The synthesis of the macrocyclic core of the cytotoxic natural product salarin C from the sponge Fascaplysinopsis sp. is described, with the two epoxides being replaced by alkene moieties. In the key step, ring-closing metathesis exclusively afforded the ( E)-product. NOESY-based conformational analysis of the macrolactone showed that the oxazole ring and its unsaturated side chains are located in a common plane. Mimicking the conversion of salarin C to salarin A, the trisubstituted oxazole unit embedded in the 17-membered ring underwent photooxidation on treatment with singlet oxygen, affording macrocyclic trisacylamines.