Convergent synthesis of polyhalogenated quinoline C-nucleosides as potential antiviral agents.
Convergent synthesis of polyhalogenated quinoline C-nucleosides as potential antiviral agents.
复制标题
作为潜在抗病毒剂的多卤代喹啉 C-核苷的聚合合成。
DOI：
10.1021/jo020643s
复制
发表时间：
2003
期刊：
影响因子：
--
通讯作者：
Townsend,LeroyB
中科院分区：
文献类型：
--
作者：
Chen,JiongJ;Drach,JohnC;Townsend,LeroyB
2,5,6-Trichloro-1-(β-d-ribofuranosyl)benzimidazole (TCRB) and 2-bromo-5,6-dichloro-1-(β-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-(β-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 thecis-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 α-stereoselectivity was contrary to the literature precedence. A double-bond isomerization was established to be the cause of the unexpected stereochemistry. The bromo group of8was 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-α-d-ribofuranosyl]-6,7-dichloroquinolin-2-one (13). Halogenation followed by deprotection of13and led to the synthesis of 4-(α-d-ribofuranosyl)-2,6,7-trichloroquinoline (17) as the major product. The 2-aminophenone α-nucleoside (11) was successfully anomerized to the β-anomer (19), which led to the synthesis of the targeted 2-chloro- and 2-bromo-6,7-dichloro-4-(β-d-ribofuranosyl)quinolines (18and21, respectively).
