The synthesis of laidlomycin is described. With an established stereocontrolled synthetic route to the aldehyde 5, the known β-keto phosphonate 4 was coupled with 5 and the resulting enone was subjected to a sequential hydrogenolysis/hydrogenation and equilibration process to effect the correct spiroketalization for the natural product. The stereogenic carbons were elaborated by desymmetrization for C12, allylation for C13, vanadyl-induced epoxidation for C16, Zn(BH4)2 reduction for C17, a chiral building block for C18 and C24, Shi epoxidation for C20 and C21, Myers' alkylation for C22, and thermodynamic control for C25.