Stereochemical Determination of the Leupyrrins and Total Synthesis of Leupyrrin A₁

The stereochemical determination of the potent antifungal agents leupyrrin A₁ and B₁ and the total synthesis of leupyrrin A₁ are reported. The relative and absolute configuration was determined by a combination of high field NMR studies, molecular modeling, and chemical derivatization. The expedient total synthesis involves a one-pot sequential Zr-mediated oxidative diyne-cyclization/regioselective opening sequence for preparation of the unique dihydrofuran ring, a highly stereoselective one-pot approach to the butyrolactone, a challenging sp²–sp³ Suzuki coupling and a high-yielding Shiina macrolactonization.