A Simple NMR-Based Rule for Stereochemical Assignment of 1,5-Diols in Polyketides

Polyketide natural products are a valuable source of inspiration for therapeutic lead compounds, but their diversity and complexity make structure elucidation highly challenging. Here, we report a comprehensive analysis of the relative stereochemical assignment of 1,5-diol moieties in polyketides – a very common but challenging structural element to elucidate. We have found that the chemical shift difference (Δδ_HaHb) between the diastereotopic central methylene protons is >0.17 ppm for syn isomers and <0.13 for anti isomers. This simple rule has been shown to correctly predict the relative 1,5-diol stereochemistries in over 40 natural products, except those cases where the flanking substituents have a large steric difference (tertiary vs primary alkyl) or are constrained within conformationally restricted rings. These resulting Δδ_HaHb rules have then been used to predict the relative configuration of several previously unassigned natural products, enabling facile, non-destructive structure elucidation.