Synthesis and Rearrangement Reactions of 4α-Bromo-5α-cholestane-3α,5-diol 3-Acetate

Abstract

The structure of the bromohydrin 4α-bromo-5β-cholestane-3β,5-diol 3-acetate (V), obtained by the addition of hypobromous acid to cholest-4-en-3β-ol3-aoetate, has been proved conclusively by an unequivocal synthesis from cholest-3-ene-5β-ol. An equilibrium mixture (approx. 1 : 2) of (V) and the isomeric bromohydrin 5-bromo-5α-cholestane-3β,4β-diol3-acetate (IV; R = Ac) [prepared1 by the addition of HBr to 4β,5-epoxy-5β-cholestan-3β-ol 3-acetate (I; R = Ac)] resulted when either pure isomer was refluxed with a trace of mineral acid in an inert solvent. The 4β-hydroxy-5α-bromo derivative (IV; R = Ac) can be acetylated or oxidized without rearrangement. Interestingly, under mild conditions of acetylation or oxidation, the isomeric bromohydrin (V) (having a tertiary 5β-hydroxyl) reacted with rearrangement to give 5-bromo-5α-cholestane-3β,4β-diol 3,4-diacetate (II; R₁ = R₂ = Ac) or 5-bromo-5α-cholestan-4β-ol-3-one 4-acetate (VI), respectively. The acetylation of (V) to (II; R₁ = R₂ = Ac) does not proceed via equilibration of (V) with (IV; R = Ac) and acetylation of the latter. Rather, it has been shown that through participation of the 5β-hydroxyl, migration of the 3-acetate to the 4-position occurs with concomitant shift of the 4α-bromine to the 5α-position, displacement of the 5β-hydroxyl, and acetylation at C3. Evidence for this mechanism follows from the fact that treatment of (V) with benzoyl chloride in pyridine afforded a benzoate different from that (II; R₁ = Ac, R₂ = Bz) obtainable from (IV; R = Ac), and identical with the 3-benzoate 4-acetate (II ; R₁ = Bz, R₂ = Ac) which was synthesized from 4β,5-epoxy-5β-cholestan-3β-ol 3-benzoate (I; R = Bz) via 5-bromo-5a-cholestane-3β,4β-diol 3-benzoate (IV; R = Bz). The proposed mechanism is supported by other evidence. It is suggested that the oxidative rearrangement of (V) to (VI) proceeds by a mechanism similar to that which operates in the acylation-rearrangement reaction, differing only in oxidation rather than acylation at C3.