Small changes, big effect: A new aureothin derivative, aureopyran, which features an unusual pyran backbone, was generated by simply altering the enzymatic methylation topology. The α-pyrone ring hampers the correct placement of the polyketide backbone in the multifunctional cytochrome P450 monooxygenase AurH. Instead of a tetrahydrofuran ring, an oxo intermediate is formed that readily undergoes a rare electrocyclization reaction.