Ether–Diol\nAmbiguity: An Inconspicuous Issue\nin the Structure Elucidation of Oxygenated Natural Products

Tertiary and allylic hydroxyl groups readily eliminate\nwater during\npositive ion mode mass spectrometry and may show similar NMR spectra\nto their corresponding ethers. In a routine structure elucidation\nworkflow, these factors can cause researchers to incorrectly assign\ndiol moieties as ethers or vice versa, leading to inaccurate chemical\nstructures. After facing this problem during our work on oxygenated\nsesquiterpenoids from a <i>Fusarium</i> sp. fungal strain,\nwe became aware of this challenging issue. We examined the literature\nfor oxygenated natural products bearing these functional groups, and\nwith the aid of density functional calculations of NMR chemical shifts,\nwe now report the structures of 15 natural products that should be\nrevised. We further establish that derivatizing sub-micromolar amounts\nof alcohols to their sulfates can be used to distinguish these from\ntheir corresponding ethers using liquid chromatography negative ion\nmode mass spectrometry. Finally, we isolated lignoren/cyclonerodiol\nfrom the <i>Fusarium</i> sp. culture extract and supported\nits revised identity as cyclonerodiol using this sulfation approach.\nOur results suggest that ether–diol ambiguity could be a prevalent\nissue affecting the structure elucidation of oxygenated natural products\nand highlight the importance of using complementary techniques, such\nas sulfation with LC-(−)-ESI-MS or density functional calculations\nof NMR chemical shifts.