Enantioselective Total Synthesis of the Marine Macrolides Salarins A and C

Here we report the first total synthesis of the marine
macrolide
salarin C, a potent anticancer agent, and demonstrate the biomimetic
oxidation–Wasserman rearrangement to access salarin A. This
synthesis relies on L-proline catalysis to install a chlorohydrin
function that masks the sensitive C16–C17 epoxide and potentially
mimics the biosynthesis of these compounds where a related chlorohydrin
may yield both THF- and epoxide-containing salarins. Additional and
key features of the synthesis include (i) macrocycle formation via
ring-closing metathesis, (ii) macrocyclic substrate-controlled epoxidation
of the C12–C13 allylic alcohol, and (iii) a late-stage Julia–Kocienski
olefination to install the side chain. Importantly, this work provides
a platform for the synthesis of other salarins and analogues of these
potentially important anticancer natural products.