Synthesis and structural elucidation of 1-(3-C-ethynyl-4-thio-β-D-ribofuranosyl)cytosine (4′-thioECyd)

Abstract

A practical synthesis of 1,4-anhydro-4-thio-D-ribitol (5) via 1,4-dibromo-1,4-dideoxy-2,3,5-tri-O-benzyl-L-lyxitol (12) is described. This method reduced our previous eleven step procedure starting from D-ribose by three steps. The Pummerer reaction of 1,4-anhydro-2-O-(2,4-dimethoxybenzoyl)-3,5-O-(1,1,3,3-tetraisopropyldisiloxane-1,3-diyl)-4-sulfinyl-D-ribitol (6) in the presence of N⁴-benzoylcytosine afforded the 4′-thiocytidine derivative 7b on a large scale. Starting with the resulting 7b, 1-(3-C-ethynyl-4-thio-β-D-ribofuranosyl)cytosine (4; 4′-thioECyd), of which the 4′-oxo congener ECyd (3) is a new type of potent antineoplastic nucleoside developed in our group, was synthesized via elaborate protection and deprotection procedures, and successive reaction with cerium trimethylsilylacetylide. X-Ray crystal structures of 4′-thioECyd (4) and ECyd (3) are presented in this paper. Although striking differences in bond lengths and angles were observed in C1′–S4′ and C4′–S4′, and C4′–S4′–C1′, the overall structures of each compound, including the sugar puckering mode and the syn/anti conformation around the glycosyl bond, were similar.