Synthesis of novel 5-fluorouracil derivatives with 1,4-oxaheteroepane moieties

Abstract A series of new ring-expanded isosteres (1,4-oxaheteroepanes) of Ftorafur [1-(2-tetrahydrofuranyl)-5-fluorouracil] has been synthesized. The branching of C-3 of the seven-membered cycloacetal and the electronegativity of the Y group on the 3-YCH 2 moities (Y being H, I and Cl), respectively, seem to direct their regiochemical and stereochemical outcome. The more electronegative the group Y is (and favouring accordingly the formation of an external ion pair), the more diastereoselectivity that is reached. The in vitro cytotoxicity versus HT-29 has been tested, showing that cis - 3g was the only moderately active compound.