Lewis-acidic polyoxometalates as reusable catalysts for the synthesis of glucuronic acid esters under microwave irradiation.

d-Glucuronic acid (GlcA) is ubiquitous in oligoand polysaccharides of biological importance. GlcA derivatives have been prepared for several applications; examples include surface-active compounds 2] and bioactive molecules. Glucuronidation is a well-known drug-metabolizing reaction and is generally regarded as a detoxification process. Glucopyranuronate derivatives have been used as glycosyl donors for glucuronidation of pharmacologically active compounds to form synthetic glucuronides, which were then compared to natural metabolites. Recently, the synthesis of nontoxic prodrugs has been extensively studied as a strategy for the development of cancer therapies, for example in antibody directed enzyme prodrug therapy (ADEPT) or in prodrug monotherapy (PMT). These prodrugs are mainly synthesized from imidate glucuronate derivatives or ester glucuronates with free anomeric hydroxyls. Esters are important industrial products, commonly obtained by condensation reactions between carboxylic acids (or their derivatives) and alcohols, transesterification of methyl or ethyl esters, and alkylation of carboxylate anions. Amongst them, sugar-based esters are an attractive class of amphiphilic compounds which have been investigated for their properties as biosurfactants, emulsifying agents, and stabilizers in the food and cosmetic industries. 7, 8] However, the esterification reaction needs to be catalyzed and in general mineral acids are used, resulting in pollution and corrosion problems. Transesterification can be catalyzed by acids, bases, or enzymes, but the use of soluble catalysts generates the same environmental problems in the scale up. The use of heterogeneous catalysts is an ecofriendly, “green” approach as it allows the recovery of the catalyst and generally diminishes the amount of waste. For example, sorbitol fatty acid esters have been prepared in a two-step cascade reaction using hetero-polyacid (HPA) catalysts. Unfortunately, these catalysts have strong Brønsted acidities and are not compatible with protecting groups that are labile in acidic conditions, and in these cases favor the formation of anhydrized sorbitol esters. Several authors of this study have reported a rapid access to esterified and/or glycosylated derivatives of d-glucuronic acid from its 6,1-lactone under microwave irradiation. The products were formed rapidly and the regioselectivity differed from that obtained by classical heating. Particularly, we observed a chemoselectivity in favor of esterified compounds when the reactions were catalyzed by FeCl3, while SnCl4 led to esterified and glycosylated products. The high reactivity and versatility of this 6,1-lactone allowed its rapid conversion to a variety of glucuronamides. At the same time, the synergy between microwave heating and catalysis by a heterogeneous acid in the reaction of d-glucuronic acid and alcohols was reported by a different group, also. Sulfuric acid and a Keggin-type heteropolyacid (H3PW12O40) were impregnated on silica or siliceous MCM-41 and proved to catalyze the formation of alkyl d-glucofuranosidurono-6,3-lactone derivatives. Depending on the solvent used, the deactivation of the catalysts was significant. Polyoxometalates (POMs) have been the subject of intense research since the beginning of the 20th century. The number of reports on catalysis by these clusters of early transition metals in high oxidation states (W, Mo, V) and oxo ligands has expanded greatly during the past years. As already mentioned above, protonated POMs (HPAs) are often used as acid catalysts, also in solvent-free and multicomponent reactions. We have introduced Lewis-acidic POMs that have opened up new options for chemists. Lewis acidity was introduced through the incorporation of Lewis-acidic cations into lacunary Dawson-type phosphotungstic structures (Figure 1), which allowed modulation of the catalytic activities.