(-)-leiodermatolide | 1006046-07-6

• 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: (-)-leiodermatolide
• 英文别名: Leiodermatolide；[(2S,3S,4Z,6Z,8S,9S,10S,11R,12E)-2-[(2E,4E)-6-[(2S,3S,4S)-2-ethyl-4-hydroxy-3-methyl-6-oxooxan-4-yl]hexa-2,4-dien-2-yl]-10-hydroxy-3,9,11,12-tetramethyl-16-oxo-1-oxacyclohexadeca-4,6,12-trien-8-yl] carbamate
• CAS: 1006046-07-6
• 化学式: C₃₄H₅₁NO₈
• 分子量: 601.781
• InChiKey: MKLPPSQFKKCRHA-SWAPZMPDSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.6
• 重原子数：
  43
• 可旋转键数：
  7
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  145
• 氢给体数：
  3
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  反式-2-甲基-2-丁烯醛 在 吡啶 、 4-二甲氨基吡啶 、 bis-triphenylphosphine-palladium(II) chloride 、 sodium chlorite 、 copper(l) iodide 、 二(氰基苯)二氯化钯 、 bis(1,5-cyclooctadiene)diiridium(I) dichloride 、 sodium dihydrogenphosphate dihydrate 、 2-甲基-2-丁烯 、 copper(II) choride dihydrate 、 [Rh(cod)2]BARF 、 2,4,6-三氯苯甲酰氯 、 potassium trimethylsilonate 、 四丁基氟化铵 、 氢气 、 氧气 、 二氯乙基铝 、 caesium carbonate 、 R-(+)-1,1'-联萘-2,2'-双二苯膦 、 silver nitrate 、 R-(+)-1,1'-联萘-2,2'-双二苯膦 、 三乙胺 、 9-硼双环[3.3.1]壬烷 、 异丙醇 、 4-氯-3-硝基苯甲酸 作用下， 以 四氢呋喃 、 甲醇 、 乙醚 、 硝基甲烷 、 正己烷 、 二氯甲烷 、 水 、 1,2-二氯乙烷 、 甲苯 、 叔丁醇 为溶剂， -78.0~50.0 ℃ 、101.33 kPa 条件下， 反应 200.83h， 生成 (-)-leiodermatolide
  参考文献：
  名称：

  通过转移氢化烯丙基化、巴豆酰化和炔丙基化全合成 Leiodermatolide A：超越离散烯丙基或烯丙基金属试剂的聚酮化合物构建

  摘要：

  leiodermatolide A 的全合成分 13 个步骤 (LLS) 完成。传统上依赖于预金属化试剂（烯丙基化、巴豆酰化和炔丙基化）的三种羰基加成的转移氢化变体在一个全合成中一起部署。

  DOI：

  10.1021/jacs.1c06062

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。
• Total Synthesis of the Antimitotic Marine Macrolide (−)-Leiodermatolide
  作者：Ian Paterson、Kenneth K.-H. Ng、Simon Williams、David C. Millican、Stephen M. Dalby

  DOI：10.1002/anie.201310164

  日期：2014.3.3

  Leiodermatolide is an antimitotic macrolide isolated from the marine sponge Leiodermatium sp. whose potentially novel tubulin‐targeting mechanism of action makes it an exciting lead for anticancer drug discovery. In pursuit of a sustainable supply, we report a highly stereocontrolled total synthesis (3.2 % yield) based on a convergent sequence of palladium‐mediated fragment assembly and macrolactonization

  Leiodermatolide 是一种从海洋海绵 Leiodermatium sp 中分离出来的抗有丝分裂大环内酯。其潜在的新颖的微管蛋白靶向作用机制使其成为抗癌药物发现的令人兴奋的先导。为了追求可持续的供应，我们报告了基于钯介导的片段组装和大内酯化的收敛序列的高度立体控制的全合成（3.2%产率）。通过采用适当的乳酸酯衍生酮7的对映体，硼介导的羟醛反应用于配置三个关键片段2、5和6。
• 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.
• Total Synthesis of Leiodermatolide A via Transfer Hydrogenative Allylation, Crotylation, and Propargylation: Polyketide Construction beyond Discrete Allyl- or Allenylmetal Reagents
  作者：Yuk-Ming Siu、James Roane、Michael J. Krische

  DOI：10.1021/jacs.1c06062

  日期：2021.7.21

  The total synthesis of leiodermatolide A was accomplished in 13 steps (LLS). Transfer hydrogenative variants of three carbonyl additions that traditionally rely on premetalated reagents (allylation, crotylation, and propargylation) are deployed together in one total synthesis.

  leiodermatolide A 的全合成分 13 个步骤 (LLS) 完成。传统上依赖于预金属化试剂（烯丙基化、巴豆酰化和炔丙基化）的三种羰基加成的转移氢化变体在一个全合成中一起部署。