Synthesis and Bioactivity of Thiocarboxylic A and Derivatives.

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.