Influence of fluorine substitution on the molecular conformation of 3'-deoxy-3'-fluoro-5-methyluridine

Fluorine substitutions on the furanose ring of nucleosides are known to strongly influence the conformational properties of oligonucleotides. In order to assess the effect of fluorine on the conformation of 3'-deoxy-3'-fluoro-5-methyluridine (^RT^F), C₁₀H₁₃FN₂O₅, we studied its stereochemistry in the crystalline state using X-ray crystallography. The compound crystallizes in the chiral orthorhombic space group P2₁2₁2₁ and contains two symmetry-independent molecules (A and B) in the asymmetric unit. The furanose ring in molecules A and B adopts conformations between envelope (²E, 2'-endo, P = 162°) and twisted (²T₃, 2'-endo and 3'exo, P = 180°), with pseudorotation phase angles (P) of 164.3 and 170.2°, respectively. The maximum puckering amplitudes, ν_max, for molecules A and B are 38.8 and 36.1°, respectively. In contrast, for 5-methyluridine (^RT^OH), the value of P is 21.2°, which is between the ³E (3'-endo, P = 18.0°) and ³T₄ (3'-endo and 4'-exo, P = 36°) conformations. The value of ν_max for ^RT^OH is 41.29°. Molecules A and B of ^RT^F generate respective helical assemblies across the crystallographic 2₁-screw axis through classical N-H...O aand O-H...O hydrogen bonds supplemented by C-H...O contacts. Adjacent parallel helices of both molecules are linked to each other via O-H...O and O...π interactions.