Conformational analysis of the complete series of 2' and 3' monofluorinated dideoxyuridines.
The solution conformations of a set of uridine 2',3'-dideoxynucleosides, where each of the hydrogens at the 2'- and 3'-positions of the sugar ring were individually replaced with a fluorine atom, were studied by nuclear magnetic resonance spectroscopy and pseudorotational analysis. The distribution of the north/south (N/S) puckering equilibrium for each compound was calculated by coupling constant analysis aided by the program PSEUROT. The data confirmed that the pseudorotational equilibrium of the fluorinated glycones is governed by the position of the fluorine atom. The preferred rotamer populations about the C4'-C5' (gamma) and C1'-N1' (chi) bonds calculated from coupling constant and NOE analysis, respectively, were also influenced by the presence of fluorine. Proton coupling to the fluorine atom was also used to qualitatively estimate the N/S equilibrium population. Through space, long range 1H-19F coupling constants were observed in compounds where the fluorine atom was above the plane of the ring ('up'). The pseudorotational parameters of the compounds described were tempered by the anomeric effect which drives the pseudorotational equilibrium towards the 2'-exo/3'-endo (northern) pucker. Ab initio calculations using the 3-21 G* basis set yielded a measure of the energy differences between the N and S local minima in each compound. These results agree with previous conformational studies of other fluorinated nucleoside analogues and prove that the furanose ring pucker is governed by the highly electronegative fluorine atom. However, the competing anomeric effect plays a major role in determining the mole fraction of the minor conformer of these compounds in solution.
Barchi
J J
JJ
Division of Basic Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
Jeong
L S
LS
Siddiqui
M A
MA
Marquez
V E
VE
D015224:Dideoxynucleosides / Q000737:chemistry*; D005461:Fluorine / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D009690:Nucleic Acid Conformation
D015224:Dideoxynucleosides; D005461:Fluorine