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Synlett 2003(8): 1192-1194
DOI: 10.1055/s-2003-39901
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

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

Dominic Thibeault, Donald Poirier*
Medicinal Chemistry Division, Oncology and Molecular Endocrinology Research Centre, Centre Hospitalier Universitaire de Québec (CHUQ) and Université Laval, 2705 Blvd Laurier, Sainte-Foy, Québec, G1V 4G2, Canada
Fax: +1(418)6542761; e-Mail: donald.poirier@crchul.ulaval.ca;
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Publikationsverlauf

Received 28 March 2003
Publikationsdatum:
11. Juni 2003 (online)

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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.

Key words

amino alcohols - amines - epoxides - steroids - lanthanides

10

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.

11

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).

12

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.