14C-Labelling of the natural steroid estrogens 17α-estradiol, 17β-estradiol, and estrone

Abstract The worldwide environmental occurrence of natural steroid estrogens has drawn increasing concerns. However, the fate of the estrogens, especially the α -isomer of estradiol, in the environmental matrices is still obscure. Using 14 C-radioactively labelled forms of these estrogens can facilitate and is sometimes a prerequisite for studying their transformation and residual distribution in the environment, but the availability of labelled compounds (owing to commercially high prices or unavailable) hampers such studies. Here we developed simple and stable methods to synthesize 14 C-labelled estradiol isomers and estrone using relatively low-priced [carboxyl- 14 C]-labelled sodium acetate as a precursor. The radiochemical syntheses started from an enol lactone, which was prepared from nandrolone by oxidation to open the A-ring followed by recyclization. Inversion of the 17 β- hydroxyl group into its 17 α- form was achieved via the Walden inversion using the Mitsunobu reaction. [3- 14 C]-17 β -estradiol, [3- 14 C]-17 α -estradiol, and [3- 14 C]-estrone were synthesized in five, six, and seven steps with an overall radiochemical yield of 17.4%, 16.2%, and 13.9%, respectively. The synthesized 14 C-labelled compounds provide materials for studying the fate and behavior of estrogens in complex environmental matrixes and for further synthesis of their 14 C-labelled sulfate and glucuronide conjugates.