Aromatic polyketides are all biosynthesized from highly reactive poly-beta-ketone intermediates. Keys to introducing the vast chemical diversity seen in these natural products are the enzymatic and non-enzymatic tailoring chemistries that occur after biosynthesis of the poly-beta-keto backbone. In this work, we expand the scope of non-enzyme-catalyzed modifications and show that primary amides can act in vivo as an electrophilic center and be attacked by an intramolecular phenol to generate dibenzopyrones. Synthetic reaction sequences were developed to confirm that the displacement can take place under neutral, low temperature aqueous conditions. We demonstrate this tailoring reaction can be rationally introduced into an engineered biosynthetic pathway to produce new compounds. This mechanism is of particular note since it demonstrates the use of a "protecting group" in polyketide biosynthesis and may be the route by which pyrones are formed in other aromatic polyketide natural products.