methyl {(2S,3S,6R)-[[1E,3E,11R,10R,9R,8R,7R,5S]-7,8-epoxy-11-hydroxy-10-methoxy-1,5,7,9-tetramethyldodeca-1,3-dienyl]-3-methyloxan-6-yl}ethanoate | 187962-44-3

• 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: methyl {(2S,3S,6R)-[[1E,3E,11R,10R,9R,8R,7R,5S]-7,8-epoxy-11-hydroxy-10-methoxy-1,5,7,9-tetramethyldodeca-1,3-dienyl]-3-methyloxan-6-yl}ethanoate
• 英文别名: methyl 2-((2R,5S,6S)-6-((S,2E,4E)-7-((2R,3R)-3-((2R,3R,4R)-4-hydroxy-3-methoxypentan-2-yl)-2-methyloxiran-2-yl)-6-methylhepta-2,4-dien-2-yl)-5-methyltetrahydro-2H-pyran-2-yl)acetate；Herboxidiene methyl ester；methyl 2-[(2R,5S,6S)-6-[(2E,4E,6S)-7-[(2R,3R)-3-[(2R,3R,4R)-4-hydroxy-3-methoxypentan-2-yl]-2-methyloxiran-2-yl]-6-methylhepta-2,4-dien-2-yl]-5-methyloxan-2-yl]acetate
• CAS: 187962-44-3
• 化学式: C₂₆H₄₄O₆
• 分子量: 452.632
• InChiKey: HMHMUCAMCRPACN-DGJNZOEVSA-N

物化性质

• 沸点：
  532.5±35.0 °C(Predicted)
• 密度：
  1.027±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  32
• 可旋转键数：
  12
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.81
• 拓扑面积：
  77.5
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  methyl {(2S,3S,6R)-[[1E,3E,11R,10R,9R,8R,7R,5S]-7,8-epoxy-11-hydroxy-10-methoxy-1,5,7,9-tetramethyldodeca-1,3-dienyl]-3-methyloxan-6-yl}ethanoate 在 三甲基氢氧化锡 作用下， 以 1,1-二氯乙烷 为溶剂， 反应 6.0h， 以98%的产率得到3-{[(6,7-二乙氧基-1,2,3,4-四氢萘-2-基)氨基]甲基}-6-(乙烯氧基)环己-2,4-二烯-1-酮盐酸
  参考文献：
  名称：

  A Stereoselective Synthesis of (+)-Herboxidiene/GEX1A

  摘要：

  A stereoselective synthesis of (+)-herboxidiene is described. The convergent synthesis utilized a Suzuki cross-coupling reaction to assemble the key segments. The synthesis of the functionalized tetrahydropyran ring utilized an Achmatowicz reaction as the key step. The synthesis of the C10-C19 segment was accomplished using Brown's crotylboration, asymmetric alkylation, and a stereoselective allylic chlorination reactions.

  DOI：

  10.1021/ol102549a
• 作为产物：
  描述：

  (2S,6S)-2-allyl-6-((tert-butyldimethylsilyloxy)methyl)-2H-pyran-3(6H)-one 在 chromium dichloride 、 盐酸 、 叔丁基过氧化氢 、 4-二甲氨基吡啶 、 platinum(IV) oxide 、 sodium chlorite 、 sodium tetrahydroborate 、 四(三苯基膦)钯 、 2,6-二叔丁基吡啶 、 sodium dihydrogenphosphate dihydrate 、 bis(acetylacetonate)oxovanadium 、 二甲基硫 、 偶氮二异丁腈 、 cerium(III) chloride heptahydrate 、 三(三甲基硅基)硅烷 、 硫酸 、 氢气 、 diethylzinc 、 potassium carbonate 、 caesium carbonate 、 戴斯-马丁氧化剂 、 臭氧 、 mercury(II) sulfate 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 四氢呋喃 、 甲醇 、 2-甲基-2-丁烯 、 1,1-二氯乙烷 、 正己烷 、 二氯甲烷 、 水 、 甲苯 、 叔丁醇 、 苯 为溶剂， 反应 24.92h， 生成 methyl {(2S,3S,6R)-[[1E,3E,11R,10R,9R,8R,7R,5S]-7,8-epoxy-11-hydroxy-10-methoxy-1,5,7,9-tetramethyldodeca-1,3-dienyl]-3-methyloxan-6-yl}ethanoate
  参考文献：
  名称：

  A Stereoselective Synthesis of (+)-Herboxidiene/GEX1A

  摘要：

  A stereoselective synthesis of (+)-herboxidiene is described. The convergent synthesis utilized a Suzuki cross-coupling reaction to assemble the key segments. The synthesis of the functionalized tetrahydropyran ring utilized an Achmatowicz reaction as the key step. The synthesis of the C10-C19 segment was accomplished using Brown's crotylboration, asymmetric alkylation, and a stereoselective allylic chlorination reactions.

