SYNTHESIS AND ANTIVIRAL ACTIVITY OF SOME 3'-C-DIFLUOROMETHYL AND 3'-DEOXY-3'-C-FLUOROMETHYL NUCLEOSIDES

The synthesis and antiviral activity of a number of 3’-C-difluoromethyl and 3'-deoxy-3’-C-fluoromethyl nucleosides are reported. The S’-C-difluoromethyl nucleosides 26a and 26b were obtained bytreatment of the corresponding 2′,5′-di-0-protected-3/-C-formyl nucleosides 25a and 25b with (diethylamino)sulfur trifluoride (DAST). Removal of the 2’-0-protecting group from 26a and subsequent reaction with DAST furnished the 2'-deoxy-2/-fluoro-|ft-D-r/6o-pentofuranosyl nucleoside 29. Selective fluorination with DAST of the 5’-0-protected analogues 3′-deoxy-3'-C'hydroxymethyl derivatives 13a and 13b gave the 3'-deoxy-3’-C-fluoromethyl derivatives 30a and 30b, while nonselective fluorination afforded the 2',3′-dideoxy-2′-fluoro-3′-C-fluoromethyl analogues 31a and 31b. The deprotected uracil analogue 17a was iodinated to the 5-iodouracil derivative 18. The fully deprotected fluorinated 3’-C-branched nucleosides 1418 and 32 were evaluated for their antiviral activity. None were active against human immunodeficiency virus type-1 (HIV-1) at concentrations up to 100 µM. However, 5-iodouracil analogue 18 showed activity, comparable to that of acyclovir, against varicella zoster virus without observed cytotoxicity. © 1990, American Chemical Society. All rights reserved.