(+)-octahydro-9β-butyl-3,6α-dimethyl-3,12-epoxy-12H-pyrano<4,3-j>-1,2-benzodioxepin-10(3H)-one | 154698-10-9

• 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: (+)-octahydro-9β-butyl-3,6α-dimethyl-3,12-epoxy-12H-pyrano<4,3-j>-1,2-benzodioxepin-10(3H)-one
• 英文别名: 9-butylartemisinin；(1R,4S,5R,8S,9R,12S,13R)-9-butyl-1,5-dimethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.04,13.08,13]hexadecan-10-one
• CAS: 154698-10-9
• 化学式: C₁₈H₂₈O₅
• 分子量: 324.417
• InChiKey: UYVNDCPGEVTENG-REMDBXRQSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  23
• 可旋转键数：
  3
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.94
• 拓扑面积：
  54
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (+)-octahydro-9β-butyl-3,6α-dimethyl-3,12-epoxy-12H-pyrano<4,3-j>-1,2-benzodioxepin-10(3H)-one 在 二异丁基氢化铝 作用下， 以 正己烷 、 二氯甲烷 为溶剂， 反应 1.25h， 以100%的产率得到(1R,4S,5R,8S,9R,12R,13R)-9-butyl-1,5-dimethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.04,13.08,13]hexadecan-10-ol
  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
• 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 在 硫酸 、 silica gel 、 臭氧 、 lithium diisopropyl amide 作用下， 反应 2.0h， 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

文献信息

• C-16 Artemisinin Derivatives and Their Antimalarial and Cytotoxic Activities:  Syntheses of Artemisinin Monomers, Dimers, Trimers, and Tetramers by Nucleophilic Additions to Artemisitene
  作者：Sanchai Ekthawatchai、Sumalee Kamchonwongpaisan、Palangpon Kongsaeree、Bongkoch Tarnchompoo、Yodhathai Thebtaranonth、Yongyuth Yuthavong

  DOI：10.1021/jm0103007

  日期：2001.12.1

  Nucleophilic additions of lithium keto and ester enolates and mono- and bifunctional Grignard reagents to artemisitene provided C-16-derived artemisinin monomers, dimers, trimers, and tetramers whose antimalarial and cytotoxic activities have been evaluated.

  锂酮和酯烯醇化物以及单和双功能格氏试剂向青蒿素的亲核加成提供了 C-16 衍生的青蒿素单体、二聚体、三聚体和四聚体，其抗疟和细胞毒活性已得到评估。
• Structure−Activity Relationships of the Antimalarial Agent Artemisinin. 5. Analogs of 10-Deoxoartemisinin Substituted at C-3 and C-9
  作者：Mitchell A. Avery、Sanjiv Mehrotra、Theresa L. Johnson、Jason D. Bonk、Jeffrey A. Vroman、Robert Miller

  DOI：10.1021/jm9603577

  日期：1996.1.1

  the presence of triethylsilane. In this manner, 10-deoxoartemisinin (3) could be obtained from artemisinin (1) in greater than 95% overall yield. All analogs were tested in vitro against W-2 and D-6 strains of Plasmodium falciparum. Several of the analogs were much more active than the natural product (+)-artemisinin (1) or 10-deoxoartemisinin (3). Conventional structure-activity relationships are discussed

  10-脱氧青蒿素 3 的新型 3-和 9-取代类似物 (4-19) 是从相应的已知内酯通过硼氢化钠和三氟化硼乙醚合一锅还原制备的。在小规模反应中遇到了与这种非均相反应相关的重现性问题，因此寻求替代方法来减少这种反应。使用两步序列，包括用二异丁基氢化铝低温还原，然后在三乙基硅烷的存在下用三氟化硼醚合物脱氧，通过相应的中间体内酯将内酯转化为四氢吡喃的重现性更高。以这种方式，10-脱氧青蒿素（3）可以从青蒿素（1）中获得，总产率超过 95%。所有类似物都针对恶性疟原虫的 W-2 和 D-6 菌株进行了体外测试。一些类似物比天然产物 (+)-青蒿素 (1) 或 10-脱氧青蒿素 (3) 更具活性。讨论了与生物测定数据相关的常规构效关系。
• 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. 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.