Synthesis of an (±)-Estrone Precursor: The Scope of Zr- and Co-Mediated Cycloannulations

The synthesis of an estrone intermediate based on a new approach was studied. The construction of the basic framework was carried out in three steps from a simple styrene derivative. The crucial reaction sequence for the steroid skeleton construction relied on a Zr-mediated cyclization (Zr-ene reaction)/propargylation followed by a Co-mediated diastereoselective Pauson-Khand reaction that afforded various D-ring-substituted tetracyclic ketones 11 with natural trans-anti stereochemistry. The conjugated addition reaction of Me2Cu-Li to tetracyclic ketone 11a aiming at the installation of the angular methyl group in the 13-position gave rise exclusively to product 12 with unnatural trans-anti-cis stereochemistry The successful synthesis of known estrone intermediate 4 with natural trans-anti-trans stereochemistry was accomplished by chemoselective reduction of the carbonyl group of ketone 11b. Attempts to use other metallo-ene reactions to affect the synthesis of steroid B-ring are also described.