Estradiol methyl Estrone

A McMurry coupling of (176, X = O Y = /5H) provides ( )-9,ll-dehydroesterone methyl ether [1670-49-1] (177) in 56% yield. 9,11-Dehydroestrone methyl ether (177) can be converted to estrone methyl ether by stereoselective reduction of the C —double bond with triethyi silane in triduoroacetic acid. In turn, estrone methyl ether can be converted to estradiol methyl ether by sodium borohydride reduction of the C17 ketone (199,200). 

Clinical trials of these orally active progestins showed that they were effective as contraceptives with a success rate that exceeded 99%. These compounds were then marketed as obtained from the reaction sequence after appropriate purification. As the analytical methodology improved it became apparent that a small amount of an impurity was present in all active samples. An examination of the reaction scheme allowed ready identification of that by-product. Any unreduced estradiol methyl ether (13-1) will go to estrone methyl ether on oxidation this will then afford the potent orally active estrogen mestranol (9-1) on ethynylation. Subsequent... 

The oxidation of phenols via HAT from the hydroxyl group (or sequential electron transfer and deprotonation) is supported by data on the oxidation of estradiol and estrone. In accord with a key role for the phenolic hydroxyl group, the predominant ortAo-hydroxylation of estradiol does not occur when the phenolic hydroxyl is replaced by a methyl ether . Early experiments established that 2-hydroxylation of estradiol occurs without a detectable NIH shift . More recent work has shown that, whereas estrone is converted to both 2- and 4-hydroxyestrone by CYP3A4, conjugation of an additional aromatic ring, as in equilenin and 2-naphthol, leads exclusively to 4-hydroxylation of estrone and 1-hydrox-ylation of 2-naphthol. In both these reactions, the site that is exclusively hydroxylated is that expected to carry the greatest share of the unpaired electron density if the initial step is... 

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