Synthesis and characterization by 1H and 13C nuclear magnetic resonance spectroscopy of 17α-cyano, 17α-aminomethyl, and 17α-alkylamidomethyl derivatives of 5α-dihydrotestosterone and testosterone

Abstract

17α-Aminomethyl, 17α-acetamidomethyl, and 17α-hemiglutaramidomethyl derivatives of dihydrotestosterone and testosterone have been prepared by hydrocyanation of 3,3′-(ethylenedioxy)-5α-androstan-17-one and 3,3′-ethylenedioxyandrost-5-en-17-one, reduction of the corresponding acetylated 17α-cyanohydrins with lithium aluminium hydride, and acylation of the resulting 17α-aminomethyl derivatives with either acetic anhydride or the mono acid chloride of glutaric acid mono methyl ester. Saponification of the 17α-hemiglutaramidomethyl methyl esters gave the corresponding hemiglutaramido derivatives, while acid hydrolysis of the 3-ethylene ketal group of 17α-acetamidomethyl and 17α-hemiglutaramidomethyl derivatives regenerated the 3-oxo and 3-oxo-4-ene functions. The 17α-configuration of 17-substituted steroids was determined by 1H and 13C NMR and confirmed by comparing with NMR data for 17α- and 17β-cyano-17-hydroxyandrost-4-en-3-one, 17β-cyano-3.3′-(ethylenedioxy)androst-5-en-17-ol, 17α-alkynyl, and 17α-hexanoic derivatives of dihydrotestosterone and testosterone, of known 17-configurations. Several ambiguous assignments of 13C NMR signals of 17α-substituted steroids and unsubstituted 17β-hydroxy or 17-oxo precursors have been resolved using steroid analogs deuterated at positions C5–7, or C16 for androstane derivatives, and at positions C6–7, or C7 for androstene derivatives. 17α-Aminomethyl and 17α-alkylamidomethyl derivatives of dihydrotestosterone and testosterone are useful intermediates for the access to potential ligands of androgen-binding proteins necessary for affinity chromatography purification or affinity-labeling experiments.