Total Synthesis of (+)-Mannolide B.

(+)-Mannolide B possesses an intriguing and complex 5/7/5/6/6/6-fused hexacyclic scaffold including two bridged-lactone moieties and nine contiguous stereocenters, and thus represents a formidable challenge for total synthesis. Herein, the evolution of a successful strategy for the synthesis of mannolide B is described. The 7/5 ring system of the 7/5/6/6 tetracyclic carbon skeleton was efficiently constructed by a ring-closing metathesis starting from commercially available (-)-methyl jasmonate. Attempts to access the 6/6 ring system were unexpectedly challenging. Initially, an intramolecular Diels-Alder reaction was designed; however, the desired cyclization precursor could not be obtained. Furthermore, a radical cascade cyclization was investigated and produced only one six-membered ring with poor stereoselectivity at C5. Finally, the 6/6 ring system was successfully generated through a Pauson-Khand reaction, followed by a highly regioselective Büchner-Curtius-Schlotterbeck reaction, enabling us to achieve the first total synthesis of (+)-mannolide B in 24 steps.