The first total synthesis of (29S,37S)-malevamide E (1), a potent ion channel inhibitor, has been achieved in a convergent fashion involving Julia–Kocienski olefination, Urpi acetal aldol and Shiina macrolactonization reactions as the key steps. The strategy developed herein is amenable for the synthesis of the other possible isomers in search for the correct stereoisomer of the naturally occurring molecule.