THROUGH-SPACE (7)J(HF) AND (6)J(CF) SPIN-SPIN COUPLINGS IN 2',3'-DIDEOXY-4'-FLUOROALKYLNUCLEOSIDES - THE ROLE OF SUGAR RING CONFORMATION AND SOLVENT EFFECT

H-1 and C-13 MMR spectra of seven compounds of a new class of syntheti c fluorinated nucleosides, 2',3'-dideoxy-4'-fluoroalkylthymidine and 2 ',3'-dideoxy-4'-fluoroalkylfluorouridine, showed long-range (7)J(HF) a nd (6)J(CF) couplings between the F of the fluoroalkyl moiety and H-6 (and C-6) of the nucleobase. All the couplings were selectively detect ed on alpha anomers only, and H-1{ F-19} NOE difference spectra indica ted that the F nucleus and H-6 are also in spatial proximity, supporti ng the hypothesis of a through-space mechanism far the transmission of the nuclear spin information. Molecular mechanics calculations on alp ha-2',3'-dideoxy-4'-fluoroalkylthymidine as a model compound indicated that F ... H-6 distance spans the range 2.58-2.73 Angstrom irrespecti ve of the sugar ring conformation and the F ... H-6 - C-6 angle is wit hin the range 145-159 degrees. Calculated data support the view of an attractive interaction between F and H-6 of the base, consistent with an intramolecular hydrogen bond. Experimental evidence to this hypothe sis are provided by NMR measurement in different solvents: the observe d values of (7)J(HF) and (6)J(CF) decrease with increasing dielectric constant of the solvent and with the increasing capability of the solv ent to establish intermolecular hydrogen bonds in competition with the intramolecular ones, i.e. passing from CDCl3 to acetone-d(6),and to D MSO-d(6). (C) 1997 by John Wiley & Sons, Ltd.