methyl (3Z)-3-[(3R)-3-(2-methoxy-2-oxoethyl)-4-oxooxetan-2-ylidene]propanoate | 898799-34-3

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: methyl (3Z)-3-[(3R)-3-(2-methoxy-2-oxoethyl)-4-oxooxetan-2-ylidene]propanoate
• CAS: 898799-34-3
• 化学式: C₁₀H₁₂O₆
• 分子量: 228.202
• InChiKey: KWKIZCQTTXIUGC-NPQKIFFKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.2
• 重原子数：
  16
• 可旋转键数：
  6
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  78.9
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  N-甲基-N-甲氧基胺盐酸盐 、 methyl (3Z)-3-[(3R)-3-(2-methoxy-2-oxoethyl)-4-oxooxetan-2-ylidene]propanoate 在 hydroxypyridine 作用下， 以 二氯甲烷 、 正戊烷 为溶剂， 反应 2.0h， 生成 (R)-3-(N-methoxy-N-methylcarbamoyl)-4-oxoheptanedioic acid dimethyl ester
  参考文献：
  名称：

  由酰氯催化，不对称制备乙烯酮二聚体。

  摘要：

  [反应：见正文]由金鸡纳生物碱催化的酰氯与二异丙基乙胺反应原位生成的单取代乙烯酮的二聚反应可高产率和对映选择性地生成乙烯酮二聚体。该反应可耐受空间上需要且功能多样的取代基。动力学研究表明，该反应的决定速率的步骤是叔胺使酰氯脱质子化以形成乙烯酮，而形成立体化学的步骤是将烯醇铵与乙烯酮相加。

  DOI：

  10.1021/ol0359517
• 作为产物：
  描述：

  丁二酸单甲酯酰氯 在 O-trimethylsilyl quinine N,N-二异丙基乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 3.0h， 以60%的产率得到methyl (3Z)-3-[(3R)-3-(2-methoxy-2-oxoethyl)-4-oxooxetan-2-ylidene]propanoate
  参考文献：
  名称：

  Practical, Catalytic, Asymmetric Synthesis of β-Lactones via a Sequential Ketene Dimerization/Hydrogenation Process:  Inhibitors of the Thioesterase Domain of Fatty Acid Synthase

  摘要：

  The recent finding that the FDA-approved antiobesity agent orlistat ( tetrahydrolipstatin, Xenical) is a potent inhibitor of the thioesterase domain of fatty acid synthase (FAS) led us to develop a concise and practical asymmetric route to pseudosymmetric 3,4-dialkyl-cis-beta-lactones. The well-documented upregulation of FAS in cancer cells makes this enzyme complex an interesting therapeutic target for cancer. The described route to 3,4-dialkyl-beta-lactones is based on a two-step process involving Calter's catalytic, asymmetric ketene dimerization of acid chlorides followed by a facial-selective hydrogenation leading to cis-substituted-beta-lactones. Importantly, the ketene dimer intermediates were found to be stable to flash chromatography, enabling opportunities for subsequent transformations of these optically active, reactive intermediates. Subsequent alpha-epimerization and alpha-alkylation or acylation led to trans-beta-lactones and beta-lactones bearing alpha-quaternary carbons, respectively. Several of the ketene dimers and beta-lactones displayed antagonistic activity (apparent K-i in the low micromolar range) in competition with a fluorogenic substrate toward a recombinant form of the thioesterase domain of fatty acid synthase. The best antagonist, a simple phenyl-substituted cis-beta-lactone 3d, displayed an apparent K-i (2.5 +/- 0.5 mu M) of only similar to 10-fold lower than that of orlistat (0.28 +/- 0.06 mu M). In addition, mechanistic studies of the ketene dimerization process by ReactionView infrared spectroscopy support previous findings that ketene formation is rate determining.

  DOI：

  10.1021/jo060392d

文献信息

• Catalytic, Asymmetric Preparation of Ketene Dimers from Acid Chlorides
  作者：Michael A. Calter、Robert K. Orr、Wei Song

  DOI：10.1021/ol0359517

  日期：2003.11.1

  monosubstituted ketenes generated in situ from the reaction of acid chlorides and diisopropylethylamine yields ketene dimers in high yields and enantioselectivities. This reaction tolerates sterically demanding and functionally diverse substituents. Kinetic studies suggest that the rate-determining step for the reaction is the deprotonation of the acid chloride by the tertiary amine to form ketene and that the

  [反应：见正文]由金鸡纳生物碱催化的酰氯与二异丙基乙胺反应原位生成的单取代乙烯酮的二聚反应可高产率和对映选择性地生成乙烯酮二聚体。该反应可耐受空间上需要且功能多样的取代基。动力学研究表明，该反应的决定速率的步骤是叔胺使酰氯脱质子化以形成乙烯酮，而形成立体化学的步骤是将烯醇铵与乙烯酮相加。
• Practical, Catalytic, Asymmetric Synthesis of β-Lactones via a Sequential Ketene Dimerization/Hydrogenation Process:  Inhibitors of the Thioesterase Domain of Fatty Acid Synthase
  作者：Vikram C. Purohit、Robyn D. Richardson、Jeffrey W. Smith、Daniel Romo

  DOI：10.1021/jo060392d

  日期：2006.6.1

  The recent finding that the FDA-approved antiobesity agent orlistat ( tetrahydrolipstatin, Xenical) is a potent inhibitor of the thioesterase domain of fatty acid synthase (FAS) led us to develop a concise and practical asymmetric route to pseudosymmetric 3,4-dialkyl-cis-beta-lactones. The well-documented upregulation of FAS in cancer cells makes this enzyme complex an interesting therapeutic target for cancer. The described route to 3,4-dialkyl-beta-lactones is based on a two-step process involving Calter's catalytic, asymmetric ketene dimerization of acid chlorides followed by a facial-selective hydrogenation leading to cis-substituted-beta-lactones. Importantly, the ketene dimer intermediates were found to be stable to flash chromatography, enabling opportunities for subsequent transformations of these optically active, reactive intermediates. Subsequent alpha-epimerization and alpha-alkylation or acylation led to trans-beta-lactones and beta-lactones bearing alpha-quaternary carbons, respectively. Several of the ketene dimers and beta-lactones displayed antagonistic activity (apparent K-i in the low micromolar range) in competition with a fluorogenic substrate toward a recombinant form of the thioesterase domain of fatty acid synthase. The best antagonist, a simple phenyl-substituted cis-beta-lactone 3d, displayed an apparent K-i (2.5 +/- 0.5 mu M) of only similar to 10-fold lower than that of orlistat (0.28 +/- 0.06 mu M). In addition, mechanistic studies of the ketene dimerization process by ReactionView infrared spectroscopy support previous findings that ketene formation is rate determining.