(2S,4R,5R)-1-((S)-4-benzyl-2-oxo-oxazolidin-3-yl)-5-hydroxy-2,4-dimethyloct-6-yne-1,3-dione | 1439376-49-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑烷类
• 英文名称: (2S,4R,5R)-1-((S)-4-benzyl-2-oxo-oxazolidin-3-yl)-5-hydroxy-2,4-dimethyloct-6-yne-1,3-dione
• 英文别名: (2S,4R,5R)-1-[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-5-hydroxy-2,4-dimethyloct-6-yne-1,3-dione
• CAS: 1439376-49-4
• 化学式: C₂₀H₂₃NO₅
• 分子量: 357.406
• InChiKey: HFZGSRKCIREAMY-OHFALNGGSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  26
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  83.9
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (2S,4R,5R)-1-((S)-4-benzyl-2-oxo-oxazolidin-3-yl)-5-hydroxy-2,4-dimethyloct-6-yne-1,3-dione 在 吡啶 、 copper(l) iodide 、 三甲基铝 、 三溴化磷 、 三乙胺 、 N,N-二异丙基乙胺 、 tetramethylammonium triacetoxyborohydride 、 lithium diisopropyl amide 作用下， 以 四氢呋喃 、 乙醚 、 正己烷 、 正庚烷 、 二氯甲烷 、 溶剂黄146 、 N,N-二甲基甲酰胺 、 甲苯 、 乙腈 为溶剂， 反应 45.0h， 生成 (6R,7S,8S,9R,E)-ethyl 9-(tert-butyldimethylsilyloxy)-7-(methoxymethoxy)-5,6,8-trimethyldodec-4-en-10-ynoate
  参考文献：
  名称：

  不同的全合成抗有丝分裂剂Leodermatolide。

  摘要：

  微妙但与众不同：生物学上很有前途的抗有丝分裂剂leiodermatolide的立体结构尚不确定。以开环炔烃复分解为关键步骤的短而有效且灵活的全合成方法现已解决了这个难题。所示结构和可能的异构体在1 H NMR光谱中的细微差异证明对于该赋值是无价的。

  DOI：

  10.1002/anie.201206670
• 作为产物：
  描述：

  (S)-4-苄基-3-丙酰基-2-噁唑烷酮 在 tin(II) trifluoromethanesulfonate 、 三氟甲磺酸二丁硼 、 三氧化硫吡啶 、 三乙胺 作用下， 以 二氯甲烷 、 二甲基亚砜 为溶剂， 反应 5.25h， 生成 (2S,4R,5R)-1-((S)-4-benzyl-2-oxo-oxazolidin-3-yl)-5-hydroxy-2,4-dimethyloct-6-yne-1,3-dione
  参考文献：
  名称：

  不同的全合成抗有丝分裂剂Leodermatolide。

  摘要：

  微妙但与众不同：生物学上很有前途的抗有丝分裂剂leiodermatolide的立体结构尚不确定。以开环炔烃复分解为关键步骤的短而有效且灵活的全合成方法现已解决了这个难题。所示结构和可能的异构体在1 H NMR光谱中的细微差异证明对于该赋值是无价的。

  DOI：

  10.1002/anie.201206670

文献信息

• Divergent Total Synthesis of the Antimitotic Agent Leiodermatolide
  作者：Jens Willwacher、Nina Kausch-Busies、Alois Fürstner

  DOI：10.1002/anie.201206670

  日期：2012.11.26

  Subtle but distinctive: The stereostructure of the biologically highly promising antimitotic agent leiodermatolide was uncertain. A short, efficient, and flexible total synthesis based on ring‐closing alkyne metathesis as the key step has now solved the puzzle. Subtle differences in the 1H NMR spectra of the structure shown and the conceivable isomer proved invaluable for the assignment.

  微妙但与众不同：生物学上很有前途的抗有丝分裂剂leiodermatolide的立体结构尚不确定。以开环炔烃复分解为关键步骤的短而有效且灵活的全合成方法现已解决了这个难题。所示结构和可能的异构体在1 H NMR光谱中的细微差异证明对于该赋值是无价的。
• Leiodermatolide derivatives and their use
  申请人：Studiengesellschaft Kohle mbH

  公开号：EP3012257A1

  公开（公告）日：2016-04-27

  The present invention refers to leiodermatolide derivatives and the use thereof as cytotoxic agents, in particular in the form of ADC s.

  本发明涉及雷欧皮质内酯衍生物及其作为细胞毒性药剂的用途，特别是作为ADC的形式。
• Synthesis, Molecular Editing, and Biological Assessment of the Potent Cytotoxin Leiodermatolide
  作者：Damien Mailhol、Jens Willwacher、Nina Kausch-Busies、Elizabeth E. Rubitski、Zhanna Sobol、Maik Schuler、My-Hanh Lam、Sylvia Musto、Frank Loganzo、Andreas Maderna、Alois Fürstner

  DOI：10.1021/ja508846g

  日期：2014.11.5

  It was by way of total synthesis that the issues concerning the stereostructure of leiodermatolide (1) have recently been solved; with the target now being unambiguously defined, the mission of synthesis changes as to secure a meaningful supply of this exceedingly scarce natural product derived from a deep-sea sponge. To this end, a scalable route of 19 steps (longest linear sequence) has been developed, which features a catalytic asymmetric propargylation of a highly enolizable beta-keto-lactone, a ring closing alkyne metathesis and a modified Stille coupling as the key transformations. Deliberate digression from this robust blueprint brought a first set of analogues into reach, which allowed the lead qualities of 1 to be assessed. The acquired biodata show that 1 is a potent cytotoxin in human tumor cell proliferation assays, distinguished by GI(50) values in the =3 nM range even for cell lines expressing the Pgp efflux transporter. Studies with human U2OS cells revealed that 1 causes mitotic arrest, micronucleus induction, centrosome amplification and tubulin disruption, even though no evidence for direct tubulin binding has been found in cell-free assays; moreover, the compound does not seem to act through kinase inhibition. Indirect evidence points at centrosome declustering as a possible mechanism of action, which provides a potentially rewarding outlook in that centrosome declustering agents hold promise of being inherently selective for malignant over healthy human tissue.