Total Synthesis of Leupyrrins A and B , Highly Potent Antifungal Agents from the Myxobacterium Sorangium cellulosum.

Full details on the design, elaboration, and application of efficient strategies for the high-yielding total syntheses of leupyrrins A and B , unique antifungal agents from the myxobacterium Sorangium cellulosum, are reported. A sequential zirconocene-mediated diyne-cyclization, and regioselective opening of the zirconacyclopentadiene intermediate enabled a concise entry into the unique dihydrofuran fragment, whereas another domino reaction was developed for the butyrolactone involving a one-pot lactol opening, stereoselective aldehyde addition and in situ lactonization. Furthermore, an innovative sp -sp -cross-coupling for pyrrole functionalization and an optimized HATU-mediated amide coupling protocol of two elaborate fragments were established.

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 sp(2)-sp(3) Suzuki coupling and a high-yielding Shiina macrolactonization.

Stereoselective synthesis of the butyrolactone and the oxazoline/furan fragment of leupyrrin A(1).

Stereoselective syntheses of the Northern and the Southern fragments 2 and 3 of leupyrrin A1 are reported. The convergent preparation of 2 is highlighted by a zirconocene-mediated one-pot cyclization-regioselective opening of an advanced diyne while the route to 3 involves a Krische allylation and a one-pot Sharpless dihydroxylation-cyclization. Comparison of the spectroscopic data with those reported for the natural product supports a relative stereochemical assignment within these heterocycles.

Highly regioselective opening of zirconacyclopentadienes by remote coordination: concise synthesis of the furan core of the leupyrrins.

An efficient protocol for the highly regioselective opening of aliphatic zirconacyclopentadienes is reported. The one-pot process involves a zirconocene-mediated cyclization of 1,6-diynes and highly selective cleavage of the metallacycles with NBS and enables a concise synthesis of the tetrahydrofuran-core of the leupyrrins.