(R,Z)-3-butyl-4-pentylideneoxetan-2-one | 898799-30-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 内酯类
• 英文名称: (R,Z)-3-butyl-4-pentylideneoxetan-2-one
• 英文别名: (3R,4Z)-3-butyl-4-pentylideneoxetan-2-one
• CAS: 898799-30-9
• 化学式: C₁₂H₂₀O₂
• 分子量: 196.29
• InChiKey: MJZLRAHODCHJCG-QLWWJYNRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  14
• 可旋转键数：
  6
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.75
• 拓扑面积：
  26.3
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  (R,Z)-3-butyl-4-pentylideneoxetan-2-one 在 palladium on activated charcoal 氢气 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， -78.0~-40.0 ℃ 、206.84 kPa 条件下， 反应 47.0h， 生成 (3R,4S)-3-butyl-3-methyl-4-pentyloxetan-2-one
  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
• 作为产物：
  描述：

  己酰氯 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 6.0h， 以75%的产率得到(R,Z)-3-butyl-4-pentylideneoxetan-2-one
  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

• Novel method for the asymmetric synthesis of beta-lactone compounds
  申请人：Smith W. Jeffrey

  公开号：US20060258620A1

  公开（公告）日：2006-11-16

  The present invention features methods of treating a cancer in a subject by administering an effective amount of a beta-lactone to the subject. The invention also features methods of inhibiting angiogenesis in a subject by administering an effective amount of an inhibitor of fatty acid synthase to the subject. These methods can be used to treat a variety of cancers and other diseases and conditions. The invention also features methods of identifying beta-lactones and other compounds that can be used in the methods of the invention for the treatment of tumors, inhibition of angiogenesis, and the treatment of diseases and conditions that involve pathological angiogenesis. The invention also features methods of synthesizing beta-lactones and features novel beta-lactone compounds.

  本发明涉及通过向患者施用有效量的β-内酰胺来治疗患者身上的癌症的方法。本发明还涉及通过向患者施用脂肪酸合成酶抑制剂的有效量来抑制患者身上的血管生成的方法。这些方法可以用于治疗各种癌症和其他疾病和病况。本发明还涉及识别β-内酰胺和其他化合物的方法，这些化合物可以用于本发明中用于治疗肿瘤、抑制血管生成以及治疗涉及病理性血管生成的疾病和病况的方法。本发明还涉及合成β-内酰胺的方法和新型β-内酰胺化合物的特点。
• Method for the asymmetric synthesis of beta-lactone compounds
  申请人：The Burnham Institute for Medical Research

  公开号：US07728153B2

  公开（公告）日：2010-06-01

  The present invention features methods of treating a cancer in a subject by administering an effective amount of a beta-lactone to the subject. The invention also features methods of inhibiting angiogenesis in a subject by administering an effective amount of an inhibitor of fatty acid synthase to the subject. These methods can be used to treat a variety of cancers and other diseases and conditions. The invention also features methods of identifying beta-lactones and other compounds that can be used in the methods of the invention for the treatment of tumors, inhibition of angiogenesis, and the treatment of diseases and conditions that involve pathological angiogenesis. The invention also features methods of synthesizing beta-lactones and features novel beta-lactone compounds.

  本发明涉及通过向患者施用有效剂量的β-内酰胺来治疗患者的癌症的方法。本发明还涉及通过向患者施用脂肪酸合成酶抑制剂的有效剂量来抑制患者的血管生成的方法。这些方法可用于治疗多种癌症和其他疾病和病况。本发明还涉及识别β-内酰胺和其他化合物的方法，这些化合物可用于本发明的治疗肿瘤、抑制血管生成以及治疗涉及病理性血管生成的疾病和病况的方法。本发明还涉及合成β-内酰胺的方法和新型β-内酰胺化合物。
• NOVEL METHOD FOR THE ASYMMETRIC SYNTHESIS OF BETA-LACTONE COMPOUNDS
  申请人：Smith Jeffrey W.

  公开号：US20100173982A1

  公开（公告）日：2010-07-08

  The present invention features methods of treating a cancer in a subject by administering an effective amount of a beta-lactone to the subject. The invention also features methods of inhibiting angiogenesis in a subject by administering an effective amount of an inhibitor of fatty acid synthase to the subject. These methods can be used to treat a variety of cancers and other diseases and conditions. The invention also features methods of identifying beta-lactones and other compounds that can be used in the methods of the invention for the treatment of tumors, inhibition of angiogenesis, and the treatment of diseases and conditions that involve pathological angiogenesis. The invention also features methods of synthesizing beta-lactones and features novel beta-lactone compounds.

  本发明涉及通过向受试者施用有效量的β-内酰胺来治疗癌症的方法。本发明还涉及通过向受试者施用脂肪酸合成酶抑制剂的有效量来抑制血管生成的方法。这些方法可用于治疗各种癌症和其他疾病和病况。本发明还涉及识别β-内酰胺和其他化合物的方法，这些化合物可用于本发明的治疗肿瘤、抑制血管生成以及涉及病理性血管生成的疾病和病况的方法。本发明还涉及β-内酰胺的合成方法和新型β-内酰胺化合物。
• US8124794B2
  申请人：——

  公开号：US8124794B2

  公开（公告）日：2012-02-28
• 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.