(2R)-2-[[tert-butyl(diphenyl)silyl]oxymethyl]-4-fluoro-2H-furan-5-one | 212954-52-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氢呋喃
• 英文名称: (2R)-2-[[tert-butyl(diphenyl)silyl]oxymethyl]-4-fluoro-2H-furan-5-one
• CAS: 212954-52-4
• 化学式: C₂₁H₂₃FO₃Si
• 分子量: 370.496
• InChiKey: SEUZBEQSAMGKOO-MRXNPFEDSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.34
• 重原子数：
  26
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  35.5
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (2R)-2-[[tert-butyl(diphenyl)silyl]oxymethyl]-4-fluoro-2H-furan-5-one 在 5percent Pd/C 咪唑 、 4-二甲氨基吡啶 、 sodium hydroxide 、 TEA 、 氢气 、 碘 、 乙酸酐 、 二异丁基氢化铝 、 二甲基亚砜 、 三苯基膦 、 六甲基二硅氮烷 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 乙醇 、 正己烷 、 二氯甲烷 、 二甲基亚砜 、 乙酸乙酯 、 N,N-二甲基甲酰胺 、 甲苯 、 乙腈 为溶剂， 反应 70.0h， 生成 (-)-1-[(1S,2S,4R)-5-O-(tert-butyldiphenylsilyl)-2,3-dideoxy-2-fluoro-2-phenylselenyl-4-thio-β-L-ribofuranosyl]uracil
  参考文献：
  名称：

  Synthesis, Anti-HIV Activity, and Molecular Mechanism of Drug Resistance of l-2‘,3‘-Didehydro-2‘,3‘-dideoxy-2‘-fluoro-4‘-thionucleosides

  摘要：

  beta-L-2',3'-Didehydro-2',3'-dideoxy-2'-fluoro-4'-thionucleosides (beta-L-2'-F-4'-S-d4Ns) have been synthesized and evaluated against HIV-1 in primary human lymphocytes. The key intermediate 8, which was prepared from 2,3-O-isopropylidene-L-glyceraldehyde 1 in 13 steps, was condensed with various pyrimidine and purine bases followed by elimination and deprotection to give the target compounds, beta-L-2'-F-4'-S-d4Ns (17-20 and 27-30). The antiviral activity of the newly synthesized compounds was evaluated against HIV-1 in human peripheral blood mononuclear (PBM) cells, among which the cytosine 17, 5-fluorocytosine 18, and adenine 27 derivatives showed potent anti-HIV activities (EC50 = 0.12, 0.15, and 1.74 muM, respectively) without significant cytotoxicity up to 100 muM in human PBM, CEM, and Vero cells. The cytosine derivative 17 (beta-L-2'-F-4'-S-d4C), however, showed cross-resistance to a 3TC-resistant variant (HIV-1(M184V)). Molecular modeling studies suggest that the pattern of antiviral activity, similar to that of beta-L-2'-F-d4N, stemmed from their conformational and structural similarities. The isosteric substitution of sulfur for 4'-oxygen was well tolerated in the catalytic site of HIV-1 reverse transcriptase in the wild-type virus. However, the steric hindrance between the sugar moiety of the unnatural L-nucleoside and the side chains of VaI184 of M184V RT in 3TC-resistant mutant HIV strains destabilizes the RT-nucleoside triphosphate complex, which causes the cross-resistance to 3TC (M184V mutant).

  DOI：

  10.1021/jm020376i
• 作为产物：
  描述：

  (R)-5-{[(tert-butyldiphenylsilyl)oxy]methyl}dihydrofuran-2(3H)-one 在 吡啶 、 双氧水 、 lithium hexamethyldisilazane 作用下， 生成 (2R)-2-[[tert-butyl(diphenyl)silyl]oxymethyl]-4-fluoro-2H-furan-5-one
  参考文献：
  名称：

  Synthesis and biological evaluation of a series of 2′-fluorinated-2′,3′-dideoxy-2′,3′-didehydro-(l)-nucleosides

