Asymmetric reduction of steroidal 20-ketones: Chemical synthesis of corticosteroid derivatives containing and 20α, 21-diol and 17α, 20α, 21-triol side chains

A method is presented for the chemical synthesis of corticosteroid derivatives containing the 20α, 21-diol and 17α, 20α, 21-triol side chains. The ketol side chains of cortisol, corticosterone, 11-deoxycortisol, and 11-deoxycorticosterone were reduced at C-20 with sodium borohydride in a two-phase system consisting of aqueous calcium chloride and an organic phase of chloroform or ethyl acetate. Stereoselectivity of reduction was 92% α-oriented for cortisol and 79% α-oriented for 11-deoxycortisol at ?27°. The 20α-form diminished relative to the 20β-form with increasing temperature. For the 17-deoxy steroids, reduction to the 20α-form was 23% for 11-deoxycorticosterone and 41% for corticosterone. The $\text{20α}\text{20β}$ ratios of 17-deoxy steroids were unchanged between 0° and ?27°. Calcium ions increased the solubility of corticosteroids in the aqueous phase. We propose that calcium ions affect the stereochemistry of reduction by forming a bidentate complex with the side chains of 17α-hydroxy steroids, fixing them in an orientation favorable to 20α-reduction, and by altering the phase partition of the steroids.