The cyanobacterial isolate largazole embodies a compelling combination
of a relatively simple, yet unique cyclic depsipeptide structure
with remarkable levels of selective cytotoxicity against cancer
cell lines versus nontransformed cells. The unique structure of
largazole inspired a strategically novel and aggressive approach
towards its expedient total synthesis. This involved an initial
dissection into an epoxy aldehyde and an unprotected tetrapeptide,
representing the polyketide and polypeptide domains of largazole,
respectively. These fragments were successfully joined using NHC-mediated
amidation, but subsequent assembly of the cyclic depsipeptide via
lactonization was thwarted. A reordering of key couplings led to
a successful assembly of largazole.
total synthesis - heterocycles - depsipeptide - N-heterocyclic carbene - thiazoline
