Enantioselective Synthesis of Both Epimers at C‑21 in the Proposed Structure of Cytotoxic Macrolide Callyspongiolide

Both epimers at C-21 in the proposed structure of (+)-callyspongiolide have been synthesized in a convergent and enantioselective manner. The 14-membered macrolide with a sensitive C2–C3 <i>cis</i>-olefin functionality was installed by a Yamaguchi macrolactonization of hydroxyl alkynoic acid followed by hydrogenation over Lindlar’s catalyst. The C5 methyl stereocenter was constructed by a ring-closing olefin metathesis followed by addition of methyl cuprate to an α,β-unsaturated δ-lactone. Other key reactions are chiral Corey–Bakshi–Shibata (CBS) reduction and Sonogashira coupling to conjoin the macrocyclic core and side chain