Reaction of thiol nucleophiles with 1,2-epoxy- and 4,5-epoxy-estrene-3-one-17β-ols

Four ring A steroidal epoxyenones as probable intermediate in the formation of catechol estrogens were synthesized. The isometric 1α,2α-epoxy-17β-hydroxyestr-4-en-3-one (9) and 1β,2β-epoxy-17β-hydroxyestr-4-en-3-one (8) were synthesized from 17β-hydroxy-5α-estra-3-one. The isometric 4α,5α-epoxy-17β-hydroxyestr-1-en-3-one (11) and 4β,5β-epoxy-17β-hydroxyestr-1-en-3-one (10) were prepared from 19-nortestosterone. The reaction of 9 and 10 with sodium/ethanethiol resulted in the formation of three types of reactions leading to multiple products: 1,4-addition, opening of epoxide, and epoxide opening followed by dehydration. Reaction of 8 with ethanethiol gave only one compound identified as 2-ethanethio-1,4-estradien-17β-ol-3-one, while reaction of 9 with ethanethiol gave an unusual product identified as 4-estren-1α,17β-diol-3-one. Unlike reaction of ethanethiol with 9 and 10, reaction with N-acetylecysteine or glutathione results in epoxide opening followed by dehydration leading to the formation of estradiol-4-thioethers.