Thioacetic acid Spironolactone

The search for compounds that had improved oral activity led initially to the 7a-thioacetyl derivative (51-2) [48]. Dehydrogenation of the enone function in (50-5) using the now-familiar quinone, chloranU, leads to the dienone (51-1). This undergoes 1,6 conjugate addition on treatment with the sodium salt from thioacetic acid to give the la derivative (51-2) this compound, under the name spironolactone, was the first clinical aldosterone antagonist. Studies on the metabolic disposition of... 

The much simpler steroid, 253, was fortuitously found to fulfill this role when injected into animals. Its lack of oral activity was overcome by incorporation of the 7a-thioacetate group. Reaction of the ethisterone intermediate, 77b, with a large excess of an organomagnesium halide leads to the corresponding acetylide salt carbonation with CO2 affords the carboxyllic acid, 251. This is then hydrogenated and the hydroxy acid cy-clized to the spirolactone. Oppenauer oxidation followed by treatment with chloranil affords the 4,6-dehydro-3-ketone (254). Conjugate addition of thiolacetic acid completes the synthesis of spironolactone (255), an orally active aldosterone antagonist. ... 

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