Synthesis and GC-MS of 6-Alkylestradiols, Possible Aromatase Reaction Products of 6-Alkylandrostenediones

Abstract

A series of 6α- and 6β-alkylestradiols (5 and 6) (alkyl : methyl, ethyl, n-propyl, n-pentyl, and n-heptyl) were synthesized as possible aromatase reaction products of 6-alkylandrost-4-ene-3, 17-diones and their Δ¹-derivatives, potent competitive and mechanism-based inhibitors of aromatase. Treatment of 6-oxoestradiol with Grignard reagents followed by acid-catalyzed dehydration and subsequent catalytic hydrogenation over Pd-C gave the 6-alkylestradiols (5 and 6). GC-MS (electron impact mode) of trimethylsilyl derivatives of bis-trimethylsilyl derivatives of compounds 5 and 6 revealed that the 6α-alkyl compounds, 5, emerged with a longer retention time compared to the corresponding 6β-alkyl isomers, 6, where the retention time was in proportion to the length of the 6-alkyl chain in each series. In the MS, a molecular ion (M⁺) peak was the base peak for all the 6-alkylestrogens, with strong and characteristic fragment ion peaks corresponding to M⁺-131 and at m/z 325. A selected ion monitoring method using a molecular ion will be sensitive enough for analysis of the aromatization reaction of the 6-alkylandrogens.