The transannular [6 + 4] cydoaddition proposed as a step in the biosynthesis of heronamide A has been modeled using density functional theory. The proposed cydoaddition is highly stereoselective, affording a single product. The reaction proceeds through an ambimodal transition state that directly leads to a [4 + 2] adduct in addition to the observed [6 + 4] adduct. Interconversion of these adducts is possible via a facile Cope rearrangement. The [6 + 4] adduct is thermodynamically more stable than the [4 + 2] adduct by 5.2 kcal mol(-1) due to a combination of the ring and steric strain in the [4 + 2] product. The results strongly support the plausibility of the proposed transannular [6 + 4] cydoaddition in the biogenesis of heronamide A and may provide insights to designing substrates that selectively undergo [6 + 4] cydoaddition to form unbridged 10-membered rings.