Synthesis and absolute stereochemical assignment of (+)-miyakolide

The first total synthesis of the marine macrolide miyakolide has been achie ved, and its absolute stereochemistry has been determined. The carbon skele ton is assembled in a convergent fashion from three fragments via esterific ation, [3 + 2] dipolar cycloaddition, and aldol addition. The utility of be ta-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 aldo l reaction followed by hemiketalization to form the oxydecalin ring system of the natural product. Deprotection afforded ent-miyakolide, which was pro duced in 6.8% overall yield and 29 linear steps.