The combination of synthesis and ultra-high-resolution NMR spectroscopy reveals the correct structure of caylobolide A

olyketide-derived natural products bearing repeat 1,5-polyols are commonly encountered but their structures are notoriously difficult to determine using spectroscopic techniques. The presence of distal 1,5-diol moieties frequently leads to spectral overlap and chemical shift degeneracy, giving rise to ambiguity in their assignment. Caylobolide A is a representative member of this class of natural products, bearing a 36-membered lactone, with six 1,5-diol units and two 1,3-diol units. Its partial structure had been proposed, but only 4 of the 12 stereogenic centres had been assigned. Here we report a blueprint for the structure determination of this class of natural products, comprising the use of ultra-high-resolution NMR spectroscopy, Mosher’s ester analysis and an efficient mixed isomer synthesis to unveil the correct structure of caylobolide A. With this approach, the partial stereochemistry proposed and the position of the triol unit within the carbon chain has been reassigned, culminating in the total synthesis of caylobolide A in 17 steps.