HMF (5-hydroxymethylfurfural), a renewable raw material from biomass, was used as the starting material to provide 5-aryl-4-hydroxymethyl-4-hydroxycyclopentenones with functionalized aryl groups. First, arylic substituents were added to the aldehyde moiety of HMF under rhodium- or palladium-catalyzed 1,2-addition of arylboronic acids, in mild conditions to respect the very sensitive HMF reactivity. Subsequently, these non-symmetrical furan-2,5-dicarbinols, through Piancantelli rearrangement, provided the desired cyclopentenones under microwave activation or subcritical water conditions (100 °C and 100 bar) using Zippertex technology, in a regio- and diastereo-selective manner. These synthesized bis-hydroxylated cyclopentenone derivatives exhibited significant antimicrobial activity against Gram-positive bacteria