5-fluorouracil derivatives. 1. Acyclonucleosides through a tin (IV) chloride-mediated regiospecific ring opening of alkoxy-1,4-diheteroepanes

Abstract The reaction of 5-fluorouracil with the seven-membered acetals 1a-g in the presence of tin (IV) chloride, trimethylchlorosilane and hexamethyldisilazane at room temperature gives 1-{[3-(2-hydroxyethylhetero)-1-alkoxy]alkyl}-5-fluorouracils 2a-f and 1-{[2-(3-hydroxypropoxy)-1- iso propoxy]ethyl}-5-fluorouracil 2g in 31–86% yields. The presence of an heteroatom on the 1-position of the cycloacetal and the use of tin (IV) chloride, capable of a 1,4-chelation, seem to impose their influence in the regiospecific ring opening of 1a-g . The conformational analyses carried out on 2b and (1 R ,3 R )-2e and (1 R ,3 S )-2e clearly indicate that the N 1 (sp 2 )-C 1 -C 2 -C 3 moiety tends to fold in a gauche conformation. The antitumour activities of compounds 2b-g were assessed against HEp human cells showing that 2c is 4-fold more active than 5-FU. The drugs studied do not show any clear toxicity in comparison with the toxic effect of 5-FU.