(3R,4S)-4-(2-cyclohexylethyl)-3-(cyclohexylmethyl)oxetan-2-one | 898799-38-7

• 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: (3R,4S)-4-(2-cyclohexylethyl)-3-(cyclohexylmethyl)oxetan-2-one
• CAS: 898799-38-7
• 化学式: C₁₈H₃₀O₂
• 分子量: 278.435
• InChiKey: BCJWNGUORPRKFK-SJORKVTESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.5
• 重原子数：
  20
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.94
• 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：

  (3R,4S)-4-(2-cyclohexylethyl)-3-(cyclohexylmethyl)oxetan-2-one 在 四甲基乙二胺 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 为溶剂， 反应 0.5h， 以40%的产率得到trans-(3S,4S)-4-(2-cyclohexylethyl)-3-(cycloexylmethyl)oxetan-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：

  3-环己基丙酰氯 在 palladium on activated charcoal 、 O-trimethylsilyl quinine 氢气 、 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 6.5h， 生成 (3R,4S)-4-(2-cyclohexylethyl)-3-(cyclohexylmethyl)oxetan-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

• 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.