Alkyne metathesis is increasingly explored as a reliable method to close macrocyclic rings, but there are no prior examples of an alkyne‐metathesis‐based homodimerization approach to natural products. In this approach to the cytotoxic C2‐symmetric marine‐derived bis(lactone) disorazole C1, a highly convergent, modular strategy is employed featuring cyclization through an ambitious one‐pot alkyne cross‐metathesis/ring‐closing metathesis self‐assembly process. Heads or tails? The self‐assembly of disorazole C1, a cytotoxic bis(lactone) natural product, has been achieved through alkyne cross‐metathesis and ring‐closing alkyne metathesis. The coupling favored the production of the desired head‐to‐tail dimer over its head‐to‐head counterpart with a ratio of 5:1.