Absolute Configuration of the Antiviral Agent (−)- cis -5-Fluoro-1-[2-Hydroxymethyl)-1,3-Oxathiolan-5-yl]Cytosine

Abstract

The structure and absolute configuration of (−)-cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine (FTC), has been determined by X-ray crystallographic analysis. The results confirm that the L-isomer of the nucleoside analogue is the most active enantiomer and that the correct absolute configuration of (−)-FTC is 5-fluoro-(2′R,5′S)-(−)-1-[2-hydroxymethyl)oxathiolan-5-yl]-fluorocytosine. The two molecules in the asymmetric unit show conformations that combine conformational features of two other classes of potent antiviral nucleosides. Both oxathiolane rings have the 3′-sulphur atom in nearly perfect S3′-exo envelope conformations, similar to what is observed for 3′-azido-3′-deoxythymidine (AZT) and 2′,3′-dideoxycytidine. One of the two molecules has a glycosylic link conformation in which the base is eclipsed with the C5′-O1′ bond. This mimics the high-anti conformation that has been observed in the structures of several 2′,3′-didehydro-2′,3′-dideoxypyrimidine nucleosides but is inaccessible for saturated pyrimidine nucleosides. However, the observed conformations cannot be superimposed adequately with other active antiviral nucleosides to suggest a common ‘active site’ conformation.