An Improved Synthesis of Glucuronide Metabolites of Hindered Phenolic Xenoestrogens

Abstract

Aims and objective: The syntheses of glucuronide metabolites of phenolic xenoestrogens triclosan and 2-phenylphenol, namely triclosan-O-glucuronide (TCS-G; 1), and 2-phenylphenol-Oglucuronide (OPP-G; 2), were achieved for use as analytical standards.

Methods: Under classical conditions previously reported for glucuronide synthesis, the final basic hydrolysis of the peracylated ester intermediate leading to the free glucuronides is often a limiting step. Indeed, the presence of contaminating by-products resulting from ester elimination has often been observed during this step. This is particularly relevant when the sugar unit is close to a crowded environment as for triclosan and 2-phenylphenol.

Results: To circumvent these problems, we proposed mild conditions for the deprotection of peracetylated glucuronate intermediates.

Conclusion: A new methodology using a key imidate following a two-step protocol for acetates and methyl ester hydrolysis was successfully applied to the preparation of TCS-d3 (1) and OPP-G (2) as well as deuterated isotopomers TCS-d3-G (1-d3) and OPP-d5-G (2-d5).

Keywords: Schmidt’s glucuronidation; Xenoestrogen; deuterium labeling; glucuronide metabolite; internal standard; phenol; zinc acetate transesterification.