Considerable effort has been expended in the synthesis of deoxylluoro sugarslm6 as a result of interest in such analogs for use as hexokinase inhibitors7, as carriers of l*F in positron emission tomography8 (PET), and as possible anticancer agents9. Also, fluorinated pentofuranose nucleosides have been investigated for the treatment of infections by Herpes simpleton (HSV) and human immunodeficiencyll (HIV) viruses.
Little has been reported on fluorinated hexopyranose nucleoside@ and, to our knowledge, the use of diethylaminosulfur trifluorider4 (DAST) has not been reported hitherto for their synthesis.
We now decribe the synthesis of 3'-, 4'-, and 6'-fluoro derivatives of P-Dglucopyranosyltheophylline.
DAST can effect2J3J4 the replacement of OH by F at primary, secondary, and tertiary positions (the last two with inversion of configuration) in high yields. 7-(2,3 ,4-Tri-O-benzoyl-6-deoxy-6-fluoro-P-D-glucopyranosyl)theophylline (3) was prepared in dry diglyme at 60" from the tribenzoate 2. The key precursor of 7-(2,4,6-tri-O-benzoyl-3-deoxy-3-fluoro-p-D-allopyranosy~theophylline (13) was 7-(4,6-O-isopropylidene-P-D-glucopyranosyl)theophylline (S), which reacted with DAST in CH,Cl, containing 4-dimethylaminopyridine to afford 7-(3-deoxy-3fluoro-4,6-O-isopropylidene-P-D-allopyranosyl)theophylline (11). 7-(2,3,6-Tri-Obenzoyl-4-deoxy-4-fluoro-P-D-galactopyranosyl)theophylline (9) was obtained by the same procedure from 7-(2,3,6-tri-O-benzoyl-P-D-glucopyranosyl)theophylline (8). If the 4-dimethylaminopyridine was omitted, then 7-(2,3,6-tri-0-benzoyl-4deoxy-P-D-eryrhro-hex-4-enopyranosyl)theophylline was obtained instead of 9. Attempts to fluorinate 7-(3,4,6-tri-O-benzoyl-P-D-glucopyranosyl)theophylline were unsuccessful even in hot diglyme15, probably because of steric hindrance in the formation of the reaction intermediate. Debenzoylation (Zemplen) of 3 and 9 gave 4 and 10, respectively, and deacetalation of 11 gave 12.
All the compounds synthesised were characterised by their proton-coupled r9F-and proton-decoupled 13C-n.m.r. spectra. The n.m.r. data given in Tables I-III