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

Abstract 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.