5-Fluorouracil nucleoside analogs having acyclic-sugar chains derived from the four D-aldopentoses

Abstract

Fusion of 5-fluoro-2,4-bis(trimethylsilyloxy)pyrimidine ( 1) with 2,3,4,5-tetra- O-acetyl-1-bromo-1- S-ethyl-1-thio- d-arabinitol ( 2) gave 59% of crystalline 2,3,4,5- tetra- O-acetyl-1- S-ethyl-1-(5-fluorouracil-1-yl)-1 -thio- d- gluco-pentitol [(1 R)-2,3,4,5- tetra- O-acetyl-1-S-ethyl-1-(5-fluorouracil-1-yl)-1-thio- d-arabinitol] ( 6), converted by methanolic ammonia into the corresponding, crystalline, free tetrol 10; X-ray crystallography, chiroptical data, and n.m.r. spectroscopy established the C-1' stereochemistry of 6 and 10, and showed that the compounds favor an extended conformation with the ethylthio group antiparallel to the planar, zigzag, carbon chain. The d- xylo analog (3) of the bromide 2 condensed with 1 to give a mixture from which 35% of the crystalline (1S) nucleoside derivative ( 7) was isolated, and converted into the crystalline tetrol; the conformation of 7 in solution was non-extended (sickle). A similar sequence from the d- lyxo bromide (3) gave a syrupy, (1 R,1S) mixture of protected nucleosides that afforded the corresponding tetrols, also as an amorphous mixture. The d- ribo bromide gave a 1:2 (1 R,1 S) mixed adduct; de-esterification produced the corresponding mixed tetrols ( 13 + 14) as a glass from which the (1S) isomer 13 could be obtained crystalline.