Chemo‐enzymatic Synthesis of 6″‐O‐(3‐Arylprop‐2‐enoyl) Derivatives of the Flavonol Glucoside Isoquercitrin

A chemo‐enzymatic approach to some 6″‐O‐(3‐arylprop‐2‐enoyl) derivatives of the flavonol glucoside isoquercitrin (2a) was explored to overcome the inability to directly introduce these acyl moieties by an enzyme‐catalyzed reaction of 2a with the corresponding activated esters. This new approach was based on the regioselective introduction of a methyl malonate residue at the CH2OH of the sugar moiety by catalysis with the protease subtilisin (→ 22a). The mixed diester 22a was then subjected to chemoselective hydrolysis of the methoxycarbonyl function by another enzyme, biophine esterase (→ 23). Finally, the malonic monoester 23 was reacted in a Knoevenagel‐type condensation with benzaldehyde, 4‐hydroxybenzaldehyde, or 4‐hydroxy‐3‐methoxybenzaldehyde to afford the target 6″‐O‐(3‐arylprop‐2‐enoyl) isoquercitrins 2b–d.