Studies on Estetrol. I. Synthesis of 15α, 16α, 17β-Trihydroxy-androst-4-en-3-one

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In order to determine the precursor role of neutral steroids in the formation of estetrol in man the titled compound was prepared as a substrate by two different routes. First, 17,17-ethylenedioxy-5α-androst-15-ene-3β, 5-diol (I), readily available by the known method, was employed as a starting material. Transformation into the 15α, 16α-glycol structure was attained by osmium tetroxide oxidation toward the Δ^<15> double bond. Dehydration with thionyl chloride provided a mixture of the Δ^4 and Δ^5-3β, 15α, 16α, 17β-tetraols (V), which was in turn led to the 15,16-acetonide (VI). Oppenaner oxidation followed by removal of the dioxolane group afforded the Δ^4-3-ketosteroid (VIIIa). Alternatively, 3β, 5β-dihydroxyandrost-15-en-17-one ethylene ketal (XIV), derivable from dehydroepiandrosterone in several steps, was similarly converted into androst-4-ene-3β, 15α, 16α, 17β-tetraol (XXa). Selective oxidation of the hydroxylic group at C-3 with N-bromoacetamide provided the desired compound (VIIIa). The latter synthetic route has proved to be more favorable in respect to overall yield.
公益社団法人日本薬学会の論文
1973-11-25