CONFORMATIONAL-ANALYSIS OF THE COMPLETE SERIES OF 2'-MONOFLUORINATED AND 3'-MONOFLUORINATED DIDEOXYURIDINES

The solution conformations of a set of uridine 2',3'-dideoxynucleoside s, where each of the hydrogens at the 2'- and 3'-positions of the suga r ring were individually replaced with a fluorine atom, were studied b y nuclear magnetic resonance spectroscopy and pseudorotational analysi s. The distribution of the north/south (N/S) puckering equilibrium for each compound was calculated by coupling constant analysis aided by t he program PSEUROT. The data confirmed that the pseudorotational equil ibrium of the fluorinated glycones is governed by the position of the fluorine atom. The preferred rotamer populations about the C4'-C5' (ga mma) and C1'-N1' (chi) bonds calculated from coupling constant and NOE analysis, respectively, were also influenced by the presence of fluor ine. Proton coupling to the fluorine atom was also used to qualitative ly estimate the N/S equilibrium population. Through space, long range H-1-F-19 coupling constants were observed in compounds where the fluor ine atom was above the plane of the ring ('up'). The pseudorotational parameters of the compounds described were tempered by the anomeric ef fect which drives the pseudorotational equilibrium towards the 2'-exo/ 3'-endo (northern) pucker. Ab initio calculations using the 3-21 G ba sis set yielded a measure of the energy differences between the N and S local minima in each compound. These results agree with previous con formational studies of other fluorinated nucleoside analogues and prov e that the furanose ring pucker is governed by the highly electronegat ive fluorine atom. However, the competing anomeric effect plays a majo r role in determining the mole fraction of the minor conformer of thes e compounds in solution. (C) 1997 Elsevier Science B.V.