Sustainable methods for the carboxymethylation and methylation of ursolic acid with dimethyl carbonate under mild and acidic conditions.

Abstract

Ursolic acid is a triterpene plant extract that exhibits significant potential as an anti-cancer, anti-tumour, and anti-inflammatory agent. Its direct use in the pharmaceutical industry is hampered by poor uptake of ursolic acid in the human body coupled with rapid metabolism causing a decrease in bioactivity. Modification of ursolic acid can overcome such issues, however, use of toxic reagents, unsustainable synthetic routes and poor reaction metrics have limited its potential. Herein, we demonstrate the first reported carboxymethylation and/or methylation of ursolic acid with dimethyl carbonate (DMC) as a green solvent and sustainable reagent under acidic conditions. The reaction of DMC with ursolic acid, in the presence of PTSA, ZnCl2, or H2SO4-SiO2 yielded the carboxymethylation product 3β-[[methoxy]carbonyl]oxyurs-12-en-28-oic acid, the methylation product 3β-methoxyurs-12-en-28-oic acid and the dehydration product urs-2,12-dien-28-oic acid. PTSA demonstrated high conversion and selectivity towards the previously unreported carboxymethylation of ursolic acid, while the application of formic acid in the system led to formylation of ursolic acid (3β-formylurs-12-en-28-oic acid) in quantitative yields via esterification, with DMC acting solely as a solvent. Meanwhile, the methylation product of ursolic acid, 3β-methoxyurs-12-en-28-oic acid, was successfully synthesised with FeCl3, demonstrating exceptional conversion and selectivity, >99% and 99%, respectively. Confirmed with the use of qualitative and quantitative green metrics, this result represents a significant improvement in conversion, selectivity, safety, and sustainability over previously reported methods of ursolic acid modification. It was demonstrated that these methods could be applied to other triterpenoids, including corosolic acid. The study also explored the potential pharmaceutical applications of ursolic acid, corosolic acid, and their derivatives, particularly in anti-inflammatory, anti-cancer, and anti-tumour treatments, using molecular ADMET and docking methods. The methods developed in this work have led to the synthesis of novel molecules, thus creating opportunities for the future investigation of biological activity and the modification of a wide range of triterpenoids applying acidic DMC systems to deliver novel active pharmaceutical intermediates.