Stereoselective Reduction of Steroidal 4-Ene-3-ketones in the Presence of Biomass-Derived Ionic Liquids Leading to Biologically Important 5ß-Steroids.

ABSTRACT

The stereoselective reduction of the steroidal 4-ene-3-ketone moiety (enone) affords the 5ß-steroid backbone that is a key structural element of biologically important neuroactive steroids. Neurosteroids have been currently studied as novel and potent central nervous system drug-like compounds for the treatment of, e.g., postpartum depression. As a green methodology, we studied the palladium-catalyzed hydrogenation of steroidal 4-ene-3-ketones in the presence of ionic liquids derived from natural carboxylic acids. The hydrogenation proceeds with improved 5ß-selectivity in the presence of tetrabutylammonium carboxylates as additives compared to the exclusive use of an organic solvent. Under optimal conditions, using tetrabutylammonium d-mandelate, the reduction of testosterone led to 5ß-dihydrotestosterone in high yield and stereoselectivity and no byproduct formation was observed. Moreover, the catalyst could be recycled. The presence of additional substituents on the steroid backbone showed a significant effect on the 5ß-selectivity.