Enzymatic Synthesis of Ascorbic Acid-Ketone Body Hybrids

Abstract

Molecular hybrids obtained by connecting two or more bioactive molecules through a metabolizable linker are used as multi-target drugs for the therapy of multifactorial diseases. Ascorbic acid, as well as the ketone bodies acetoacetate and (R)-3-hydroxybutyrate, are bioactive molecules that have common fields of application in the treatment and prevention of neurodegenerative diseases and cardiac injuries as well. In spite of this, the preparation of ascorbic acid ketone body hybrids is uncovered by the literature. Herein, we report the lipase-catalyzed condensation of methyl acetoacetate with ascorbic acid, which affords the 6-O-acetoacetyl ascorbic acid in quantitative yield. The same approach, employing the methyl (R)-3-hydroxybutyrate in place of the methyl acetoacetate, allows the preparation of the 6-O-(R)-3-hydroxybutyryl ascorbic acid in 57% yield. A better result (90% overall yield) is achieved through the lipase-catalyzed coupling of ascorbic acid with methyl (R)-3-O-methoxymethyl-3-hydroxybutyrate followed by the cleavage of the MOM protecting group. The two novel products are fully characterized and additional information on the antioxidant activity of the new products is also given.