The MINDO/3 technique was used to evaluate the geometry of thymidine and four structural analogs, 3'-fluoro-3'-deoxythymidine (2), 3'-fluoro-2',3'-dideoxy-beta-D-lyxofuranosylthymine (3), 3'-deoxythymidine (4), and 3',3'-difluoro-3'-deoxythymidine (5). The relative proportion of N (3'-endo, 2'-exo, P = 0-degrees) and S (2'-endo, 3'-exo, P = 180-degrees) conformers was determined for each of the analogs. Whereas the energy difference between the N and S forms of most deoxyribonucleoside derivatives differ by at most 1 to 2 kcal/mol, the N conformation for nucleosides 4 and 5 are respectively 2.9 and 4.0 kcal/mol more stable than the S form. The optimal value of chi for each of the analogs in the N conformation was -102-degrees (4) and -97-degrees (5). The fluorine in the up position at C3' of deoxyribose appears to be a strong attractor for the H-6 proton on the thymine when the the sugar is in the N conformation.
