efforts to generate and characterize strained amides. For years, Kirby dominated the landscape of unusual amides characterized by the lack of C/N overlap. Then came Stoltz and his imaginative use of the Aubé-Schmidt reaction. This area of research has been a race toward the most strained amide structure. Stoltz’s recent addition to the list of weird amides (see the structure shown below) is the front-runner at this point. Notable spectroscopic features include a C=O IR stretch of 1877 cm-1. The X-ray analysis holds the most interesting result: the ξ angle of 5.8o. The authors propose to use “ξ” to refer to the O-C-N deviation from 120o degrees. For clarity, I am exaggerating the ξ value in my drawing below. The explanation for the deviation offered by Stoltz has to do with the p-like oxygen orbital and its interaction with the C-N σ* orbital. In my view, there is an interesting connection here to the “n-to-π*” interactions popularized by Raines. I talked about it the past and raised a point about the “infamous” rabbit ears (https://amphoteros.com/2015/06/25/rabbit-ears/).




Unanticipated confounders

The burden of proof varies depending on the branch of science. When we establish causal relations in organic chemistry, we beat the drums and open up champaigne. Fundamental mechanistic insights enable us to formulate reliable hypotheses and pursue the next round of questions. Not long ago, I was reading a piece from The New England Journal of Medicine (my wife subscribes to this journal). I came across a most peculiar statement. It was something along these lines: “now that the causality has been established, really meaningful randomized control studies can commence”. That’s right: for those guys causality is just the tip of the iceberg. The reason is that, with causality demonstrated, one needs to balance the unanticipated confounders. The only way to do it properly is to design a double-blinded randomized controlled trial. Serious studies in medicine are unthinkable without analysis of large data sets. Imagine if chemistry were held to this standard. It might involve a respectable journal such as Org. Syn. sending 1000 referees a paper along with blinded bottles for each reagent used, asking them to repeat the experiments. What would a placebo for n-butyllithium be? I am not sure… Wouldn’t that be fun though? Of course I am joking, but elimination of subjective factors is the powerful feature of a double-blinded randomized controlled study.

Reversible covalent interactions

Happy New Year, everyone! I am back.

There are many types of reversible covalent interactions but the one I am most curious about these days is the one between two nitrogens. I learned about it from Professor Jim Wuest (http://www.wuestgroup.com) while visiting Université de Montréal just before Christmas. Jim and his lab leverage the reversible coupling between nitroso compounds to make materials of controlled porosity. Being a small molecule guy, I am intrigued by the pair of reactions I saw in his nice Chemical Reviews account (http://pubs.acs.org/doi/abs/10.1021/cr500520s). Why is it that a 6-membered ring is not formed in the naphthalene case? There are a couple of lessons about aromaticity and strain here, among other things. This fascinating type of N=N bonding also takes me back to some of my earlier claims about the rarity of heterocycle construction using heteroatom-heteroatom bond formation. Here it is on display. However, these heterocycles are metastable.