(1''S,1'''S,3''S,6''R)-(2''E)-2-<2'-<3''-(1'''-carboxypentyl)-6''-methyl-2''-<(trimethylsilyl)methylene>cyclohexyl>ethyl>-2,5,5-trimethyl-1,3-dioxane | 154698-42-7

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 异戊烯醇脂质
• 英文名称: (1''S,1'''S,3''S,6''R)-(2''E)-2-<2'-<3''-(1'''-carboxypentyl)-6''-methyl-2''-<(trimethylsilyl)methylene>cyclohexyl>ethyl>-2,5,5-trimethyl-1,3-dioxane
• 英文别名: (1''S,1'''R,3''S,6''R)-(2''E)-2-[2'-[3''-(1'''-carboxypentyl)-6''-methyl-2''-[(trimethylsilyl)methylene]cyclohexyl]ethyl]-2,5,5-trimethyl-1,3-dioxane；(2R)-2-[(1S,2E,3S,4R)-4-methyl-3-[2-(2,5,5-trimethyl-1,3-dioxan-2-yl)ethyl]-2-(trimethylsilylmethylidene)cyclohexyl]hexanoic acid
• CAS: 154698-42-7
• 化学式: C₂₆H₄₈O₄Si
• 分子量: 452.75
• InChiKey: HDYNTRFEJPFZID-GWHHXELBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.91
• 重原子数：
  31
• 可旋转键数：
  9
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.88
• 拓扑面积：
  55.8
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (1''S,1'''S,3''S,6''R)-(2''E)-2-<2'-<3''-(1'''-carboxypentyl)-6''-methyl-2''-<(trimethylsilyl)methylene>cyclohexyl>ethyl>-2,5,5-trimethyl-1,3-dioxane 在 硫酸 、 silica gel 、 臭氧 作用下， 生成 (+)-octahydro-9β-butyl-3,6α-dimethyl-3,12-epoxy-12H-pyrano<4,3-j>-1,2-benzodioxepin-10(3H)-one
  参考文献：
  名称：

  抗疟药青蒿素的构效关系。1. 青蒿素和10-脱氧青蒿素的C-9类似物的合成和比较分子场分析。

  摘要：

  一系列 C-9 β 取代的青蒿素类似物 (2-21) 是通过总合成中间体 57 的二价阴离子烷基化合成的，随后进行臭氧分解/酸化，或通过从 (+)-9-去甲基青蒿素衍生的烯醇化物的烷基化， 2.通过亲核环氧化物开环合成无活性无环类似物22和23，通过替代路线制备环收缩类似物24。10-Deoxo-9-烷基衍生物68和70是从制备9-烷基衍生物的中间体集中合成的。在抗药性恶性疟原虫的 W-2 和 D-6 克隆中进行体外生物测定。9-烷基内酯衍生物的比较分子场分析 (CoMFA) 提供了一个具有交叉验证 r2 = 0.793 的模型。包含无活性的 1-脱氧青蒿素类似物 26-42 提供了一个值为 0.857 的模型。使用 CoMFA 模型以良好的准确性预测了许多其他不同结构的类似物 (43-56) 的活性。

  DOI：

  10.1021/jm00078a017
• 作为产物：
  描述：

  2,5,5-trimethyl-2-<2'-<4''-(carboxymethyl)-1''(R)-methyl-3''-<(trimethylsilyl)methylene>cyclohex-2''-yl>ethyl>-1,3-dioxane 、 alkaline earth salt of/the/ methylsulfuric acid 在 lithium diisopropyl amide 作用下， 以 四氢呋喃 为溶剂， 反应 5.17h， 以88%的产率得到(1''S,1'''S,3''S,6''R)-(2''E)-2-<2'-<3''-(1'''-carboxypentyl)-6''-methyl-2''-<(trimethylsilyl)methylene>cyclohexyl>ethyl>-2,5,5-trimethyl-1,3-dioxane
  参考文献：
  名称：

  Structure−Activity Relationships of the Antimalarial Agent Artemisinin. 7. Direct Modification of (+)-Artemisinin and In Vivo Antimalarial Screening of New, Potential Preclinical Antimalarial Candidates

  摘要：

  On the basis of earlier reported quantitative structure-activity relationship studies, a series of 9beta-16-(arylalkyl)-10-deoxoartemisinins were proposed for synthesis. Several of the new compounds 7 and 10-14 were synthesized, employing the key synthetic intermediate 23. In a second approach, the natural product (+)-artemisinic acid was utilized as an acceptor for conjugate addition, and the resultant homologated acids were subjected to singlet oxygenation and acid treatment to provide artemisinin analogues. Under a new approach, we developed A one step reaction for the interconversion of artemisinin 1 into artemisitene 22 that did not employ selenium-based reagents and found that 2-arylethyliodides would undergo facile radical-induced conjugate addition to the exomethylene lactone of 22 in good yield. The lactone carbonyls, were removed sequentially by diisobutylaluminum hydride reduction followed directly by a second reduction (BF3-etherate/Et3SiH) to afford the desired corresponding pyrans. Six additional halogen-substituted aromatic side chains were installed via 22 furnishing the bioassay candidates 15-20. The analogues were examined for in vitro antimalarial activity in the W-2 and D-6 clones of Plasmodium falciparum and were additionally tested. in vivo in Plasmodium berghei- and/or Plasmodium yoelii-infected mice. Several of the compounds emerged as highly potent orally active candidates without obvious toxicity, Of these, two were chosen for pharmacokinetic evaluation, 14 and 17.

