Henry Rzepa's Blog

Calicheamicin was noted in the previous post as a natural product with antitumour properties and having many weird structural features such as  an unusual “enedidyne” motif. The representation is shown below.

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Calicheamicin is a natural product with antitumour properties discovered in the 1980s, with the structure shown below. As noted elsewhere, this structure has many weird properties, including amongst other features an unusual “enedidyne” motif and the presence of an iodo group on an aromatic ring. Its isolated 3D structure is quite difficult to get hold of (embedded structures in a DNA fragment are available however); the 3D model associated with the Wikipedia entry is essentially only in 2D. The representation shown below, including the absolute stereochemistry, was obtained from the SciFinder entry.

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The Masamune-Bergman reaction[1],[2] is an example of  a highly unusual class of chemical mechanism[3] involving the presumed formation of the biradical species shown as Int1 below by cyclisation of a cycloenediyne reactant. Such a species is  so reactive that it will be quickly trapped, as for example by dihydrobenzene to form the final product. This cycloenediyne is not just an obscure chemical curiosity, the motif is incorporated into the natural product Calicheamicin, which is a potent antitumor antibiotic discovered in the 1980s. This drug owes its activity to the cyclisation TS1 shown below, which for n=2 occurs at the low temperature of 310K. The resulting biradical Int1 is a potent hydrogen abstractor, the species acting this way for hydrogen atoms associated with deoxyribose of DNA, ultimately leading to strand scission. Although I have explored many a mechanism on this blog using computational methods, I have never included any biradical examples. Here I explore the computational aspects of this reaction, and also include a pathway proceeding vis TS2- Int2 – TS3 in which hydrogen abstraction precedes cyclisation, in order to see how competitive such an alternative might be as a function of the ring size (n in scheme below).

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References

1. N. Darby, C.U. Kim, J.A. Salaün, K.W. Shelton, S. Takada, and S. Masamune, "Concerning the 1,5-didehydro[10]annulene system", J. Chem. Soc. D, vol. 0, pp. 1516-1517, 1971. https://doi.org/10.1039/c29710001516
2. R.R. Jones, and R.G. Bergman, "p-Benzyne. Generation as an intermediate in a thermal isomerization reaction and trapping evidence for the 1,4-benzenediyl structure", Journal of the American Chemical Society, vol. 94, pp. 660-661, 1972. https://doi.org/10.1021/ja00757a071
3. R.K. Mohamed, P.W. Peterson, and I.V. Alabugin, "Concerted Reactions That Produce Diradicals and Zwitterions: Electronic, Steric, Conformational, and Kinetic Control of Cycloaromatization Processes", Chemical Reviews, vol. 113, pp. 7089-7129, 2013. https://doi.org/10.1021/cr4000682

Back in 2017, I was asked to peer review an article and its author asked if I would like the review to be “open” – that is that my name would be shown as a reviewer; [1]10.1073/pnas.1709586114[/cite/] indeed it was!

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References

1. https://doi.org/

Metadata is something that goes on behind the scenes and is rarely of concern to either author or readers of scientific articles. Here I tell a story where it has rather greater exposure. For journals in science and chemistry, each article published has a corresponding metadata record, associated with the persistent identifier of the article and known to most as its DOI. The metadata contains information about the article such as its authors and their affiliations, the title of the article and its abstract, and is submitted to/registered with Crossref –  an organisation set up in 1999 on behalf of publishers, libraries, research institutions and funders. Relatively recent additions to Crossref metadata are the citations included in the article, so-called Open Citations. Doing so has helped to create the new area of article metrics, used by e.g. Altmetrics or Dimensions  to help identify the impacts that science publications have. Basically, if one article is cited by another, it is making an impact. Many citations of a given article by other articles means a larger impact. Most researchers love to have a high – and of course positive – impact and perhaps for better or worse, academic careers to some extent depend on such impacts.

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I should start by saying that the server on which this blog is posted was set up in June 1993. Although the physical object has been replaced a few times, and had been “virtualised” about 15 years ago, a small number of the underlying software base components may well date way back, perhaps even to 1993. This system had begun to get unreliable in recent years, and it was decided about 6 months ago to build an entirely new virtual server and then migrate stuff to it.

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Chemists now use the term “curly arrows” as a language to describe the electronic rearrangements that occur when a (predominately organic) molecule transforms to another – the so called chemical reaction. It is also used to infer, via valence bond or resonance theory, what the mechanistic implications of that reaction are. It was in this latter context that the very first such usage occured in 1924[1] taking the form of a letter by Robert Robinson to the secretary of the Chemical Society and “read” on December 18th 1924. The following diagram was included:

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References

1. "Forthcoming events", Journal of the Society of Chemical Industry, vol. 43, pp. 1295-1298, 1924. https://doi.org/10.1002/jctb.5000435208

