Synthesis and hydrolytic stability of the α and β anomers of 4′-thio-2′-deoxyuridine and their 5-substituted analogs. Competition between the acid-catalysed depyrimidination and isomerisation to a 5-thiopyranoside nucleoside

Abstract

The α and β anomers of 4′-thio-2′-deoxyuridine were readily synthesised as an anomeric mixture using adapted methodology and separated chromatographically as their 3′,5′-di-O-benzyl-N 3-benzoyl derivatives. The 5-fluoro analogs were prepared in a similar manner, but the anomers could be separated simply as their 3′,5′-di-O-benzyl derivatives. The kinetics of acid-catalysed hydrolysis for the four compounds and their 5-alkylated analogs are reported. Under these conditions, cleavage of the N-glycosidic bond competes with the reversible isomerisation between the furano (4′-thio) and pyrano (5′-thio) ring systems. This was confirmed by isolation and NMR characterisation of the α and β pyranose intermediates of the parent compounds.