One more nail in the coffin of the widely disputed Le Clair structure of hexacyclinol is provided by the B97-2/cc-pVTZ/B3LYP/6-31G(d,p) computed proton and 13C NMR for the two “structures” (see my previous blog post for structures and background). These computations1 are at a more rigorous level than those performed by Rychnovsky, and the addition of the proton spectrum helps clearly settle this issue. Rychnovsky’s structure is the correct one – the mean absolute error between the experimental and computed structure is half that for Rychnovsky structure. The computed coupling constants also are in much better agreement with the Rychnovsky structure. So, Bagno’s contribution accomplishes, I hope, two things: (1) convinces everyone that DFT NMR spectra can be an important tool in identifying natural product structure and (2) closes the book on hexacylinol!
References
(1) Saielli, G.; Bagno, A., "Can Two Molecules Have the Same NMR Spectrum? Hexacyclinol Revisited," Org. Lett. 2009, 11, 1409-1412, DOI: 10.1021/ol900164a.
Henry Rzepa responded on 01 Apr 2009 at 1:42 am #
Steve makes the point that DFT-based simulation of NMR spectra is a sine qua non of modern practice in organic chemistry. We too were inspired by the Hexacyclinol saga, a direct consequence of which is the introduction of a computational lab into our own chemistry curriculum to do just this last year. Thus here one can see our script for doing this, although there are some interesting minor differences between our protocol and that of Bagno (they claim solvation effects are negligible, but we found perturbations of up to 4 ppm in 13C predictions, and prefer to include a solvation correction by default; see http://dx.doi.org/10.1021/np0705918, in which we also reanalyse Hexacyclinol, with much the same conclusion as Bagno). We have our own students scour the literature for reports of compounds with more than one structural outcome, and have them compute the NMR spectra for all these outcomes and compare them with the actual reported spectra. Thus far, around 30 reports have been analyzed by the students, although thus far, no clear cut anomalies have in fact emerged. What is certainly true is that the NMR simulations do a much better job at assigning the peaks in spectra than the guesswork that is often reported in the literature.