The Penicillium metabolite thiocarboxylic A (1a) and three close analogues were synthesized in 14 steps. The stereogenic elements were installed via stereoselective Sharpless epoxidation, (E)-selective reduction of a dibromide, and a Suzuki cross coupling. Thiocarboxylic A (1a) was obtained in 6% overall yield. The synthetic product and the natural isolate differed markedly in their specific rotations and antibiotic activities against Escherichia coli and Staphylococcus aureus. This modular synthetic route should be flexible enough to allow the synthesis of other natural and non-natural 3-methoxycarbonyldihydrofuran-4-ones for biological studies.