Total Synthesis of Laulimalide: Synthesis of the Northern and Southern Fragments

The first stage in the development of a synthetic route for the total synthesis of laulimalide ( 1 ) is described. Our retrosynthetic analysis envisioned a novel macrocyclization route to the natural product by using a Ru‐catalyzed alkene–alkyne coupling. This would be preceded by an esterification of the C19 hydroxyl group, joining together two equally sized synthons, the northern fragment 7 and the southern fragment 8 . Our first generation approach to the northern fragment entailed a key sequential Ru/Pd coupling sequence to assemble the dihydropyran. The key reactions proceeded smoothly, but the inability to achieve a key olefin migration led to the development of an alternative route based on an asymmetric dinuclear Zn‐catalyzed aldol reaction of a hydroxyl acylpyrrole. This key reaction led to the desired diol adduct 66 with excellent syn / anti selectivity (10:1), and allowed for the successful completion of the northern fragment 7 . The key step for the synthesis of the southern fragment was a chemoselective Rh‐catalyzed cycloisomerization reaction to form the dihydropyran ring from a diyne precursor. This reaction proved to be selective for the formation of a six‐membered ring, over a seven. The use of an electron‐deficient bidentate phosphine allowed for the reaction to proceed with a reduced catalyst loading.