(5E,7R,8S,9R,10S,11Z,13Z,15S,16S)-16-[(2E,4E)-6-[(2S,3S,4S)-2-ethyl-4-hydroxy-3-methyl-6-oxooxan-4-yl]hexa-2,4-dien-2-yl]-10-hydroxy-8-(methoxymethoxy)-6,7,9,15-tetramethyl-1-oxacyclohexadeca-5,11,13-trien-2-one | 1439376-64-3

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 大环内酯类和类似物
• 英文名称: (5E,7R,8S,9R,10S,11Z,13Z,15S,16S)-16-[(2E,4E)-6-[(2S,3S,4S)-2-ethyl-4-hydroxy-3-methyl-6-oxooxan-4-yl]hexa-2,4-dien-2-yl]-10-hydroxy-8-(methoxymethoxy)-6,7,9,15-tetramethyl-1-oxacyclohexadeca-5,11,13-trien-2-one
• CAS: 1439376-64-3
• 化学式: C₃₅H₅₄O₈
• 分子量: 602.809
• InChiKey: KLDNOKNXWBXKEF-MRMFGQFVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.1
• 重原子数：
  43
• 可旋转键数：
  8
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.66
• 拓扑面积：
  112
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  (5E,7R,8S,9R,10S,11Z,13Z,15S,16S)-16-[(2E,4E)-6-[(2S,3S,4S)-2-ethyl-4-hydroxy-3-methyl-6-oxooxan-4-yl]hexa-2,4-dien-2-yl]-10-hydroxy-8-(methoxymethoxy)-6,7,9,15-tetramethyl-1-oxacyclohexadeca-5,11,13-trien-2-one 在 二甲基溴化硼 作用下， 以 二氯甲烷 为溶剂， 反应 4.5h， 生成 (1S,2R,3E,9S,10S,11Z,13Z,15S,19R)-9-[(2E,4E)-6-[(2S,3S,4S)-2-ethyl-4-hydroxy-3-methyl-6-oxooxan-4-yl]hexa-2,4-dien-2-yl]-2,3,10,19-tetramethyl-8,16,18-trioxabicyclo[13.3.1]nonadeca-3,11,13-trien-7-one
  参考文献：
  名称：

  Synthesis, Molecular Editing, and Biological Assessment of the Potent Cytotoxin Leiodermatolide

  摘要：

  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.

  DOI：

  10.1021/ja508846g
• 作为产物：
  描述：

  (6R,7S,8S,9R,E)-ethyl 9-(tert-butyldimethylsilyloxy)-7-(methoxymethoxy)-5,6,8-trimethyldodec-4-en-10-ynoate 在 4-二甲氨基吡啶 、 四(三苯基膦)钯 、 copper/silver activated zinc 、 三(N-叔丁基-3,5-二甲基苯胺基)钼(III) 、 potassium trimethylsilonate 、 四丁基氟化铵 、 水 、 thallium (I) ethoxide 、 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 、 乙醚 、 二氯甲烷 、 水 、 甲苯 为溶剂， 反应 45.84h， 生成 (5E,7R,8S,9R,10S,11Z,13Z,15S,16S)-16-[(2E,4E)-6-[(2S,3S,4S)-2-ethyl-4-hydroxy-3-methyl-6-oxooxan-4-yl]hexa-2,4-dien-2-yl]-10-hydroxy-8-(methoxymethoxy)-6,7,9,15-tetramethyl-1-oxacyclohexadeca-5,11,13-trien-2-one
  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。
• 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.