Goniodenin is a lipophilic polyketide originating from plant sources and which possesses a potent cytotoxic activity against cancer cell lines. The first total synthesis of (+)-goniodenin has been achieved in 23 steps from (R)-glycidol. The synthetic sequence featured a cross metathesis for the formation of the C8-C9 bond and installation of the terminal γ-butenolactone ring unit by the alkylation of α-phenylthio-γ-butyrolactone with the corresponding C3-O-triflate. The stereogenic center at C18 carbon was created by Hiyama-Fujita reduction of the corresponding ketone with high diastereoselectivity.