Synthesis of the Death-Cap Mushroom Toxin α‑Amanitin

α-Amanitin is an extremely toxic bicyclic octapeptide isolated from the death-cap mushroom, <i>Amanita phalloides</i>. As a potent inhibitor of RNA polymerase II, α-amanitin is toxic to eukaryotic cells. Recent interest in α-amanitin arises from its promise as a payload for antibody–drug conjugates. For over 60 years, <i>A. phalloides</i> has been the only source of α-amanitin. Here we report a synthesis of α-amanitin, which surmounts the key challenges for installing the 6-hydroxy-trypta­thionine sulfoxide bridge, enantio­selective synthesis of (2<i>S</i>,3<i>R</i>,4<i>R</i>)-4,5-dihydroxy-isoleucine, and diastereo­selective sulfoxidation