Stereospecific Synthesis of 16α-Hydroxy-17-oxo Steroids by Controlled Alkaline Hydrolysis of Corresponding 16-Bromo 17-Ketones and Its Reaction Mechanism

Article abstract of DOI:10.1021/jo00142a004

Synthesis of 16α-hydroxy-17-oxo steroids 3, 5b, and 3β,16α-dihydroxy-5-17-oxoandrosten-3-yl sulfate (7) from 16α-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 16α-hydroxy 17-ketones stereoselectively in 95percent yield without formation of other ketols.The sodium salt of 3-sulfate 7 was also obtained in one step in 85percent yield from the corresponding bromo ketone (1a).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 S_N2 displacement of the 16β-bromine.The 16β-morpholino derivative 8 obtained by reaction of 1 with morpholine was shown to be an isomerized product of the 16α isomer which is produced also by S_N2 displacement of the 16β-bromine.The mechanism of ketol rearrangement of 3 to the 17β-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.