2,5,5-trimethyl-2-<2'-<4''-(carboxymethyl)-1''(R)-methyl-3''-<(trimethylsilyl)methylene>cyclohex-2''-yl>ethyl>-1,3-dioxane | 116399-92-9

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 2,5,5-trimethyl-2-<2'-<4''-(carboxymethyl)-1''(R)-methyl-3''-<(trimethylsilyl)methylene>cyclohex-2''-yl>ethyl>-1,3-dioxane
• 英文别名: 2,5,5-trimethyl-2-(2'-{4''-(carboxymethyl)-1''(R)-methyl-3''-[(trimethylsilyl)methylene]cyclohex-2''-yl}ethyl)-1,3-dioxane；2-[(1S,2Z,3S,4R)-4-methyl-3-[2-(2,5,5-trimethyl-1,3-dioxan-2-yl)ethyl]-2-(trimethylsilylmethylidene)cyclohexyl]acetic acid
• CAS: 116399-92-9
• 化学式: C₂₂H₄₀O₄Si
• 分子量: 396.643
• InChiKey: GGZCGCFRYXRMFC-UWTLDHTDSA-N

物化性质

• 沸点：
  473.0±20.0 °C(Predicted)
• 密度：
  0.982±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.5
• 重原子数：
  27
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.86
• 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：

  2,5,5-trimethyl-2-<2'-<4''-(carboxymethyl)-1''(R)-methyl-3''-<(trimethylsilyl)methylene>cyclohex-2''-yl>ethyl>-1,3-dioxane 在 氧气 、 草酸 、 silica gel 、 臭氧 、 三氟乙酸 、 lithium diisopropyl amide 作用下， 以 二氯甲烷 为溶剂， 反应 23.5h， 生成 青蒿素
  参考文献：
  名称：

  Stereoselective total synthesis of (+)-artemisinin, the antimalarial constituent of Artemisia annua L

  摘要：

  A 10-step stereoselective total synthesis of the antimalarial cadinane sesquiterpene (+)-artemisinin (1) is described. Elaboration of (R)-(+)-pulegone to the known sulfoxide 11 was followed by dianion alkylation and desulfurization to provide the trans-2,3-substituted cyclohexanone 7. Homologation to the cyclohexenecarboxaldehyde 6 was followed by a diastereoselective silyl anion addition to afford the silyl acetate 15. Tandem Claisen ester-enolate rearrangement and dianion alkylation furnished the fully functionalized vinylsilane 18 that underwent abnormal ozonolysis and cyclization to provide the natural product 1.

  DOI：

  10.1021/ja00029a028
• 作为产物：
  描述：

  2,5,5-trimethyl-2-<2'-<1''R-methyl-3''-<(trimethylsilyl)hydroxymethyl>cyclohex-3''-en-2''-yl>ethyl>-1,3-dioxane acetyl ester 在 正丁基锂 、 二乙胺 作用下， 以 四氢呋喃 、 正己烷 为溶剂， 以63%的产率得到2,5,5-trimethyl-2-<2'-<4''-(carboxymethyl)-1''(R)-methyl-3''-<(trimethylsilyl)methylene>cyclohex-2''-yl>ethyl>-1,3-dioxane
  参考文献：
  名称：

  Stereoselective total synthesis of (+)-artemisinin, the antimalarial constituent of Artemisia annua L

  摘要：

  A 10-step stereoselective total synthesis of the antimalarial cadinane sesquiterpene (+)-artemisinin (1) is described. Elaboration of (R)-(+)-pulegone to the known sulfoxide 11 was followed by dianion alkylation and desulfurization to provide the trans-2,3-substituted cyclohexanone 7. Homologation to the cyclohexenecarboxaldehyde 6 was followed by a diastereoselective silyl anion addition to afford the silyl acetate 15. Tandem Claisen ester-enolate rearrangement and dianion alkylation furnished the fully functionalized vinylsilane 18 that underwent abnormal ozonolysis and cyclization to provide the natural product 1.

  DOI：

  10.1021/ja00029a028

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. 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。
• Avery; Bonk; Chong, Journal of Medicinal Chemistry, 1995, vol. 38, # 26, p. 5038 - 5044
  作者：Avery、Bonk、Chong、Mehrotra、Miller、Milhous、Goins、Venkatesan、Wyandt、Khan、Avery

  DOI：——

  日期：——
• Radiolabeled antimalarials: Synthesis of 14C-artemisinin
  作者：Mitchell A. Avery、Jason D. Bonk、James Bupp

  DOI：10.1002/(sici)1099-1344(199603)38:3<263::aid-jlcr839>3.0.co;2-o

  日期：1996.3

  The stereoselective total synthesis of the antimalarial agent C-14-(+)-artemisinin (1), incorporating C-14 at C-16 (C-9 methyl) is reported, in 18% radiochemical yield from acid 3.
• The Total synthesis of (+)-artemisinin and (+)-9-desmethyltemesinin
  作者：Mitchell A. Avery、Clive Jennings-White、Wesley K.M. Chong

  DOI：10.1016/s0040-4039(00)96582-1

  日期：1987.1