  DOI：

  10.1021/jm020142z

文献信息

• Structure-activity relationships of the antimalarial agent artemisinin. 1. Synthesis and comparative molecular field analysis of C-9 analogs of artemisinin and 10-deoxoartemisinin
  作者：Mitchell A. Avery、Fenglan Gao、Wesley K. M. Chong、Sanjiv Mehrotra、Wilbur K. Milhous

  DOI：10.1021/jm00078a017

  日期：1993.12

  series of C-9 beta-substituted artemisinin analogs (2-21) were synthesized via dianion alkylation of the total synthetic intermediate 57 followed by subsequent ozonolysis/acidification, or by alkylation of the enolate derived from (+)-9-desmethylartemisinin, 2. Inactive acyclic analogs 22 and 23 were synthesized by nucleophilic epoxide opening and the ring contracted analog 24 was prepared by an alternate

  一系列 C-9 β 取代的青蒿素类似物 (2-21) 是通过总合成中间体 57 的二价阴离子烷基化合成的，随后进行臭氧分解/酸化，或通过从 (+)-9-去甲基青蒿素衍生的烯醇化物的烷基化， 2.通过亲核环氧化物开环合成无活性无环类似物22和23，通过替代路线制备环收缩类似物24。10-Deoxo-9-烷基衍生物68和70是从制备9-烷基衍生物的中间体集中合成的。在抗药性恶性疟原虫的 W-2 和 D-6 克隆中进行体外生物测定。9-烷基内酯衍生物的比较分子场分析 (CoMFA) 提供了一个具有交叉验证 r2 = 0.793 的模型。包含无活性的 1-脱氧青蒿素类似物 26-42 提供了一个值为 0.857 的模型。使用 CoMFA 模型以良好的准确性预测了许多其他不同结构的类似物 (43-56) 的活性。
• Structure−Activity Relationships of the Antimalarial Agent Artemisinin. 4. Effect of Substitution at C-3
  作者：Mitchell A. Avery、Sanjiv Mehrotra、Jason D. Bonk、Jeffrey A. Vroman、D. Keith Goins、Robert Miller

  DOI：10.1021/jm960200e

  日期：1996.1.1

  Novel antimalarial artemisinin analogs, 3-alkylartemisinins as well as 3-(arylalkyl)- and 3-(carboxyalkyl)artemisinins, were prepared via the synthetic intermediate 2. Formation of the N,N-dimethylhydrazones 5 and 24 and then regio- and chemoselective deprotonation followed by alkylation provided initially alkylated hydrazones that upon chromatography gave ketones 6-13 and 25-30. Direct ozonolysis of the ketones followed by in situ acidification lead directly to the formation of title compounds 14-21 and 31-36. The analogs were tested in vitro against W-2 and D-6 strains of Plasmodium falciparum and found to be in some cases much more active than the natural product (+)-artemisinin. The results were included in structure-activity relationship (CoMFA) studies for further analog design.
• Structure−Activity Relationships of the Antimalarial Agent Artemisinin. 7. Direct Modification of (+)-Artemisinin and In Vivo Antimalarial Screening of New, Potential Preclinical Antimalarial Candidates
  作者：Mitchell A. Avery、Maria Alvim-Gaston、Jeffrey A. Vroman、Baogen Wu、Arba Ager、Wallace Peters、Brian L. Robinson、William Charman

  DOI：10.1021/jm020142z

  日期：2002.9.1

  On the basis of earlier reported quantitative structure-activity relationship studies, a series of 9beta-16-(arylalkyl)-10-deoxoartemisinins were proposed for synthesis. Several of the new compounds 7 and 10-14 were synthesized, employing the key synthetic intermediate 23. In a second approach, the natural product (+)-artemisinic acid was utilized as an acceptor for conjugate addition, and the resultant homologated acids were subjected to singlet oxygenation and acid treatment to provide artemisinin analogues. Under a new approach, we developed A one step reaction for the interconversion of artemisinin 1 into artemisitene 22 that did not employ selenium-based reagents and found that 2-arylethyliodides would undergo facile radical-induced conjugate addition to the exomethylene lactone of 22 in good yield. The lactone carbonyls, were removed sequentially by diisobutylaluminum hydride reduction followed directly by a second reduction (BF3-etherate/Et3SiH) to afford the desired corresponding pyrans. Six additional halogen-substituted aromatic side chains were installed via 22 furnishing the bioassay candidates 15-20. The analogues were examined for in vitro antimalarial activity in the W-2 and D-6 clones of Plasmodium falciparum and were additionally tested. in vivo in Plasmodium berghei- and/or Plasmodium yoelii-infected mice. Several of the compounds emerged as highly potent orally active candidates without obvious toxicity, Of these, two were chosen for pharmacokinetic evaluation, 14 and 17.