Nucleophilic vinylic “addition-elimination” substitution reaction of 3β-acetoxy-17-chloro-16-formylandrosta-5,16-diene: A novel and general route to 17-substituted steroids. Part 1 - synthesis of novel 17-azolyl-Δ16 steroids; inhibitors of 17α-hydroxylase

We have discovered that chlorine in 3β-acetoxy-17-chloro-16-formylandrosta-5,16-diene (1) can be smoothly displaced by nitrogen heterocyclic nucleophiles (het−) to give heretofore unknown 17-substituted-Δ16 steroids in high yields (73–92%). This enabled us to synthesize novel 3β-hydroxy-17-(1H-1,2,4-triazol-1-yl)androsta-5,16-diene (4) and 3β-hydroxy-17-(1H-imidazol-1-yl)androsta-5,16-diene (7), both of which are potent inhibitors of rat testicular 17α-lyase. Spectroscopic studies with a modified form of human 17α-lyase indicates that the inhibition process involves coordination of steroidal azole nitrogen to the heme-iron of the enzyme.