Stereochemistry of NaBH_4 Reduction of a 19-Carbonyl Group of 3-Deoxy Androgens. Synthesis of [19S-^3H]- and [19R-^3H]-Labeled Aromatase Inhibitors Having a 19-Hydroxy Group

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To study the stereochemical aspects of the aromatase reaction of androst-4-en-17-one (1) and its 5-ene isomer 4, competitive inhibitors of aromatase, the [19S-^3H]- and [19R-^3H]-labeled 19-hydroxy derivatives 2 and 5, were synthesized through NaB^3H_4 reduction of the corresponding 19-aldehydes 3 and 6 as a key reaction. The hitherto unknown stereochemistry of the NaB^3H_4 reduction was established based on the deuterium-labeling experiments with NaB^2H_4. A comparison of ^1H-NMR spectra of the NaB^2H_4 reduction products of 19-als 3 and 6 with those of the respective authentic steroids revealed that the ratios of 19S-^2H to 19R-^2H were 90 : 10 for the 4-ene steroid 2 and 70 : 30 for the 5-ene isomer 5, respectively. Jones oxidation of the [19S-^2H]19-ols, followed by the non-labeled NaBH_4 reduction, gave the corresponding [19R-^2H]19-ols 2 and 5 (R-^2H : S-^2H=90 : 10 for steroid 2 and 70 : 30 for steroid 5). The stereoselectively ^3H-labeled compounds 2 and 5 were similarly obtained in these sequences.
公益社団法人日本薬学会の論文
2004-06-01