Urolithins, 6 H -dibenzo b,d pyran-6-one derivatives, are metabolites produced by gut microbiota from ellagic acid, a natural antioxidant. They are more efficiently absorbed than ellagic acid and contribute to the health benefits of ellagitannin-rich foods. Among these, urolithin A (UA) and its conjugated metabolites play key roles in biological activity and pharmacokinetics. Access to structurally defined UA glucuronides is therefore important for metabolic and functional studies. Here, we describe a framework-assembly approach to the total synthesis of UA 3- and 8-glucuronides, in which the urolithin scaffold is constructed via a palladium-mediated intramolecular biaryl coupling of a phenyl benzoate precursor. The coupling step provides a predominant regioisomer together with a minor isomer, which can be separated to furnish a structurally defined intermediate. Subsequent orthogonal protection-deprotection sequences and Schmidt glycosylation enable the preparation of UA 3- and 8-glucuronides as individual regioisomers in pure form. This strategy offers an alternative route to well-defined UA metabolites and provides a platform for the synthesis of diverse urolithin derivatives relevant to studies of metabolism, gut microbiota interactions, and therapeutic potential. • Urolithin A glucuronide derivatives were synthesised by Pd-mediated intramolecular biaryl coupling reaction. • By selecting appropriate protecting groups, we succeeded in the selective synthesis of two regioisomers.
Nagai et al. (Fri,) studied this question.