FLUORINATED PYRIMIDINES .4. SYNTHESIS, PROPERTIES AND STEREOCHEMICAL CONVERSION OF THE CIS AND TRANS ISOMERS OF 6-ALKOXY-5-FLUORO-5,6-DIHYDROURACILS

The reaction of 6-acetoxy-5-fluoro-5,6-dihydrouracil with ROH (R = Me, Et, Pr, Pr-i, Bu, Bu(t)) under acidic conditions has been investigate d using F-18 as a tracer. The quantitative replacement of the OAc-grou p proceeded predominantly with cisoid (gauche) stereochemistry, but up on prolonged heating the amount of the trans compound increased. This isomerization did not originate from epimerization at C-5. The trans c ompounds-apart from being more stable towards substitution and elimina tion than the corresponding cis compounds-gave invariably substitution products with inversion of configuration, while the cis compounds mai nly retained their configuration. Within the concept of the unifying i on-pair mechanism it is proposed that the trans compound reacts via an intimate protonated intermediate and the cis compound via a solvent-s eparated protonated intermediate. As a result, it was not the gauche a ttraction between the fluorine atom and the incoming nucleophile, but the poor pi-donor ability of the C-F bond that was the determining fac tor in the cisoid stereochemistry of 5-fluoro-5,6-dihydrouracil adduct s.