Steroids: Ii. The Stereochemistry of the Addition of Grignard Reagents to 12-Ketosteroids

Abstract

The action of methyl magnesium iodide on 3a,20cu-diacctoxyprcgna1~-12-one (IIa) led to thc formation of the cpimeric 12-methyl-12-hydroxypreg~ianes 111 and V, in which the 12a-hydrosy-120-methyl isonier 111 predominated.Infrared measurements on the corresponding 12-hydroxy-12-rnethyIpreg1ia1~e-3,20-dioi~es VI and IV permitted unambiguous assignment of configuration a t C13.The pregnanedione IV was transformed to 120-hydroxy-12cu-methylprogesterone.In the first paper of this series (1) we described the conversion of pregnane-3aI12a,20P-trio1 to 12a-hydroxy-12P-methylprogesterone. We should now like to report on the conversion of pregnane-3a,12a,20a-triol (I) t o the epi~neric 12-hydroxy-12-methyl-3,20-pregnanediones IV and VI and on the conversion of the former to 12P-hydroxy-12a-inethylprogesterone (VII).Partial succinylation (I) of pregnane-3a,l2a,2Oa-triol (I) with succinic anhydride in pyridine, followed by methylation of the hemisuccinate with ethereal diazomethane, afforded a 91% yield of pregnane-3a,12a,20a-triol 3,20-bis-methyl succinate (Ia). Oxidation of Ia with chromium trioxide in acetic acid gave the corresponding 12-ketone IIb. Our experience in the 20P-hydroxy series (1) indicated t h a t the reaction of methyl magnesium iodide on pregnan-12-ones proceeded in better yield in the presence of a 20-acetate group rather than a 20-succinate function. Hence, the disuccinoxy ketone IIb was hydrolyzed with methanolic potassiuin hydroxide to 3a,20a-dihydroxypregnan-12-one (11) and the latter acetylated with acetic anhydride in pyridine. T h e resulting diacetoxy ltetone I I a was treated with an excess of ethereal methyl magnesium iodide for 20 hours. Acetylation, chromatography, alkaline hydrolysis, and repeated crystallizations gave the epi~neric 12-inethylpregnane-3a,12,20a-triols I11 and V. T h e mono-, di-, and triacetates IIIa-c and Va were prepared and interrelated (see Experimental). Since the separation of the epiineric triols I11 and V by crystallization was tedious and incomplete, the mother liquors of the crystallization of the Grignard product containing the epimeric triols 111 and V were oxidized with chromic oxide in acetic acid. Chromatography on alumina of the oxidation product afforded 12P-methyl-12a-hydroxypregnane-3,20-dione (VI) and its 12a-methyl isomer IV. The total yield of the Grignard adducts 111 (VI) and V (IV) was 60.5% and 25.0% respectively. T h e hydroxy ltetone VI was identical with the 12~-methyl-l2a-hydroxypregnane-3,2O-dione, isolated previously in the 20P-series (1) in 73y0 yield as the only product of the correspoilding Grignard reaction. The infrared spectrum of this hydrosy dilcctone showed bands a t 3680 cm-I (free 01-1) and 1713 cm-I (3,20-dione) .? 1Manzrscript received Janzrary 6 , 1961. Contribution fronz the