Sustainable Synthesis of α-Glucosidase Inhibitors by Gas-Free Pd-Carbonylation of Nature-Based Hydroxytyrosol

This study outlines the sustainable synthesis of novel hydroxytyrosol (HT) and tyrosol (T) ester derivatives via a Pd-catalyzed alkoxycarbonylation of aromatic iodides. The high sustainability of the process is attributed to the use of (1) a solid carbon monoxide source, Mo(CO)6, in place of dangerous gaseous CO; (2) a biomass-derived organic solvent, CPME (cyclopentyl methyl ether); (3) naturally occurring hydroxylated compounds, such as HT and T, which could be derived from agricultural waste rather than produced from petroleum-based sources. The method enables the regioselective preparation of various HT and T esters in a short reaction time (4–8 h), under mild temperatures (80 °C), and with moderate-to-excellent yields (62–93%). Moreover, in vitro biological tests have demonstrated that, in addition to the well-known antioxidant properties typical of natural phenolic compounds such as HT and T, some of the newly synthesized derivatives have a safe profile and are effective inhibitors of the α-glucosidase with potential application in the management of hyperglycemia. This synthetic approach offers a promising strategy for exploring biologically relevant chemical space, bridging the gap between natural products and sustainable drug synthesis.