  摘要：

  DOI：

  10.1016/s0960-894x(98)00277-7

文献信息

• Synthesis and Potent Anti-HIV Activity of <scp>l</scp>-2‘,3‘-Didehydro-2‘,3‘-dideoxy-2‘-fluoro-4‘-thiocytidine
  作者：Yongseok Choi、Hyunah Choo、Youhoon Chong、Sookwang Lee、Sureyya Olgen、Raymond F. Schinazi、Chung K. Chu

  DOI：10.1021/ol0171665

  日期：2002.1.1

  GRAPHICSL-2'-Fluoro-4'-thio-2',3'-unsaturated cytidine 11 was synthesized from (R)-2-fluorobutenolide 2, which was prepared from 2,3-O-isopropylidene-L-glyceraldehyde 1. The synthesized compound 11 shows potent antiviral activity against HIV-1.
• 2′-Fluoro-4′-thio-2′,3′-unsaturated Nucleosides: Anti-HIV Activity, Resistance Profile, and Molecular Modeling Studies
  作者：Youhoon Chong、Hyunah Choo、Raymond F. Schinazi、Chung K. Chu

  DOI：10.1081/ncn-120021965

  日期：2003.10

  Both D- and L-2'-fluoro-4-thio-2',3'-unsaturated nucleosides were synthesized and their anti-HIV activity against the drug sensitive virus and lamivudine-resistant mutant (M184V) were evaluated. In vitro antiviral evaluation indicated that the L-isomers are more potent than the D-isomers, but unfortunately all were cross-resistant with 3TC. Molecular modeling studies revealed that the unnatural sugar moiety of the L-nucleosides as well as 4'-sulfur atom of the D-isomer has a steric conflict with the bulky side chain of valine 184, resulting in cross-resistance.
• Synthesis and biological evaluation of a series of 2′-fluorinated-2′,3′-dideoxy-2′,3′-didehydro-(l)-nucleosides
  作者：Shu-Hui Chen、Qin Wang、John Mao、Ivan King、Ginger E. Dutschman、Elizabeth A. Gullen、Yung-Chi Cheng、Terrence W. Doyle

  DOI：10.1016/s0960-894x(98)00277-7

  日期：1998.7
• Synthesis, Anti-HIV Activity, and Molecular Mechanism of Drug Resistance of <scp>l</scp>-2‘,3‘-Didehydro-2‘,3‘-dideoxy-2‘-fluoro-4‘-thionucleosides
  作者：Hyunah Choo、Youhoon Chong、Yongseok Choi、Judy Mathew、Raymond F. Schinazi、Chung K. Chu

  DOI：10.1021/jm020376i

  日期：2003.1.1

  beta-L-2',3'-Didehydro-2',3'-dideoxy-2'-fluoro-4'-thionucleosides (beta-L-2'-F-4'-S-d4Ns) have been synthesized and evaluated against HIV-1 in primary human lymphocytes. The key intermediate 8, which was prepared from 2,3-O-isopropylidene-L-glyceraldehyde 1 in 13 steps, was condensed with various pyrimidine and purine bases followed by elimination and deprotection to give the target compounds, beta-L-2'-F-4'-S-d4Ns (17-20 and 27-30). The antiviral activity of the newly synthesized compounds was evaluated against HIV-1 in human peripheral blood mononuclear (PBM) cells, among which the cytosine 17, 5-fluorocytosine 18, and adenine 27 derivatives showed potent anti-HIV activities (EC50 = 0.12, 0.15, and 1.74 muM, respectively) without significant cytotoxicity up to 100 muM in human PBM, CEM, and Vero cells. The cytosine derivative 17 (beta-L-2'-F-4'-S-d4C), however, showed cross-resistance to a 3TC-resistant variant (HIV-1(M184V)). Molecular modeling studies suggest that the pattern of antiviral activity, similar to that of beta-L-2'-F-d4N, stemmed from their conformational and structural similarities. The isosteric substitution of sulfur for 4'-oxygen was well tolerated in the catalytic site of HIV-1 reverse transcriptase in the wild-type virus. However, the steric hindrance between the sugar moiety of the unnatural L-nucleoside and the side chains of VaI184 of M184V RT in 3TC-resistant mutant HIV strains destabilizes the RT-nucleoside triphosphate complex, which causes the cross-resistance to 3TC (M184V mutant).