Notes - Synthesis of 17α-Methyl-4-androstene-3β,17,β-diol

Abstract

R. I. Dorfman1 has recently found that the diacetate of 4-androstene-3/3(or a) 17/3-diol was a highly potent long acting androgen, comparable in activity to testosterone esters. This observation was of some interest in view of the finding of Butenandt and coworkers2 that the parent compound, 4-androstene-3/3,17/3-diol,3 exhibited very little activity in the capon comb test. In view of the work by Dorfman which indicated that hormone activity could be maintained with a 4 5-3-1 grouping in the molecule, it was decided to prepare the unknown 17a-methyl-4-androstene-3/3,17/3-diol (Ila) for a comparative study of its androgenic activity especially with methyl testosterone (I) and 17a-methyI-5-androstene-3/3,17/3-diol.Methyl testosterone (I) on reduction with sodium borohydride4 in methanol-ethyl acetate gave in 70% yield 17a-methyI-4-androstene-3/3,17/3-diol (Ila), which was isolated and purified by crystallization directly from the reduction mixture. The /3-configuration at C3 was assigned on the basis of digitonide formation. The digitonide on decomposition with pyridine gave back the 3/3,17/3-diol Ila identical with the starting material. This established that the product Ila was not contaminated with the chemically possible 3a,17/3-diol. The presence of the latter in the purification mother liquors was not investigated.The 3-acetate lib and 3-propionate lie were prepared in the usual manner.

17a-Methyl-4-androstene-3b,17b-diol monohydrate

“…17a-Methyl-4-androstene-3b,17b-diol in the form of a powder, synthesized according to Bernstein et al (1957), was kindly supplied by Mr Pan of Jiubang Chemistry Corporation Ltd, Shanghai, China. Crystals of (I) suitable for structure analysis were obtained by slow evaporation of a solution in tetrahydrofuran, acetone and water (4:4:2) as colourless plates.…”

“…Owing to negligible anomalous scattering effects, Friedel pairs were averaged in the refinement. The absolute stereochemistry of the compound (I) was known from the synthetic route (Bernstein et al, 1957). H atoms bonded to the O atoms were located in difference Fourier maps; those of water molecule were refined isotropically with the restraint O-H = 0.83 (1) Å .…”

Methyl 17,17-ethylenedioxy-7-oxo-15β,16β-methylene-5-androstene-3β-carboxylate

“…The absolute stereochemistry of the title compound was known from the synthetic route (Bernstein et al, 1957). H atoms were placed at calculated positions and refined using a riding model, with U iso (H) = 1.2U eq (C) or 1.5U eq (methyl C) and C-H = 0.96-0.98 Å .…”

3β-Acetoxy-17,17-ethylenedioxy-15β,16β-methylene-5-androsten-7β-ol

“…In the absence of significant anomalous dispersion effects, Friedel pairs were merged before the final refinement. The absolute stereochemistry of the title compound was known from the synthetic route (Bernstein et al, 1957).…”