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

TL;DR

Scientists developed a green method to create biologically important steroids using ionic liquids, achieving high selectivity and efficiency.

Contribution

A biomass-derived ionic liquid improves stereoselectivity in steroid hydrogenation, enabling efficient and clean synthesis of 5β-steroids.

Findings

Tetrabutylammonium d-mandelate enables high yield and stereoselectivity in steroid reduction.

The catalyst can be recycled without loss of efficiency.

Additional steroid substituents significantly affect 5β-selectivity.

Abstract

The stereoselective reduction of the steroidal 4-ene-3-ketone
moiety
(enone) affords the 5β-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
5β-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 5β-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 5β-selectivity.

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