I can remember a time when journal articles carried selected data within their body as e.g. Tables, Figures or Experimental procedures, with the rest consigned to a box of paper deposited (for UK journals) at the British library. Then came ESI or electronic supporting information. Most recently, many journals are now including what is called a “Data availability” statement at the end of an article, which often just cites the ESI, but can increasingly  point to so-called FAIR data. The latter is especially important in the new AI-age (“FAIR is AI-Ready”). One attribute of FAIR data is that it can be associated with a DOI in addition to that assigned to the article itself, and we have been promoting the inclusion of that Data DOI in the citation list of the article.[1] Since the data can also cite the article, a bidirectional link between data and article is established. ESI itself can exceed 1000 “pages” of a PDF document and examples of chemical FAIR data exceeding 62 Gbytes[2] (Also see DOI: 10.14469/hpc/10386) are known. Finding the chemical needle in that data haystack can become a serious problem. So here I illustrate a recent suggestion for moving to the next stage, namely the inclusion of a “Data Availability and Discovery” statement. The below is the text of such a statement in a recently published article.[3]

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References

1. H. Rzepa, "The journey from Journal "ESI" to FAIR data objects: An eighteen year old (continuing) experiment.", 2023. https://doi.org/10.59350/g2p77-78m14
2. T. Mies, A.J.P. White, H.S. Rzepa, L. Barluzzi, M. Devgan, R.A. Layfield, and A.G.M. Barrett, "Syntheses and Characterization of Main Group, Transition Metal, Lanthanide, and Actinide Complexes of Bidentate Acylpyrazolone Ligands", Inorganic Chemistry, vol. 62, pp. 13253-13276, 2023. https://doi.org/10.1021/acs.inorgchem.3c01506
3. D.C. Braddock, S. Lee, and H.S. Rzepa, "Modelling kinetic isotope effects for Swern oxidation using DFT-based transition state theory", Digital Discovery, vol. 3, pp. 1496-1508, 2024. https://doi.org/10.1039/d3dd00246b

Following on from my template exploration of the Wilkinson hydrogenation catalyst, I now repeat this for the Grubbs variant of the Alkene metathesis reaction. As with the Wilkinson, here I focus on the stereochemistry of the mechanism as first suggested by Chauvin[1], an aspect lacking in eg the Wikipedia entry. As before, the diagram below is hyperlinked to the appropriate data repository identifier so that you can go straight from the scheme to the data (Top level Data DOI: [2]).

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References

1. P. Jean‐Louis Hérisson, and Y. Chauvin, "Catalyse de transformation des oléfines par les complexes du tungstène. II. Télomérisation des oléfines cycliques en présence d'oléfines acycliques", Die Makromolekulare Chemie, vol. 141, pp. 161-176, 1971. https://doi.org/10.1002/macp.1971.021410112
2. H. Rzepa, "Mechanistic templates computed for the Grubbs alkene-metathesis reaction.", 2024. https://doi.org/10.14469/hpc/13796

Geoffrey Wilkinson first reported his famous work on the hydrogenation catalyst that now bears his name in 1965[1] and I met him at Imperial College around 1969 and again when I returned there in 1977. He was still working on these catalysts then and I was privileged to collaborate with him on unravelling the NMR spectra of some of these compounds.[2],[3],[4]. During that period, computational modelling of the mechanisms of molecules containing transition elements was still in its infancy and I never extended my collaboration into this area at that time. Now, even if belatedly, I decided to explore this aspect and started to do this about two weeks ago. Here I thought that I would use this opportunity to show how I am going about it.

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References

1. J.F. Young, J.A. Osborn, F.H. Jardine, and G. Wilkinson, "Hydride intermediates in homogeneous hydrogenation reactions of olefins and acetylenes using rhodium catalysts", Chemical Communications (London), pp. 131, 1965. https://doi.org/10.1039/c19650000131
2. K.W. Chiu, H.S. Rzepa, R.N. Sheppard, G. Wilkinson, and W. Wong, "Two-dimensional δ/J-resolved³¹P n.m.r. spectroscopy of [bis(diphenylphosphino)methane](trimethylphosphine)chlororhodium(<scp>I</scp>)", J. Chem. Soc., Chem. Commun., pp. 482-484, 1982. https://doi.org/10.1039/c39820000482
3. C. Kwok W., C.G. Howard, H.S. Rzepa, R.N. Sheppard, G. Wilkinson, A.M. Galas, and M.B. Hursthouse, "Trimethyl and diethylphenylphosphine complexes of rhenium(I, III, IV, V) and their reactions. X-ray crystal structures of a bis(η5-cyclopentadienyl)-ethane-bridged dirhenium(I) complex obtained from phenylacetylene, tetrakis-(diethylphenylphosphine) (dinitrogen) hydridorhenium (I), tetrakis(trimethyl-phosphine) (η2-dimethylphosphinomethyl) rhenium(I) and tetrakis(trimethylphosphine) (iodo)methyl rhenium(III) iodide-tetramethylphosphonium iodide", Polyhedron, vol. 1, pp. 441-451, 1982. https://doi.org/10.1016/s0277-5387(00)86558-4
4. K.W. Chiu, H.S. Rzepa, R.N. Sheppard, G. Wilkinson, and W. Wong, "Bis(diphenylphosphino)methane trimethylphosphine alkyl and η5-cyclopentadienyl compounds of rhodium(I); 31P{1H} two dimensional δ/J resolved and Overhauser effect nuclear magnetic resonance spectroscopy", Polyhedron, vol. 1, pp. 809-817, 1982. https://doi.org/10.1016/0277-5387(82)80008-9