An Efficient Synthesis of Deoxyrhapontigenin-3-O-β-d-glucuronide, a Brain-Targeted Derivative of Dietary Resveratrol, and Its Precursor 4′-O-Me-Resveratrol

Bioactive dietary polyphenols have health benefits against a variety of disorders, but some benefits of polyphenols may be not directly related to them, but rather to their metabolites. Recently, we have identified the brain-available phenol glucuronide metabolite deoxyrhapontigenin-3- O - β -D-glucuronide ( 5 ) in perfused rat brains following sub-acute treatment with the stilbene resveratrol ( 1 ). However, the role of such a metabolite in the neuroprotective activity of resveratrol ( 1 ) is not understood, in part due to the non-commercial availability of 5 for performing biological evaluation in animal models of Alzheimer's disease or other neurological disorders. Here, we describe a concise chemical synthesis of deoxyrhapontigenin-3- O - β -D-glucuronide ( 5 ) and its precursor, 4- O -Me-resveratrol ( 2 ), accomplished in 4 and 6 steps with 74% and 21% overall yields, respectively, starting from commercially available 3,5-dihydroxybenzaldehyde. Pivotal reactions employed in the synthesis include the palladium-catalyzed C-C coupling between 3,5-di- tert -butyldiphenylsilyloxystyrene and p -iodoanisole in the presence of tributylamine and the acid-catalysed glucuronidation between the trichloroacetimidate-activated glucuronic acid and 4- O -Me-resveratrol.