(1S,2R)-8,9-dihydroxy-3,6,8-trimethyl-7-spiro-cyclopropylbicyclo[4.3.0]nona-1,3,5-triene | 652134-50-4

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: (1S,2R)-8,9-dihydroxy-3,6,8-trimethyl-7-spiro-cyclopropylbicyclo[4.3.0]nona-1,3,5-triene
• 英文别名: (6'R,7'S)-2',4',6'-trimethyl-6',7'-dihydrospiro[cyclopropane-1,5'-indene]-6',7'-diol；(4S,5R)-2,5,7-trimethylspiro[4H-indene-6,1'-cyclopropane]-4,5-diol
• CAS: 652134-50-4
• 化学式: C₁₄H₁₈O₂
• 分子量: 218.296
• InChiKey: FSYXIZGUFPMLTQ-STQMWFEESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.3
• 重原子数：
  16
• 可旋转键数：
  0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  40.5
• 氢给体数：
  2
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  (1S,2R)-8,9-dihydroxy-3,6,8-trimethyl-7-spiro-cyclopropylbicyclo[4.3.0]nona-1,3,5-triene 在 2-碘酰基苯甲酸 作用下， 以 二甲基亚砜 为溶剂， 以83%的产率得到5'-羟基-2',5',7'-三甲基螺[环丙烷-1,6'-茚]-4'-酮
  参考文献：
  名称：

  (-)-酰基富烯和(-)-异富烯的对映选择性全合成

  摘要：

  我们报告了对 (-)-acylfulvene ( 1 ) 和 (-)-irofulven ( 2 )的对映选择性全合成的完整描述，其特征是复分解反应，用于快速组装这些抗肿瘤药物的分子框架。我们讨论了 (1) 使用应变环丙基烯酮硫缩醛的 Evans Cu 催化羟醛加成反应的应用，(2) 在具有挑战性的环境中有效的烯炔闭环复分解级联反应，(3) 用于后期阶段的试剂 IPNBSH还原烯丙基转座反应，和（4）的形成最终RCM /脱氢序列（ - ） - acylfulvene（1）和（ - ） - irofulven（2）。

  DOI：

  10.1021/jo901926z
• 作为产物：
  描述：

  (1S,2R)-1,2-dihydroxy-2,4-dimethyl-3-spiro-cyclopropyl-1-[(2S)-2-methoxy-phenylacetyloxy]bicylo[4.3.0]nona-5,9-dien-7-one 在 cerium(III) chloride 、 甲基锂 作用下， 以 四氢呋喃 为溶剂， 反应 1.0h， 以90%的产率得到(1S,2R)-8,9-dihydroxy-3,6,8-trimethyl-7-spiro-cyclopropylbicyclo[4.3.0]nona-1,3,5-triene
  参考文献：
  名称：

  Investigating the Role of Stereochemistry in the Activity of Anticancer Acylfulvenes:  Synthesis, Reductase-Mediated Bioactivation, and Cellular Toxicity

  摘要：

  Acylfulvenes comprise a family of semisynthetic natural product derivatives with potent antitumor activities. Previous studies indicated that acylfulvenes are bioactivated by NADPH-dependent alkenal/one reductase (AOR), presumably generating intermediates with the capacity to alkylate cellular targets, such as DNA, proteins, and glutathione. This process is thought to induce apoptosis, and the chemical and biochemical pathways involved are topics of current investigation. In this study, four acylfulvene analogues were synthesized: (-)-acylfulvene, (+)-acylfulvene, (-)-(hydroxymethyl)acylfulvene, and (+)-(hydroxyrnethyl)-acylfulvene. These compounds were synthesized by a chiral-resolution method, described for the first time in this report, and by asymmetric synthesis using a method formally demonstrated previously. Cell toxicity studies indicate a positive con-elation between AOR level and acylfulvene sensitivity. The absolute configuration of acylfulvene analogues has a significant influence on cytotoxicity. (-)-(Hydroxymethyl)acylfulvene is 25 times more potent than (+)-(hydroxymethyl)acylfulvene in cells transfected with an AOR overexpression vector. Based on kinetic parameters, the rates of AOR-mediated activation are more strongly dependent on acylfulvene substitution than on absolute stereochemistry. These data support the role of AOR-mediated metabolism and indicate the involvement of other stereochemically dictated pathways, such as transport and biomolecule binding, in contributing to the cytotoxicity of acylfulvenes.

