A Short, Stereoselective Route to 16α-(Substituted-alkyl)estradiol Derivatives

A variety of 16α-substituted 17β-estradiol derivatives can be prepared by a convenient two-step procedure: The lithium enolate of estrone 3-0-benzyl or 3-O-tert-butyldimethylsilyl ether undergoes clean, stereospecific alkylation with a variety of allylic, benzylic, or propargylic bromides (some bearing additional functionality) to furnish the 16α-substituted estrone ethers. Even with relatively bulky 16α-substituents, reduction of the C-17 ketone with lithium aluminum hydride proceeds with very high stereoselectivity to give the 16α-substituted 170-estradiol 3-O-ethers. This sequence provides ready access to a wide variety of 16α-functionalized estradiol derivatives.