title: Convergent synthesis of polyhalogenated quinoline C-nucleosides as potential antiviral agents.
abstract: 2,5,6-Trichloro-1-(beta-d-ribofuranosyl)benzimidazole (TCRB) and 2-bromo-5,6-dichloro-1-(beta-d-ribofuranosyl)benzimidazole (BDCRB) are benzimidazole nucleosides that exhibit strong and selective anti-HCMV activity. We proposed to synthesize 2-halo-6,7-dichloro-4-(beta-d-ribofuranosyl)quinolines as 6 + 6 bicyclic analogues of TCRB. The synthesis used Wittig reactions in two key steps. The first Wittig reaction coupled a fully functionalized benzene with a ribofuranose derivative to provide (Z)-6-O-(tert-butyldimethylsilyl)-1-(4,5-dichloro-2-nitrophenyl)-1,2-dideoxy-3,4-O-isopropylidene-d-allo-1-enitol (5) as the basic skeleton for the target compounds. The following electrophile-mediated intramolecular cyclization of the cis-alkene (5) was found to afford (1S,2S)-2,5-anhydro-1-bromo-6-O-(tert-butyldimethylsilyl)-1-deoxy-1-(4,5-dichloro-2-nitrophenyl)-3,4-O-isopropylidene-d-allitol (8) as the major product. This alpha-stereoselectivity was contrary to the literature precedence. A double-bond isomerization was established to be the cause of the unexpected stereochemistry. The bromo group of 8 was displaced by a hydroxyl group. Oxidation of the hydroxy group and the reduction of a phenylnitro group provided (2S)-1-(2-amino-4,5-dichlorophenyl)-2,5-anhydro-6-O-(tert-butyldimethylsilyl)-3,4-O-isopropylidene-d-allose (11), which was subjected to the second Wittig reaction with a phosphacumulene to construct 4-[5-O-(tert-butyldimethylsilyl)-2,3-O-isopropylidene-alpha-d-ribofuranosyl]-6,7-dichloroquinolin-2-one (13). Halogenation followed by deprotection of 13 and led to the synthesis of 4-(alpha-d-ribofuranosyl)-2,6,7-trichloroquinoline (17) as the major product. The 2-aminophenone alpha-nucleoside (11) was successfully anomerized to the beta-anomer (19), which led to the synthesis of the targeted 2-chloro- and 2-bromo-6,7-dichloro-4-(beta-d-ribofuranosyl)quinolines (18and 21, respectively).
authors.affiliation: Department of Chemistry, College of Literature, Sciences and Arts, University of Michigan, Ann Arbor 48109-1065, USA.
authors.forename: Jiong J
authors.initials: JJ
authors.lastname: Chen
authors.forename: John C
authors.initials: JC
authors.lastname: Drach
authors.forename: Leroy B
authors.initials: LB
authors.lastname: Townsend
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002384:Catalysis; D020650:Combinatorial Chemistry Techniques; D003587:Cytomegalovirus / Q000187:drug effects*; D005347:Fibroblasts / Q000187:drug effects; D018259:Herpesvirus 1, Human / Q000187:drug effects*; D006801:Humans; D006846:Hydrocarbons, Halogenated / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007202:Indicators and Reagents; D020128:Inhibitory Concentration 50; D007624:KB Cells / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D009705:Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism
chemical_list: D000998:Antiviral Agents; D006846:Hydrocarbons, Halogenated; D007202:Indicators and Reagents; D009705:Nucleosides; D011804:Quinolines