  DOI：

  10.1021/jm051104t

文献信息

• Synthesis and Biological Activity of Enantiomers of Antitumor Irofulven
  作者：Trevor C. McMorris、Michael D. Staake、Michael J. Kelner

  DOI：10.1021/jo035084j

  日期：2004.2.1

  Stereoselective synthesis of (−)-irofulven has been achieved by cycloaddition of (R)-5-chloro-5-methyl-2-cyclopentenone to the 1,3-dipolar intermediate from 1-acetyl-1-(diazoacetyl)cyclopropane. The enantiomer, (+)-irofulven, was prepared in a similar way starting with (S)-5-chloro-5-methyl-2-cyclopentenone. (+)-Irofulven was 5 to 6 times less toxic than (−)-irofulven to adenocarcinoma (MV 522) cells

  通过将（R）-5-氯-5-甲基-2-环戊烯酮环加成到1-乙酰基-1-（重氮乙酰基）环丙烷的1,3-偶极中间体中，已经实现了（-）-碘富勒烯的立体选择性合成。以（S）-5-氯-5-甲基-2-环戊烯酮为起始原料，以类似的方式制备对映体（+）-碘伏富烯。（+）-艾洛富尔文对腺癌（MV 522）细胞的毒性比（-）-艾洛富尔文低5至6倍。
• Enantioselective Total Synthesis of (−)-Acylfulvene and (−)-Irofulven
  作者：Dustin S. Siegel、Grazia Piizzi、Giovanni Piersanti、Mohammad Movassaghi

  DOI：10.1021/jo901926z

  日期：2009.12.18

  We report our full account of the enantioselective total synthesis of (−)-acylfulvene (1) and (−)-irofulven (2), which features metathesis reactions for the rapid assembly of the molecular framework of these antitumor agents. We discuss (1) the application of an Evans Cu-catalyzed aldol addition reaction using a strained cyclopropyl ketenethioacetal, (2) an efficient enyne ring-closing metathesis cascade

  我们报告了对 (-)-acylfulvene ( 1 ) 和 (-)-irofulven ( 2 )的对映选择性全合成的完整描述，其特征是复分解反应，用于快速组装这些抗肿瘤药物的分子框架。我们讨论了 (1) 使用应变环丙基烯酮硫缩醛的 Evans Cu 催化羟醛加成反应的应用，(2) 在具有挑战性的环境中有效的烯炔闭环复分解级联反应，(3) 用于后期阶段的试剂 IPNBSH还原烯丙基转座反应，和（4）的形成最终RCM /脱氢序列（ - ） - acylfulvene（1）和（ - ） - irofulven（2）。
• Investigating the Role of Stereochemistry in the Activity of Anticancer Acylfulvenes:  Synthesis, Reductase-Mediated Bioactivation, and Cellular Toxicity
  作者：Jiachang Gong、James F. Neels、Xiang Yu、Thomas W. Kensler、Lisa A. Peterson、Shana J. Sturla

  DOI：10.1021/jm051104t

  日期：2006.4.1

  Acylfulvenes comprise a family of semisynthetic natural product derivatives with potent antitumor activities. Previous studies indicated that acylfulvenes are bioactivated by NADPH-dependent alkenal/one reductase (AOR), presumably generating intermediates with the capacity to alkylate cellular targets, such as DNA, proteins, and glutathione. This process is thought to induce apoptosis, and the chemical and biochemical pathways involved are topics of current investigation. In this study, four acylfulvene analogues were synthesized: (-)-acylfulvene, (+)-acylfulvene, (-)-(hydroxymethyl)acylfulvene, and (+)-(hydroxyrnethyl)-acylfulvene. These compounds were synthesized by a chiral-resolution method, described for the first time in this report, and by asymmetric synthesis using a method formally demonstrated previously. Cell toxicity studies indicate a positive con-elation between AOR level and acylfulvene sensitivity. The absolute configuration of acylfulvene analogues has a significant influence on cytotoxicity. (-)-(Hydroxymethyl)acylfulvene is 25 times more potent than (+)-(hydroxymethyl)acylfulvene in cells transfected with an AOR overexpression vector. Based on kinetic parameters, the rates of AOR-mediated activation are more strongly dependent on acylfulvene substitution than on absolute stereochemistry. These data support the role of AOR-mediated metabolism and indicate the involvement of other stereochemically dictated pathways, such as transport and biomolecule binding, in contributing to the cytotoxicity of acylfulvenes.