B.R.S.M. Yield isn't everything


And Another Thing…

While the recently misassigned structure of a certain binaphthyl compound has raised eyebrows here, and over at In The Pipeline, eliciting an entirely appropriate response from Chemjobber, I was reminded of an even sillier case of mistaken identity that was highlighted last year, but seems to have escaped comment on the blogosphere. The problem started back in 2007 when a paper was published in the Journal of Natural Products, where the authors claimed to have isolated a most improbable natural product from a fungus:

From J. Nat. Prod., 2007, 70, 989

Amazingly, nobody called bullshit on this until April 2011 despite the fact the paper was cited 32 times during that period. I mean, I still remember seeing the paper that blew away this structure, entitled "Is 2,3,4,5-Tetramethoxybenzoyl Chloride a Natural Product?", and just staring in wonder that such a question could be seriously posed in an ACS journal. Surely no one ever believed that is was?

The isolation paper is remarkable in a number of ways. Given that it proposed the first acid chloride-containing natural product ever isolated, the result of a truly remarkable feat of biosynthesis in the invariably aqueous media of cells, no comment was made about the uniqueness of the proposed structure. Nor the fact that an acid chloride had been isolated from the methanol extract of the sample material, after column chromatography in methanol. Even 2,4,6-tri-tert-butylbenzoylchloride wouldn't stand up to that abuse, if the literature is to be believed. It turns out that at the time of isolation, data for the compound itself hadn't been reported. So what did the group do? Obtain a sample of the corresponding acid and.... compare the data to that instead! Apparently, the data show that they are 'closely related'.

Why didn't the authors (or reviewers!) realise that such an exceptional claim requires exceptional evidence? I guess the authors didn't appreciate what an outlandish proposal they were making, or they'd surely have begged, borrowed or stolen some thionyl chloride to test their hypothesis. Hell, they're from China, land of outsourcing, and probably could have ordered a kilo of the stuff for a few dollars.[1]  I find the fact that people like this can run academic groups and publish such crap in peer-reviewed journals a little disturbing.

A rather punchy graphical abstract from J. Nat. Prod. 2011, 74, 1348

Fast forward 4 years, and the Piggott group finally did the experiment that the original authors should have - making the damn thing - and perhaps unsurprisingly, the data didn't match. A look at the original report, which on the surface appeared fairly comprehensive, revealed some alarming discrepancies:

"The structural elucidation of the natural product by Chen et al. was based upon detailed spectroscopic studies, including 2D NMR experiments, low- and high-resolution mass spectra, and the product of methanolysis. While the spectroscopic data could not be faulted at face value (in the absence of authentic material), close examination of the other evidence revealed several anomalies. Most immediately obvious wasthe absence of the 37Cl isotope peaks from the low-resolution electron impact ionization mass spectral data. Furthermore,the molecular ion (containing 35Cl) was the base peak, and there was no [M - Cl]+ fragment at m/z 225. The [M - Cl]+ fragment gives rise to the base peak in the mass spectra of o-,m-, and p-anisoyl chloride, 2,6-, 3,4-, and 3,5-dimethoxybenzoyl chloride, and all produce molecular ions of relatively low abundance (26% at most, but generally less than 10%). Thus,on the basis of the mass spectrum alone, it seemed highly unlikely that the natural product was an acid chloride."

A comparison of some more data is given, and few new structures that might be consistent with the reported data are proposed and then refuted. As far as I can tell, there's no mention of contacting the original authors and ultimately it is concluded that the structure of the natural product has to remain unknown for the time being.

Does anyone know of any other egregiously misassigned natural products from recent years?


1. They did report a methanolysis product, resulting from standing the putative acid chloride in 1:1 methanol-pyridine at room temperature for 10 hours. What's really silly is that methyl 2,3,4,5-tetramethoxybenzoate was a well characterised, known natural product at the time of isolation. Although the isolation guys never bothered to compare the data with that already known, it may not surprise you to learn that they don't match. So they also misassigned a known compound. Excellent.

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  1. There are so many examples of misassigned natural products from recent years. Using Computer Assisted Structure Elucidation Approaches we have generated MANY examples. We reported on many of them here “Elyashberg, M.; Williams, A. J.; Blinov, K. (2010). “Structural revisions of natural products by Computer-Assisted Structure Elucidation (CASE) systems”. Natural Product Reports 27 (9): 1296–1328. doi:10.1039/C002332a”

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