| Summary: | The present work aimed at the valorization of biomass derived compounds by their transformation into new added-value compounds with enhanced antioxidant properties. In this context, betulinic acid (BA) was decorated with polyphenolic fragments, and polyhydroxylated (<i>E</i>)-2-benzylidene-19,28-epoxyoleanane-3,28-diones <b>4a</b>–<b>d</b> were obtained. For that, the synthetic strategy relied on base-promoted aldol condensation reactions of methyl betulonate, which was previously prepared from natural BA, with appropriate benzaldehydes, followed by cleavage of the methyl protecting groups with BBr<sub>3</sub>. It is noteworthy that the HBr release during the work-up of the cleavage reactions led to the rearrangement of the lupane-type skeleton of the expected betulonic acid derivatives into oleanane-type compounds <b>4a</b>–<b>d</b>. The synthesized compounds <b>4a</b>–<b>d</b> were designed to have specific substitution patterns at C-2 of the triterpene scaffold, allowing the establishment of a structure-activity relationship. The radical scavenging ability of <b>4a</b>–<b>d</b> was evaluated using the 2,2-diphenyl-1-picrylhydrazyl radical (DPPH<sup>•</sup>) and 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid radical cation (ABTS<sup>•+</sup>) scavenging assays. In particular, derivative <b>4c</b>, bearing a catechol unit, revealed to be the most efficient scavenger against both free radicals DPPH<sup>•</sup> and ABTS<sup>•+</sup>. Subsequently, we designed two analogues of the hit derivative <b>4c</b> in order to achieve more potent antioxidant agents: (i) the first analogue carries an additional unsaturation in its lateral chain at C-2 (analogue <b>5</b>) and (ii) in the second analogue, E-ring was kept in its open form (analogue <b>6</b>). It was observed that the presence of an extended π-conjugated system at C-2 contributed to an increased scavenging effect, since analogue <b>5</b> was more active than <b>6</b>, α-tocopherol, and <b>4c</b> in the ABTS<sup>•+</sup> assay.
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