Microwave assisted synthesis of lipophilic hydroxytyrosol fatty esters

Natural products display various biological activities and, therefore, constitute important targets for drug synthesis. Hydroxytyrosol is natural antioxidant largely investigated owing to his safety and his usefulness in food, cosmetic and pharmaceuticals. Hydroxytyrosol fatty esters, compared with hydroxytyrosol, show a better skin permeability and have a greater antioxidant activity in biological models [2]. In a previous report, we developed a mild method for the synthesis of lipophilic hydroxytyrosol esters at room temperature using THF dry and Er(OTf)3 as a catalyst [1]. In this report, instead, we explain a new green protocol developed for the synthesis of these compounds. This new method expect the use of fatty chlorides and hydroxytyrosol acetonide, a protected form of hydroxytyrosol where the oxidation during the storage is avoided, reacted by a microwave assisted one-pot synthesis. In particular, because of the acetonide can be removed from hydroxytyrosol in acid environment, we thought that the hydroxytyrosol fatty ester synthesis and the hydroxytyrosol deprotection may occur simultaneously thanks to the HCl formed in the first reaction step This new economic and eco-friendly protocol allows to synthetize hydroxytyrosol fatty esters not using any catalyst and toxic organic solvent. It is critical to note that neither the reagents nor the products are soluble in water, thus creating an oil/water interface where the reaction could take place allowing eater to play a pivotal role in accelerating the reaction thanks to the so-called “on-water effect”. This compounds are synthetized by one-pot reaction with a slightly molar excess of acyl chloride with a yield higher than the 60%.