I’m sure life as an isolation chemist is hard. First of all, you have to actually find a source of interesting molecules, and while this sometimes involves diving in spectacular locations, or trekking through unspoiled rainforest to pick rare fruit, I’m sure it more often involves literally HPLCing shit or eviscerating four tons of eels. Furthermore, when you’ve actually got the compound, that’s only half the battle, as Nature is unbelievably creative at devising unique and surprising architectures to baffle the unwary. Synthetic chemists spend large amounts of time bewildered by NMR, and we get some pretty big clues from what we actually put in the flask to start with. Starting from scratch is even harder, even with the modern array of analytical equipment. Even the gold standard technique of X-ray crystallography isn’t perfect, and there have been some very famous natural products misassigned even with the aid of this breathtakingly powerful tool, including competition molecule diazonamide A, and kinamycin C. Having said all that, looking at this recent example of a proposed natural product structure that was revised by synthesis, I have to say that I think I could have done a better job myself. Drunk.
Seriously? For starters, the structure on the left has a chemical formula of C22H18O6, which the authors somehow acquired incorrectly from HRMS data, whereas the one on the right has the formula C13H8Br4O3, with a highly uncommon splitting pattern thanks to its four bromine atoms, and is a known compound, having already been isolated from similar organisms twenty one years ago. After Kozlowski and Podlesny synthesised the original structure and noticed a few discrepancies with the reported data they did what synthetic chemists usually do in such circumstances – contact the isolation chemists. Fortunately, both the spectra used to assign the structure and a sample of the natural product itself were both available, which is better than one can usually hope for in such circumstances. Then, in a surprising turn of events they found that
‘after an analysis of the original spectroscopic data, it also appears that there are 13 peaks in the 13C NMR spectrum rather than the 11 published. These two extra peaks are very closely associated with peaks at 117.4 and 150.4 ppm’
Huh? That’s a bit odd, isn’t it? It seems they were a bit careless with proton NMR, too:
‘On the other hand, the 1H NMR data for the reported natural product (Table 1) are missing both phenol peaks and lack any of the expected splitting patterns. Analysis of the original spectrum indicates that it was obtained at high concentration, which could account for the observed broad peaks and the missing phenol signals. ‘
I can’t believe no eyebrows were raised by the supervisor and reviewers when every single aromatic CH was reported as a singlet! Yes, ortho-couplings on naphthalenes are smaller, but still pretty commonly observable! Fortunately, solving the puzzle proved easy, as once Kozlowski and co-workers obtained the correct molecular formula (by HRMS) then a literature search turned up a tetrabrominated phenyl ether with a matching formula. The data matched, and thus it transpired that all they had was a sample of a known natural product, and the binaphthyl system that drew their attention was just a figment of someone's imagination.I feel particularly bad for the student who put all the effort into synthesising a single atropisomer of the reported structure, when it was assigned so carelessly!
- In the first case, oxygen and nitrogen were confused, and in the second a diazofluorene was misassigned as an N-cyanocarbazole. Nicolaou and Snyder reviewed a bunch of examples of Molecules That Were Never There in angewandte a few years back, and you can grab the paper for free off Snyder’s website here. In a bizarre coincidence, while researching the Yonemitsu oxidation this morning, I accidently found this presentation that gives good background on the reassignment of diazonamide a.
- Yes, really. The isolation guys report an optical rotation, which given the true structure, seems surprising to me. See the paper for details of the asymmetric biaryl coupling used.