(2R,4R/S)-5-tert-butyldiphenylsilyloxy-2-fluoro-4-iodopentanoic acid methyl ester | 479035-90-0

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 脂肪酰基
• 英文名称: (2R,4R/S)-5-tert-butyldiphenylsilyloxy-2-fluoro-4-iodopentanoic acid methyl ester
• 英文别名: methyl (2R)-5-[tert-butyl(diphenyl)silyl]oxy-2-fluoro-4-iodopentanoate
• CAS: 479035-90-0
• 化学式: C₂₂H₂₈FIO₃Si
• 分子量: 514.451
• InChiKey: FUAAFEPSMJCPEJ-UUSAFJCLSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.27
• 重原子数：
  28
• 可旋转键数：
  10
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.41
• 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,4R/S)-5-tert-butyldiphenylsilyloxy-2-fluoro-4-iodopentanoic acid methyl ester 在 4-二甲氨基吡啶 、 TEA 、 乙酸酐 、 二异丁基氢化铝 、 二甲基亚砜 、 六甲基二硅氮烷 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 正己烷 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 甲苯 、 乙腈 为溶剂， 反应 60.0h， 生成 (-)-N⁴-benzoyl-1-[(1S,2S,4R)-5-O-(tert-butyldiphenylsilyl)-2,3-dideoxy-2-fluoro-2-phenylselenyl-4-thio-β-L-ribofuranosyl]cytosine
  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：

  (2R,4R)-(-)-4-tert-butyldiphenylsilyloxymethyl-2-fluoro-γ-butyrolactone 在 咪唑 、 sodium hydroxide 、 碘 、 三苯基膦 作用下， 生成 (2R,4R/S)-5-tert-butyldiphenylsilyloxy-2-fluoro-4-iodopentanoic acid methyl ester
  参考文献：
  名称：

  2′-Fluoro-4′-thio-2′,3′-unsaturated Nucleosides: Anti-HIV Activity, Resistance Profile, and Molecular Modeling Studies

  摘要：

  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.

  DOI：

  10.1081/ncn-120021965