Herein, the biogenesis of the hydrindane ring system within coronafacic acid (CFA) has been investigated. These studies reveal that in addition to the canonical polyketide chain elongation and functionalization encoded by type I polyketide synthase (PKSs), cascade reactions can take place during assembly line-like biosynthesis. Indeed, upon Cfa7-catalyzed Claisen condensation between enzyme-bound malonate and an N-acetylcysteamine (SNAC) thioester, latent reactivity within the elongated enzyme-bound intermediate is unveiled. This reactivity translates into an intramolecular cyclization, which can proceed in a facile manner as observed by the enzyme-independent cyclization of a linear beta-ketothioester intermediate.