Keto-Enol Tautomerism in Nucleobase-Substituted Aldols

Abstract

Acyclic nucleosides, which exhibit significant antiviral activity, are usually synthesised using traditional chemical strategies. However, the efficient and selective formation of carbon-carbon bonds using small organic molecules as catalysts provides a promising alternative route for the sustainable synthesis of this family of compounds. Following this organocatalytic strategy, 5-(adenyl, thyminyl and cytosyl)-4-hydroxy-2-pentanones were prepared by the pyrrolidine catalysed reaction between the 2-oxoethyl derivative of the corresponding nucleobases and acetone. In order to investigate the keto-enol equilibrium of these compounds in basic media, H-D exchange studies were carried out by 1H and 13C NMR spectroscopy. The obtained results suggest that the mechanism by which this exchange occurs is of first order with respect to all the substrates, but of second order with regard to pyrrolidine in the case of the cytosine and adenine derivatives and of first order for the thymine analogue. Theoretical calculations of the structures involved in this equilibrium also suggest that the stability of the different ionic intermediates depends on the pKa of the corresponding nucleobases.