1H ΝΜR chemical shift assignment, structure and conformational elucidation of hypericin with the use of DFT calculations - The challenge of accurate positions of labile hydrogens

Hypericin is one of the principal active constituents of Hypericium (Saint John's wort). We present in this paper: (i) chemical shift assignment of the neutral and ionic form of hypericin based on DFT 1H NMR calculations, and conflicting literature experimental OH 1H NMR chemical shifts are critically evaluated; (ii) investigation of the cooperative nature of intra- and intermolecular hydrogen bonding of the bay OH groups in the neutral form of hypericin in acetone and DMSO; (iii) demonstration of a very strong intramolecular hydrogen bonding of the deprotonated bay OH…O- moiety in DMSO and (iv) excellent linear correlation between experimental and computed 1H chemicals shifts for a variety of basis sets. Comparison of the literature X-ray structures with those obtained with DFT calculations clearly demonstrates the advantages of computation in investigating resonance assignments, ionization state, accurate labile hydrogen positions, and structural and conformational properties of natural products at an atomic level.

1H ΝΜR chemical shift assignment, determination of accurate labile hydrogen positions, beyond the limits of X-ray diffraction methods, and structure and conformational elucidation of hypericin with the use of DFT calculations has been achieved.