Stereoselective synthesis, chemistry and antiviral evaluation of [formula omitted] derivatives

Abstract

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.