An efficient stereocontrolled synthesis of apoptolidinone A, the aglycone of apoptolidin A is described. The synthetic strategy relies on a cross coupling between C11/C12 of a northern half (C1-C11) and a southern part (C12-C28) followed by a ring-size selective macrolactonization. Key steps for the introduction of the southern half stereocenters are a stereoselective aldol reaction, a substrate controlled dihydroxylation and a chelation-controlled Grignard/aldehyde addition. The conjugated triene of the northern half was built up successively by E-selective Wittig reactions. L-Malic acid was chosen as the chiral pool source for the C8/C9 stereocenters. The final cleavage of the silyl ethers and the conversion of the C21 methyl ketal into the hemiketal was achieved by HF.pyridine.