(2S,4R)-(-)-4-tert-butyldiphenylsilyloxymethyl-2-fluoro-2-phenylselenyl-γ-thiobutyrolactone | 398133-33-0

• 分子结构分类: 有机化合物 - 有机金属化合物 - 有机类金属化合物
• 英文名称: (2S,4R)-(-)-4-tert-butyldiphenylsilyloxymethyl-2-fluoro-2-phenylselenyl-γ-thiobutyrolactone
• 英文别名: (3S,5R)-5-[[tert-butyl(diphenyl)silyl]oxymethyl]-3-fluoro-3-phenylselanylthiolan-2-one
• CAS: 398133-33-0
• 化学式: C₂₇H₂₉FO₂SSeSi
• 分子量: 543.636
• InChiKey: KMWVXUMCOJXFBJ-ZBLYBZFDSA-N

物化性质

• 沸点：
  568.5±50.0 °C(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.29
• 重原子数：
  33
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  51.6
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (2S,4R)-(-)-4-tert-butyldiphenylsilyloxymethyl-2-fluoro-2-phenylselenyl-γ-thiobutyrolactone 在 4-二甲氨基吡啶 、 TEA 、 二异丁基氢化铝 、 六甲基二硅氮烷 作用下， 以 正己烷 、 二氯甲烷 、 甲苯 、 乙腈 为溶剂， 反应 25.0h， 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：

  (S)-5-(tert-Butyl-diphenyl-silanyloxymethyl)-3-fluoro-tetrahydro-thiophen-2-ol 在 乙酸酐 、 二甲基亚砜 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 为溶剂， 反应 24.0h， 生成 (2S,4R)-(-)-4-tert-butyldiphenylsilyloxymethyl-2-fluoro-2-phenylselenyl-γ-thiobutyrolactone
  参考文献：
  名称：

  D-2'，3'-didehydro-2'，3'-dideoxy-2'-fluoro-4'-thionucleosides的立体选择性合成和抗病毒活性。

  摘要：

  由于2'，3'-didehydro-2'，3'-dideoxy-2'-氟核苷对HIV-1和HBV表现出令人感兴趣的抗病毒作用，因此，合成等位取代的4'-硫代核苷令人感兴趣。 4'-氧被硫原子取代。为了研究结构活性关系，从关键中间体（2R，4S）-1-O-乙酰-5-O-（叔丁基二苯基甲硅烷基）-2,3-二脱氧-2-氟-合成了各种嘧啶和嘌呤核苷。由2，3-O-异亚丙基-D-甘油醛1以13个步骤制备2-苯基硒基-4-硫代-β-D-呋喃呋喃糖苷8。在人外周血单核（PBM）细胞中评估了合成化合物对HIV-1的抗病毒活性，其中包括胞苷17、5-氟胞苷18，腺苷24，和2-氟腺苷32显示中等至有效的抗HIV活性（分别为EC（50）1.3、11.6、8.1和1.2 microM）。值得注意的是，2-氟腺苷类似物32显示出抗病毒效力以及高细胞毒性（对于PBM，CEM和Vero，IC（50）分别为1.5、1.1和7

  DOI：

  10.1021/jm020246+

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.