Total Synthesis of\n(+)-Mannolide B

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