Stereochemistry of NaBH4 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.
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-(3)H]- and [19R-(3)H]-labeled 19-hydroxy derivatives 2 and 5, were synthesized through NaB(3)H(4) reduction of the corresponding 19-aldehydes 3 and 6 as a key reaction. The hitherto unknown stereochemistry of the NaB(3)H(4) reduction was established based on the deuterium-labeling experiments with NaB(2)H(4). A comparison of (1)H-NMR spectra of the NaB(2)H(4) reduction products of 19-als 3 and 6 with those of the respective authentic steroids revealed that the ratios of 19S-(2)H to 19R-(2)H were 90 : 10 for the 4-ene steroid 2 and 70 : 30 for the 5-ene isomer 5, respectively. Jones oxidation of the [19S-(2)H]19-ols, followed by the non-labeled NaBH(4) reduction, gave the corresponding [19R-(2)H]19-ols 2 and 5 (R-(2)H : S-(2)H=90 : 10 for steroid 2 and 70 : 30 for steroid 5). The stereoselectively (3)H-labeled compounds 2 and 5 were similarly obtained in these sequences.
Numazawa
Mitsuteru
M
Tohoku Pharmaceutical University, 4-4-1 Komatsusima, Aoba-ku, Sendai 981-8558, Japan. numazawa@tohoku-pharm.ac.jp
Sohtome
Norishige
N
Nagaoka
Masao
M
D001141:Aromatase / Q000378:metabolism*; D001894:Borohydrides / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000032:analysis / Q000138:chemical synthesis*; D006878:Hydroxides / Q000032:analysis / Q000138:chemical synthesis*; D010084:Oxidation-Reduction; D013237:Stereoisomerism; D045165:Testosterone Congeners / Q000032:analysis / Q000138:chemical synthesis*
D001894:Borohydrides; D004791:Enzyme Inhibitors; D006878:Hydroxides; D045165:Testosterone Congeners; C025364:sodium borohydride; C031356:hydroxide ion; D001141:Aromatase