Title:An Improved Synthesis of Glucuronide Metabolites of Hindered Phenolic
Xenoestrogens
Volume: 19
Issue: 7
Author(s): Jean-Yves Sancéau*, Patrick Bélanger, René Maltais and Donald Poirier*
Affiliation:
- Organic Synthesis Service, Medicinal Chemistry Platform, University Hospital Center (CHU), Quebec-Research Center,
Québec, QC, G1V 4G2, Canada
- Organic Synthesis Service, Medicinal Chemistry Platform, University Hospital Center (CHU), Quebec-Research Center,
Québec, QC, G1V 4G2, Canada
- Department of Molecular Medicine, Faculty of Medicine, Université Laval, Québec, QC, G1V
0A6, Canada
Keywords:
Xenoestrogen, phenol, glucuronide metabolite, deuterium labeling, internal standard, Schmidt’s glucuronidation, zinc acetate transesterification.
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).
