Control of Olefin Geometry in the Bryostatin B-Ring through Exploitation of a <i>C</i>₂-Symmetry Breaking Tactic and a Smith−Tietze Coupling Reaction

Abstract

A completely stereocontrolled asymmetric synthesis of an advanced B-ring synthon for the bryostatin family of antitumor agents is reported. Noteworthy features of our synthesis include the Smith−Tietze bis-alkylation reaction between 12 and 13 en route to C2-symmetrical ketone 10 and the totally stereoselective conversion of 10 into triol 18 via a Grignard addition tactic. Triol 18 was converted to epoxide 3 in nine steps, and an acid-catalyzed intramolecular Williamson etherification reaction completed the synthesis of 2.