Stereospecific synthesis of 16.alpha.-hydroxy-17-oxo steroids by controlled alkaline hydrolysis of corresponding 16-bromo-17-ketones and its reaction mechanism

Abstract

Synthesis of 16a-hydroxy-17-oxo steroids 3, 5b, and 6b and 3/3,16a-dihydroxy-5-17-oxoandrosten-3-yl sulfate (7) from 16a-bromo-17-oxo steroids 1,5a, and 6a and the reaction mechanism of the controlled alkaline hydrolysis are described. Treatment of the bromo ketones with NaOH in aqueous DMF gave the 16a-hydroxy 17-ketones stereoselectively in 95% yield without formation of other ketols. The sodium salt of 3-sulfate 7 was also obtained in one step in 85% yield from the corresponding bromo ketone (la). Isotope-labeling experiments and time-course studies showed that equilibration between the 16-bromo epimers 1 and 2 precedes the formation of 3, in which the true intermediate is 2 and not 1, and that the ketol 3 is formed by the direct SN2 displacement of the 16/3-bromine. The 16d-morpholino derivative 8 obtained by reaction of 1 with morpholine was shown to be an isomerized product of the 16a isomer which is produced also by SN2 displacement of the 16/3-bromine. The mechanism of ketol rearrangement of 3 to the 17/3-hydroxy-16-oxo compound 4 was found to involve a hydration to the carbonyl function. The new hydration-dehydration mechanism is proposed for the ketol rearrangement.

Synthesis of Demissidine by a Ring Fragmentation 1,3-Dipolar Cycloaddition Approach

“…Our synthetic route started from epiandrosterone ( 6 ), which was converted into α-hydroxy ketone 7 (Scheme 2) by a modification of the procedure reported by Numazawa and Nagaoka 14 for the conversion of epiandrosterone to 16-hydroxy epiandrosterone. This sequence involved a CuBr 2 mediated bromination α to the ketone followed by protection of the secondary alcohol as the tert -butyldiphenylsilyl ether and subsequent displacement of bromide with hydroxide to provide alcohol 7 .…”

Anti-Adenovirus Activity of Epiandrosterone and Dehydroepiandrosterone Derivatives

“…Briefly, bromination of the acetal E8 with pyridinium bromide perbromide in tetrahydrofuran provided the 16 ␣ -bromo acetal (16 ␣ -bromo-17,17-ethylenedioxy-5 ␣ -androstan-3 ␤ -yl acetate) with a 84% yield [28] , and followed by deacetylation with KOH diluted in methanol-toluene water (5: 1:1) resulting in E7 (16 ␣ -bromo-17,17-ethylenedioxy-5 ␣ -androstan-3 ␤ -ol) with a 90% yield. Dehydrobromination was achieved in 83% with potassium t-butoxide in dimethylsulfoxide at 40 ° C overnight to give E5 (17,17-ethylenedioxy-5 ␣ -androst-15-en-3 ␤ -ol).…”

Aromatase Inhibition by 4.BETA.,5.BETA.-Epoxides of 16.ALPHA.-Hydroxyandrostenedione and Its 19-Oxygenated Analogs, Potential Precursors of Estriol Production in the Feto-Placental Unit.

“…[16][17][18] [2,4,6 Enzyme Preparations Human term placental microsomes (sedimented after 60 min at 105000ϫg were obtained as described by Ryan. 20) They were washed once with 0.5 mM dithiothreitol solution, lyophilized, and stored at Ϫ20°C.…”