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 (+)-call-yspongiolide have been synthesized in a convergent and enantioselective manner. The 14-membered macrolide with a sensitive C2-C3 cis-olefin functionality was installed by a Yamaguchi macrolactonization of hydroxyl alkynoic acid followed by hydrogenation over Lindlar's catalyst. The CS methyl stereocenter was constructed by a ring-dosing olefin metathesis followed by addition of methyl cuprate to an alpha,beta-unsaturated delta-lactone. Other key reactions are chiral Corey-Bakshi Shibata (CBS) reduction and Sonogashira coupling to conjoin the macrocyclic core and side chain.