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.