Comprehensive Structural Studies of 2′,3′-Difluorinated Nucleosides: Comparison of Theory, Solution, and Solid State

Abstract

The conformations of three 2′,3′-difluoro uridine nucleosides were studied by X-ray crystallography, NMR spectroscopy, and ab initio calculations in an attempt to define the roles that the two vicinal fluorine atoms play in the puckering preferences of the furanose ring. Two of the compounds examined contained fluorine atoms in either the arabino or xylo dispositions at C2′ and C3′ of a 2′, 3′-dideoxyuridine system. The third compound also incorporated fluorine atoms in the xylo configuration on the furanose ring but was substituted with a 6-azauracil base in place of uracil. A battery of NMR experiments in D 2 O solution was used to identify conformational preferences primarily from coupling constant and NOE data. Both 1 H and 19 F NMR data were used to ascertain the preferred sugar pucker of the furanose ring through the use of the program PSEUROT. Compound-dependent parameters used in the PSEUROT calculations were newly derived from complete sets of conformations calculated from high-level ab initio methods. The solution and theoretical data were compared to the conformations of each molecule in the solid state. It was shown that both gauche and antiperiplanar effects may be operative to maintain a pseudodiaxial arrangement of the C2′and C3′ vicinal fluorine atoms. These data, along with previously reported data by us and others concerning monofluorinated nucleoside conformations, were used to propose a model of how fluorine influences different aspects of nucleoside conformations.

Synthesis and Conformational Analysis of Fluorinated Uridine Analogues Provide Insight into a Neighbouring-Group Participation Mechanism

“…However, the 2 -fluoro-β-d-dideoxyuridine molecules are reported with a coupling constant of 3.3 Hz for H1 -H2 [36] and in general, J H1 -H2 in β-nucleosides with a 2 -ara substituent is in the range of 3-4 Hz [37]. Barchi et al [38] reported the synthesis and conformational analysis of the 2 ,3 -dideoxy-2 ,3 -difluoro uridine analogues with the araand xylo-stereochemistry (Table S1), and the general trend of the values of the coupling constants mentioned above are in agreement with McAtee et al [37].…”

The C–F bond as a conformational tool in organic and biological chemistry

“…Interestingly however, fluorinated isomer 23 is inactive against HIV reverse transcriptase, whereas the diastereomeric compound 24 maintains the potency of the parent compound 22 . This result can be explained by the effect of the fluorine atoms on the molecular conformations of 23 and 24 [ 24 ]. In isomer 23 , the fluorine atom aligns gauche to the ring oxygen, resulting in a C3′- endo ring pucker which is not recognised by HIV reverse transcriptase [ 24 – 25 ].…”

“…This result can be explained by the effect of the fluorine atoms on the molecular conformations of 23 and 24 [ 24 ]. In isomer 23 , the fluorine atom aligns gauche to the ring oxygen, resulting in a C3′- endo ring pucker which is not recognised by HIV reverse transcriptase [ 24 – 25 ]. By contrast, in isomer 24 the fluorine once again aligns gauche to the ring oxygen, but this leads to a C3′- exo ring pucker which is known to be optimal for biological activity.…”

“…4 ). If the C3′ stereochemistry is appropriate, the C3′- exo ring pucker can be further reinforced, with both fluorines aligned gauche to the ring oxygen (note that a potential difluoro gauche effect is overridden in this case) [ 24 , 26 ].…”

Investigation and Conformational Analysis of Fluorinated Nucleoside Antibiotics Targeting Siderophore Biosynthesis

“…Marquez and co-workers previously observed similar extreme inclination of 2′,3′-dideoxy-2′,3′-FF- xylo uridine nucleosides towards C3′- endo conformation (~100% N). 32 …”