Conformational studies. Part 9. Some exceptions to the axial halogeno-ketone rule

Abstract

Methylation of 6α-methylcholest-4-en-3-one gives 4,4,6-trimethylcholest-5-en-3-one (2; R¹= R²= H). The corresponding androst-5-ene (6; R¹= Me, R²= R³= H) was prepared similarly.

4,4-Dimethyl-19-norandrost-5-en-3-one was converted into the ethylene acetal (7) and thence into the (S)- and (R)-17β-tetrahydropyranyl ethers (8), which were readily separable. The (S)-17β-ether was hydroborated to yield the 5α-androstan-6α-ol (9) as the principal product, together with smaller quantities of the isomeric 6β-ol (10). The structures of these alcohols have been defined and the genesis of (10) rationalised.

Reaction of the derived 4,4-dimethyl-6-ketone (12) with methyl-lithium gave 6ξ-hydroxy-4,4,6ξ-trimethyl-19-nor-5α-androstane (13), from which the blocking groups were removed to yield 6ξ, 17β-dihydroxy-4,4,6ξ-trimethyl-19-nor-5α-androstan-3-one (14). The ethylene acetal of the (S)-17-β-tetrahydropyranyl ether series (8) underwent an analogous series of transformations and gave the same trimethyl ketone (14), which was dehydrated to 17β-hydroxy-4,4,6-trimethyl-19-norandrost-5-en-3-one.

The bromination of these three 4,4,6-trimethyl-5-en-3-ones was investigated. In each case the principal product was the 2α-derivative in which the halogen is axially oriented, and in each case the sign of the o.r.d. curve was at variance with the predictions of the Axial Halogeno-ketone Rule.