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

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 N-4-benzoylcytosine afforded the 4'-thiocytidine derivative 7b on a large scale. Starting with the resulting 7b, 1-(3-C-ethynyl-4-thio-beta-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.