Stereoselective synthesis of chiral flavonoid metabolites and related phase II conjugates
Flavan-3-ols constitute a complex subclass of flavonoids, ranging from simple monomers to oligomeric and polymeric proanthocyanidins, which are also known as condensed tannins. The presence of these compounds in foods, whose epidemiology is associated with reduced incidences of cardiovascular and metabolic diseases, makes the investigation of their biological effects and mechanisms of action a topic of great interest.
These compounds undergo extensive metabolism in the gut to form products with a γ-valerolactone structure, which subsequently undergo hepatic phase II transformation yielding sulphate, methyl and glucuronide conjugates. γ-Valerolactone metabolites are generally not commercially available and, due to their low natural abundance in organic fluids, their isolation from natural sources in the amounts required for biological testing is not practical.
Hence, asymmetric synthesis is an attractive alternative considering that, being these metabolites chiral, the development of an efficient and versatile route that enables construction of the targeted compounds in an enantiopure form would be of great value.
The aim of the proposed research is to develop an efficient asymmetric synthetic route to obtain the physiologically relevant human γ-valerolactone conjugates, in particular those from (-)-epicatechin and oligomeric procyanidins, the main flavan-3-ols in cocoa, red wine and nuts, and to rigorously evaluate their biological activity in vitro and in experimental animal models of cardiovascular disease and diabetes, at dosages coherent with dietary exposure.