Synthesis of 1,10-seco-5α-estr-1-ynes: Potential mechanism-based inhibitors of 3α- and 3β-hydroxysteroid dehydrogenases

Oxido-reductase reactions mediated by 3α- and 3β-hydroxysteroid dehydrogenases alter the biological effects of steroid hormones. A novel and practical synthetic route from 19-nortestosterone 1 to (3R,S)-1,10-seco- 5α-estr-1-yne-3,17β-diol 13a and structurally related analogues has been developed so that the potential of these 1,10-secosteroids as mechanism-based inhibitors of 3α- and 3β-hydroxysteroid dehydrogenases can be evaluated. Following double-bond reduction and acetylation of steroid 1, the Δ²-enol tert-butyldimethylsilyl ether derivative 4 is formed with high regioselectivity, then cleaved by ozonolysis, reduced with NaBH₄, and methylated with CH₂N₂ to give 2,3-secosteroid 6. Carbons C¹ and C² are then sequentially removed to yield the (dodecahydro-1H-benz[e]inden-7-yl)acetic acid derivative 10. Partial reduction and deacetylation of compound 10 by DIBALH yields the (dodecahydro-1H-benz[e]inden-7-yl)acetaldehyde derivative 11. The addition of HC≡CMgBr, LiC≡CCl and LiC≡CCF₃ to aldehyde 11 yields 1,10-seco-5α-estr-1-yne 13a, and the chloro- and trifluoro-methylacetylenic analogues 13b and 13c, respectively. Selective oxidation by DDQ of 13a, and 13b, but not 13c, yields the corresponding 3-keto-1,10-secosteroids 14a and 14b.