The first total synthesis of the bacterial RNA-polymerase inhibitor ripostatin A (1) was achieved. The route utilizes a cyclic methyl acetal intermediate and a sequence of a double Stille cross-coupling reaction followed by a ring-closing metathesis for the construction of the macrolactone ring. Additionally, an unprecedented formation of the 4-methoxy substituted tetrahydropyrans was observed during the acid catalyzed acetalization of the β,δ-dihydroxyketone.