An Efficient Method for the Regioselective Aminolysis of 2,3α-Steroidal Epoxide

Abstract

The opening of hindered 2,3α-steroidal epoxide with primary and secondary amines was performed nearly quantitatively with a catalytic amount of Gd(OTf)₃ in toluene in a sealed tube at high temperature. This new method is much more efficient (48-97% yields) than the older classical one (0-64% yields) using a large excess of amine.

amino alcohols - amines - epoxides - steroids - lanthanides

References

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<A NAME="RS01703ST-10">10</A>

The classical method (A) for synthesis of 2β-aminosteroids 2 consists in refluxing epoxide 1 (1 mmol) with the desired amine (30 mmol) and H₂O (18 mmol) overnight. The mixture is then cooled, triturated with H₂O and the precipitate filtered. The solid is dissolved in CH₂Cl₂ and the solution is dried with MgSO₄, filtered and evaporated. The crude product is then purified by silica gel flash chromatography using an appropriate mixture of MeOH:CH₂Cl₂.

<A NAME="RS01703ST-11">11</A>

The new method (B) for synthesis of 2β-aminosteroids 2 consists in heating epoxide 1 (1 mmol) dissolved in toluene (30 mL) with the desired amine (3 mmol) and Gd(OTf)₃ (0.2 mmol) in a Schlenk tube purged with argon, at 150-190 °C for 2 h (primary amines) or overnight (secondary and cyclic amines). The reaction mixture is cooled and then poured on a silica gel column for flash chromatography (MeOH:CH₂Cl₂).

<A NAME="RS01703ST-12">12</A>

The relative configuration of the 2β-aminosteroids given in Table [1] was confirmed by X-ray crystallographic examination of a representative compound. A comparison of the NMR spectroscopic data allowed the assignment of the 2β-amino-3α-hydroxy configuration in the other compounds.