STEREOCHEMISTRY OF ADDITION REACTIONS OF GRIGNARD REAGENTS TO 20-KETO STEROIDS . SYNTHESIS OF 17ALPHA,20ALPHA-DIHYDROXYCHOLESTEROL

The stereochemistry of the addition reactions of Grignard reagents to 20-keto steroids and their 17α-hydroxy, 21-hydroxy, and 16α,17α-oxido derivatives has been determined by means of some stereospecific reactions, e.g., hydroboration and osmylation. It has been shown that the 20-hydroxycholestanol (9) obtained by the addition of methylmagnesium bromide to 3β-acetoxy-21-nor-5α-cholestan-2O-one (11) has the 20β-hydroxy configuration (as predicted by Cram's rule), since it was found to be identical with a synthetic sample prepared by hydroboration followed by oxidation of 5α-cholest-cis-17(20)-en-3β-ol (8). The 20α epimer 12 has been prepared by the addition of isohexylmagnesium bromide to 3β-acetoxy-5α-pregnan-20-one (10). The same stereochemical results were obtained with a 21-hydroxy-20-keto steroid. The reactions with the 17α-hydroxy derivatives, however, led to the opposite steric configurations at C-20. The 5,6-dihydro derivative of the product 15, obtained by the addition of isohexylmagnesium bromide to 3β-acetoxy-17α-hydroxypregn-5-en-20-one (13), was identical with the osmylation product of 8, which has the 20β-hydroxy configuration 16. It was established that the compound known in the literature as “17α,20α-dihydroxycholesterol” is actually the 20β-hydroxy epimer. Authentic 17α,20α-dihydroxycholesterol (14) had been synthesized by the addition of methylmagnesium bromide to 3β-acetoxy-17α-hydroxy-21-norcholest-5-en-2O-one (23). It has been shown by nmr spectroscopy that the Grignard reactions with 16α,17α-oxido-20 ketones are not stereospecific. The proportion of the 20α- and 20β-hydroxy epimers in the mixture depends on the Grignard reagent employed. © 1969, American Chemical Society. All rights reserved.