Asymmetric Tandem Claisen-Ene Strategy for Convergent Synthesis of (+)-9(11)-Dehydroestrone Methyl Ether : Stereochemical Studies on the Ene Cyclization and Cyclic Enol Ether Claisen Rearrangement for steroid Total Synthesis

K. Mikami, K. Takahashi, T. Nakai, and T. Uchimaru
[Journal of the American Chemical Society, pp. 116, 1994]

An asymmetric synthesis of (+)-9(11)-dehydroestrone methyl ether, a key intermediate for estrogen analogs, has been carried out using a new strategy of consecutive carbocyclizations for D and C rings of steroid skeleton based on an asymmetric tandem Claisen-ene sequence. Studies of the stereochemical features of the cyclic enol ether Claisen rearrangement and intramolecular ene reaction are also reported. In the model study of the ene cyclizations, high trans diastereofacial selectivity is found for the a-alkylcrotyl and a,b-dialkylcrotyl ether systems with a methoxycarbonyl group at the acetylenic terminus, which remarkably facilitates the ene cyclization. Computanional studies support the trans diastereofacial selectivity in these ene reactions (Figure). The Cliasen rearrangements of the enol ethers of cyclic ketones were found to exhibit a high level either anti or syn diastereoselectivity along with high E olefinic stereoselectivity by making judicious use of either 2,6-dimethylphenol or PdCl₂(RCN) as the catalyst.