Total Synthesis of (-)-Zampanolide and Questionable Existence of (-)-Dactylolide as the Elusive Biosynthetic Precursor of (-)-Zampanolide in an Okinawan Sponge

A new and concise total synthesis of (-)-zampanolide, (-)-1, and (-)-dactylolide, (-)-2, is described. Synthetic highlights include (1) a mild Horner-Wadsworth-Emmons reaction providing the seco acid, (ii) an unusual stepwise cross-coupling reaction of a 1,1-dibromodiene with inversion of olefin geometry, and (iii) specific O-Michael reaction conditions using catalytic LHMDS with TMEDA for the synthesis of functionalized 2,6-cis-tetrahydropyran. A marine sponge extract was analyzed for the presence of (-)-2 as the biosynthetic precursor of (-)-zampanolide.