In answering tutorial problems, students often need skills in deciding how much time to spend on explaining what does not happen, as well as what does. Here I explore alternatives to the mechanism outlined in the previous post to see what computation has to say about what does (or might) not happen.
A tutorial problem in stereoelectronic control. A Grob alternative to the Tiffeneau-Demjanov rearrangement?November 28th, 2015
A tutorial problem in stereoelectronic control. The Tiffeneau-Demjanov rearrangement as part of a prostaglandin synthesis.November 23rd, 2015
This reaction emerged a few years ago (thanks Alan!) as a tutorial problem in organic chemistry, in which students had to devise a mechanism for the reaction and use this to predict the stereochemical outcome at the two chiral centres indicated with *. It originates in a brief report from R. B. Woodward’s group in 1973 describing a prostaglandin synthesis, the stereochemical outcome being crucial. Here I take a look at this mechanism using computation.
- R.B. Woodward, J. Gosteli, I. Ernest, R.J. Friary, G. Nestler, H. Raman, R. Sitrin, C. Suter, and J.K. Whitesell, "Novel synthesis of prostaglandin F2.alpha.", J. Am. Chem. Soc., vol. 95, pp. 6853-6855, 1973. http://dx.doi.org/10.1021/ja00801a066
Derek Lowe has a recent post entitled “Another Funny-Looking Structure Comes Through“. He cites a recent medchem article in which the following acetal sub-structure appears in a promising drug candidate (blue component below). His point is that orally taken drugs have to survive acid (green below) encountered in the stomach, and acetals are famously sensitive to hydrolysis (red below). But if X=NH2, compound “G-5555” is apparently stable to acids. So I pose the question here; why?
- C.O. Ndubaku, J.J. Crawford, J. Drobnick, I. Aliagas, D. Campbell, P. Dong, L.M. Dornan, S. Duron, J. Epler, L. Gazzard, C.E. Heise, K.P. Hoeflich, D. Jakubiak, H. La, W. Lee, B. Lin, J.P. Lyssikatos, J. Maksimoska, R. Marmorstein, L.J. Murray, T. O’Brien, A. Oh, S. Ramaswamy, W. Wang, X. Zhao, Y. Zhong, E. Blackwood, and J. Rudolph, " Design of Selective PAK1 Inhibitor G-5555: Improving Properties by Employing an Unorthodox Low-p K a Polar Moiety ", ACS Med. Chem. Lett., 2015. http://dx.doi.org/10.1021/acsmedchemlett.5b00398
Steve Bachrach on his own blog has commented on a recent article discussing the structure of the trimer of fluoroethanol. Rather than the expected triangular form with three OH—O hydrogen bonds, the lowest energy form only had two such bonds, but it matched the microwave data much better. Here I explore this a bit more.
- J. Thomas, X. Liu, W. Jäger, and Y. Xu, "Unusual H-Bond Topology and Bifurcated H-bonds in the 2-Fluoroethanol Trimer", Angewandte Chemie International Edition, vol. 54, pp. 11711-11715, 2015. http://dx.doi.org/10.1002/anie.201505934
In Jingdezhen an Imperial Kiln was built in 1369 to produce porcelain that was “white as jade, thin as paper, bright as a mirror and tuneful as a bell”. It’s the colours of the glazes that caught my eye, achieved by a combination of oxidative and reductive firing in the kiln, coupled with exquisite control of the temperature.
Yes, no, yes. Computational mechanistic exploration of (nickel-catalysed) cyclopropanation using tetramethylammonium triflate.October 1st, 2015
A fascinating re-examination has appeared of a reaction first published in 1960 by Wittig and then repudiated by him in 1964 since it could not be replicated by a later student. According to the new work, the secret to a successful replication seems to be the presence of traces of a nickel catalyst (originally coming from e.g. a nickel spatula?). In this recent article a mechanism for the catalytic cycle is proposed. Here I thought I might explore this mechanism using calculations to see if any further insights might emerge.
- S.A. Künzi, J.M. Sarria Toro, T. den Hartog, and P. Chen, " Nickel-Catalyzed Cyclopropanation with NMe 4 OTf and n BuLi ", Angewandte Chemie International Edition, vol. 54, pp. 10670-10674, 2015. http://dx.doi.org/10.1002/anie.201505482
- V. Franzen, and G. Wittig, "Trimethylammonium-methylid als Methylen-Donator", Angewandte Chemie, vol. 72, pp. 417-417, 1960. http://dx.doi.org/10.1002/ange.19600721210
- G. Wittig, and D. Krauss, "Cyclopropanierungen bei Einwirkung vonN-Yliden auf Olefine", Justus Liebigs Ann. Chem., vol. 679, pp. 34-41, 1964. http://dx.doi.org/10.1002/jlac.19646790106
How does an anaesthetic work? Surprisingly, it is only recently that the possible binding sites of the anaesthetic propofol (2,6-di-isopropylphenol) have been identified using a technique known as photoaffinity labelling. A propofol analogue was constructed by replacing one of the isopropyl groups with a trifluoromethyl diazirine group (R=CF3, X=Y=N below). Upon photolysis, this species looses nitrogen and forms a carbene as a reactive species, which with further chemistry binds covalently to adjacent amino acids in the binding pocket.These modified segments could then be analysed by mass spectrometry. An isomer of diazirine is diazomethane, which is some 11 kcal/mol lower in free energy, but fortunately the diazirene is preventing from thermally isomerising to this species by a large kinetic barrier. That was the intro; now for a connection.‡ I recently attended a presentation on another medical topic, the therapeutic uses of carbon monoxide. In higher concentrations it is notoriously lethal, but with appropriate delivery it can be therapeutic. So, intertwingling, I asked myself what the properties of the carbon monoxide isoelectronic analogue of a diazirine might be (X=C, Y=O below).
- G.M.S. Yip, Z. Chen, C.J. Edge, E.H. Smith, R. Dickinson, E. Hohenester, R.R. Townsend, K. Fuchs, W. Sieghart, A.S. Evers, and N.P. Franks, "A propofol binding site on mammalian GABAA receptors identified by photolabeling", Nature Chemical Biology, vol. 9, pp. 715-720, 2013. http://dx.doi.org/10.1038/nchembio.1340
- L. Dubinsky, B.P. Krom, and M.M. Meijler, "Diazirine based photoaffinity labeling", Bioorganic & Medicinal Chemistry, vol. 20, pp. 554-570, 2012. http://dx.doi.org/10.1016/j.bmc.2011.06.066
- R. Motterlini, and L.E. Otterbein, "The therapeutic potential of carbon monoxide", Nature Reviews Drug Discovery, vol. 9, pp. 728-743, 2010. http://dx.doi.org/10.1038/nrd3228