Synthesis of the Death-Cap Mushroom Toxin α‑Amanitin

α-Amanitin is an extremely
toxic bicyclic octapeptide isolated
from the death-cap mushroom, Amanita phalloides.
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, A. phalloides 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 (2S,3R,4R)-4,5-dihydroxy-isoleucine,
and diastereo­selective sulfoxidation.