Synthesis and absolute stereochemical assignment of (+)-miyakolide

The first total synthesis of the marine macrolide miyakolide has been achieved, and its absolute stereochemistry has been determined. The carbon skeleton is assembled in a convergent fashion from three fragments via esterification, [3 + 2] dipolar cycloaddition, and aldol addition. The utility of beta-ketoimide aldol reactions in fragment coupling was demonstrated on fully elaborated intermediates. The coupled material was transformed into a 1,3,7-triketone-containing macrocycle that underwent a facile transannular aldol reaction followed by hemiketalization to form the oxydecalin ring system of the natural product. Deprotection afforded ent-miyakolide, which was produced in 6.8% overall yield and 29 linear steps.