Formal total synthesis of (±)-estrone and zirconocene-promoted cyclization of 2-fluoro-1,7-octadienes and Ru-catalyzed ring closing metathesis

A new and diastereoselective method for the synthesis of the estrone skeleton from a substituted styrene based on sequential 3-fold use of Cp2ZrBu2 (Oxidative addition - alkylation and two cyclization-alkylation sequences) and a ruthenium complex catalyzed RC-metathesis of a sterically hindered diene was developed. The prepared estratetraene was obtained in 7 steps from a commercially available starting material and thus the overall synthesis of estrone could be accomplished in 9 steps. Moreover, we have also found that the course of the reaction of substrates bearing the 2-halo-1,7-diene moiety with CP2ZrBu2, i.e., cyclization or oxidative addition to the C-X bond, could be controlled by the nature of the halogen leaving group.