Functionalization of Betulinic Acid with Polyphenolic Fragments for the Development of New Amphiphilic Antioxidants

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 (E)-2-benzylidene-19,28-epoxyoleanane-3,28-diones 4a-d 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 BBr3. 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 4a-d. The synthesized compounds 4a-d 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 4a-d was evaluated using the 2,2-diphenyl-1-picrylhydrazyl radical (DPPH center dot) and 2,2 '-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid radical cation (ABTS(center dot+)) scavenging assays. In particular, derivative 4c, bearing a catechol unit, revealed to be the most efficient scavenger against both free radicals DPPH center dot and ABTS(center dot+). Subsequently, we designed two analogues of the hit derivative 4c in order to achieve more potent antioxidant agents: (i) the first analogue carries an additional unsaturation in its lateral chain at C-2 (analogue 5) and (ii) in the second analogue, E-ring was kept in its open form (analogue 6). It was observed that the presence of an extended pi-conjugated system at C-2 contributed to an increased scavenging effect, since analogue 5 was more active than 6, alpha-tocopherol, and 4c in the ABTS(center dot+) assay.

Automated summary

This study focused on valorizing biomass derived compounds by transforming them into new added-value compounds with enhanced antioxidant properties. Through the design of specific substitution patterns, a derivative was found to exhibit the highest scavenging ability against free radicals. Additionally, analogues were designed and tested, with one showing an increased scavenging effect due to the presence of an extended pi-conjugated system at a particular position.