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

• Published in: Chemical & Pharmaceutical Bulletin Vol. 52; no. 6; pp. 722 - 726
• Main Authors: Numazawa, Mitsuteru, Sohtome, Norishige, Nagaoka, Masao
• Format: Journal Article
• Language: English; Japanese
• Published: TOKYO The Pharmaceutical Society of Japan 01.06.2004; Pharmaceutical Society of Japan; Pharmaceutical Soc Japan; Japan Science and Technology Agency
• Subjects: [19-2H]19-hydroxy androgen; [19-3H]19-hydroxy androgen; Aromatase - metabolism; aromatase inhibitor; Borohydrides - chemistry; Chemistry; Chemistry, Medicinal; Chemistry, Multidisciplinary; Enzyme Inhibitors - analysis; Enzyme Inhibitors - chemical synthesis; Hydroxides - analysis; Hydroxides - chemical synthesis; isotope labeling; Life Sciences & Biomedicine; NaB3H4 reduction; Oxidation-Reduction; Pharmacology & Pharmacy; Physical Sciences; Science & Technology; stereochemistry; Stereoisomerism; Testosterone Congeners - analysis; Testosterone Congeners - chemical synthesis; (NaBH4)-H-3 reduction; CATALYTIC PROBES; [19-H-2]19-hydroxy androgen; STEROIDS; MECHANISM; [ I9-H-3]19-hydroxy androgen; ACTIVE-SITE; CONVERSION; HUMAN PLACENTAL AROMATASE; AROMATIZATION; PURIFICATION; stereochemistry; ESTROGEN BIOSYNTHESIS; isotope labeling; CYTOCHROME-P-450; aromatase inhibitor
• ISSN: 0009-2363; 1347-5223
• DOI: 10.1248/cpb.52.722

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 NaB3H4 reduction of the corresponding 19-aldehydes 3 and 6 as a key reaction. The hitherto unknown stereochemistry of the NaB3H4 reduction was established based on the deuterium-labeling experiments with NaB2H4. A comparison of 1H-NMR spectra of the NaB2H4 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 NaBH4 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.