The first total synthesis of the marine natural product (-)-clavosolide D is described confirming the structure of the unsymmetrical 16-membered diolide glycosylated by permethylated d-xylose moieties. Following efficient assembly of the two tetrahydropyrans using stereoselective Prins cyclizations, the side chains were introduced via an allylation/isomerization/anti cyclopropanation sequence; the final macrolactonization step was achieved under Yamaguchi conditions.