Stereoselective synthesis, chemistry and antiviral evaluation of 1-(2,3-dideoxy-3-C-hydroxymethyl-β-d-threo-pentofuranosyl)thymine derivatives

A series of novel 3′-C-branched 2′,3′-dideoxynucleosides have been synthesized and evaluated as anti-HIV agents. Hydroboration of 2′,3′-dideoxy-3′-C-methylene nucleoside proceeded regio- and stereoselectively to give 1-(2,3-dideoxy-C-hydroxy methyl-5-O- trityl-β-d-threo-pentofuranosyl)thymine (5) after oxidation. 3′-C-Chloromethyl and 3′-C-iodomethyl5′-O-protected 2′,3′-dideoxynucleosides 9 and 12 were obtained from 5 by reaction with carbon tetrachloride/triphenylphosphine and methyltriphenoxyphosphonium iodide, respectively. Arbuzov reaction of 12 with triethyl phosphite afforded 3′-C-(diethylphosphono)methyl5′-O-protected 2′,3′-dideoxynucleoside 14. Compounds 5, 9, 12 and 14 were detritylated to give 1-(3-C-chlromethyl-2,3- dideoxy-β-d-threo-pentofuranosyl)thymine (10), 1-(2,3-dideoxy-3-C-hydroxymethyl-β-d-threo-pentofuranosyl)- thymine (11), 1-(2,3-dideoxy-3-C-iodomethyl-β-d- threo-pentofuranosyl)thymine (13) and 1-(2,3-dideoxy-3-C- (O,O′-diethylphosphono)methyl-β-d-threo-pentofuranosyl)- thymine (15), respectively. These nucleoside analogues were evaluated for antiviral activity against human immunodeficiency virus type 1 (HIV-1) and herpes simplex virus type 1 (HSV-1) in vitro. Compound 5 demonstrated selective antiviral activity against HIV-1 but not HSV-1.