An asymmetric synthesis of (-)-callyspongiolide is described. The route builds the macrolide domain atypically from a disaccharide and a monoterpene without passing through a seco-acid. Chiral iridium catalysis selectively joins fragments. Subsequent degradation of an imbedded butyrolactone via perhemiketal fragmentation affords a stereo- and regio-defined homoallylic alcohol that is engaged directly in a carbonylative macrolactonization. Further elaboration of the polyunsaturated appendage provides the natural product in a particularly direct and flexible manner.