  DOI：

  10.1021/ol102549a

文献信息

• The synthesis and evaluation of the antiproliferative activity of deacidified GEX1A analogues
  作者：Takamichi Imaizumi、Hiroshi Nakagawa、Ran Hori、Yasuo Watanabe、Shiro Soga、Kyoichiro Iida、Hideyuki Onodera

  DOI：10.1038/ja.2016.166

  日期：2017.5

  assumed that the carboxylic acid moiety was one of the causes of this toxicity. In this study, a series of amide, carbamate and urea analogues of 1 were synthesized and their antiproliferative activity was evaluated in vitro. The synthesis of urea analogues featured Curtius rearrangement following amine treatment with the one-pot procedure from 1. Furthermore, a structure-activity relationship study of the

  GEX1A / herboxidiene（1）是从链霉菌（Streptomyces sp。）分离得到的天然产物。据报道，其靶向前mRNA剪接过程。尽管已显示1在体内具有抗肿瘤活性，但连续给药1则可在小鼠中观察到体重减轻。我们假设羧酸部分是这种毒性的原因之一。在这项研究中，合成了一系列1的酰胺，氨基甲酸酯和尿素类似物，并在体外评估了它们的抗增殖活性。尿素类似物的合成具有从1开始的一锅法胺处理后经过Curtius重排的特征。此外，尿素类似物的结构-活性关系研究表明，药理学上优选的碱性侧链是可以接受的，并且化合物9g与母体等价1。
• Herboxidiene: Determination of absolute configuration by degradation and synthetic studies
  作者：A.J.F. Edmunds、W. Trueb、W. Oppolzer、P. Cowley

  DOI：10.1016/s0040-4020(97)00021-5

  日期：1997.2

  Degradation of the novel polyketide herbicide herboxidiene leads to useful fragments for further analogue synthesis and also enabled determination of the absolute configuration of the natural product via asymmetric synthesis of the respective fragments.

  新的聚酮化合物除草剂除草二烯的降解导致有用的片段用于进一步的类似物合成，并且还能够通过各个片段的不对称合成来确定天然产物的绝对构型。
• A Total Synthesis of Herboxidiene Methyl Ester
  作者：Martin G. Banwell、Rajaratnam Premraj、Malcolm D. McLeod、Gregory W. Simpson

  DOI：10.3987/com-12-12597

  日期：——

  The total synthesis of the methyl ester, 35, of herboxidiene (1, a.k.a. GEX1A and TAN-1609), a polyketide displaying both herbicidal and anti-tumor activity, is described. The convergent reaction sequence involves, in its closing stages, the union of the phosphine oxide 3 with the aldehyde 21 to deliver, via a Horner-Wittig reaction with accompanying epimerization at C12, compound 33 that after deprotection affords an alcohol, 34, capable of participating in a regio- and diastereo-selective epoxidation reaction to give target 35. Phosphine oxide 3 was prepared via the intramolecular hetero-Michael addition of a secondary alcohol to a tethered and Z-configured acrylate while aldehyde 21 was generated, in the crucial step of the relevant reaction sequence, via an Ireland-Claisen rearrangement reaction.
• Pre-mRNA Splicing-Modulatory Pharmacophores: The Total Synthesis of Herboxidiene, a Pladienolide–Herboxidiene Hybrid Analog and Related Derivatives
  作者：Chandraiah Lagisetti、Maria V. Yermolina、Lalit Kumar Sharma、Gustavo Palacios、Brett J. Prigaro、Thomas R. Webb

  DOI：10.1021/cb400695j

  日期：2014.3.21

  Herboxidiene is a natural product that has previously been shown to exhibit antitumor activity by targeting the spliceosome. This activity makes herboxidiene a valuable starting point for the development of anticancer drugs. Here, we report an improved enantioselective synthesis of herboxidiene and the first report of its biologically active totally synthetic analog: 6-norherboxidiene. The synthesis of the tetrahydropyran moiety utilizes the novel application of inverse electron-demand Diels-Alder chemistry and the Ferrier-type rearrangement as key steps. We report, for the first time, cytotoxicity IC(50)s for synthetic herboxidiene and analogs in human tumor cell lines. We have also demonstrated that synthetic herboxidiene and its analogs can potently modulate the alternate splicing of MDM-2 pre-mRNA.