16-丁烷-2-基-10,11,14-三甲基-3-(环氧乙烷-2-基甲基)-13-丙-2-基-4-氧杂-1,8,11,14,17-五氮杂双环[17.3.0]二十二烷-2,5,9,12,15,18-六酮 | 76689-14-0

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 肽模拟物
• 中文名称: 16-丁烷-2-基-10,11,14-三甲基-3-(环氧乙烷-2-基甲基)-13-丙-2-基-4-氧杂-1,8,11,14,17-五氮杂双环[17.3.0]二十二烷-2,5,9,12,15,18-六酮
• 英文名称: destruxin E
• 英文别名: Destruxin DE；(3R,10S,13S,16S,19S)-16-[(2S)-butan-2-yl]-10,11,14-trimethyl-3-[[(2S)-oxiran-2-yl]methyl]-13-propan-2-yl-4-oxa-1,8,11,14,17-pentazabicyclo[17.3.0]docosane-2,5,9,12,15,18-hexone
• CAS: 76689-14-0
• 化学式: C₂₉H₄₇N₅O₈
• 分子量: 593.721
• InChiKey: NIAYGGCQOYIHAF-OHOJESAGSA-N

物化性质

• 沸点：
  909.6±65.0 °C(Predicted)
• 密度：
  1.24±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  42
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.79
• 拓扑面积：
  158
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  (S)-HA-Pro-OH 在 盐酸 、 4-二甲氨基吡啶 、 N-羟基-7-氮杂苯并三氮唑 、 2-甲基-6-硝基苯甲酸酐 、 四丁基氟化铵 、 4-(二甲胺基丙基)吡啶 、 potassium carbonate 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 、 异丙醇 为溶剂， 反应 99.0h， 生成 16-丁烷-2-基-10,11,14-三甲基-3-(环氧乙烷-2-基甲基)-13-丙-2-基-4-氧杂-1,8,11,14,17-五氮杂双环[17.3.0]二十二烷-2,5,9,12,15,18-六酮
  参考文献：
  名称：

  Scalable Solution-Phase Synthesis of the Biologically Active Cyclodepsipeptide Destruxin E, a Potent Negative Regulator of Osteoclast Morphology

  摘要：

  The scalable solution-phase synthesis of the cyclodepsipeptide destruxin E (1) has been achieved. Diastereoselective dihydroxylation of the terminal alkene in a 2-alkoxy-4-pentenoic amide, 7, was successfully accomplished utilizing (DHQD)(2)PHAL as the chiral ligand, and it was found that the use of the L-proline moiety in the substrate as a chiral auxiliary was essential for the induction of high diastereoselectivity to afford the key compound 4 on a gram scale. MNBA-mediated macrolactonization of 3 was also performed without formation of the dimerized product even under higher-dilution conditions, and it is noteworthy that the internal hydrogen bonds and s-cis configuration of the amide bond between N-methylalanine and N-methylvaline in the cyclization precursor 3 would assist in the macrolactonization to provide the macrolactone 2 without forming a dimerized product. Finally, epoxide formation in the side chain afforded destruxin E (1) on a gram scale in high purity (>98%).

  DOI：

  10.1021/jo402437z

文献信息

• Synthesis, Structure Determination, and Biological Evaluation of Destruxin E
  作者：Masahito Yoshida、Hisayuki Takeuchi、Yoshitaka Ishida、Yoko Yashiroda、Minoru Yoshida、Motoki Takagi、Kazuo Shin-ya、Takayuki Doi

  DOI：10.1021/ol101449x

  日期：2010.9.3

  The total synthesis of destruxin E (1) has been achieved for the first time, and the stereochemistry of its chiral center at the epoxide has been determined to be (S). The cyclization precursor 3a was synthesized by solid-phase peptide synthesis. Macrolactonization of 3a utilizing MNBA-DMAPO, followed by formation of the epoxide, then furnished destruxin E. Its diastereomer, epi-destruxin E (2), was

  首次获得了destruxin E（1）的全合成，并且其手性中心在环氧化物上的立体化学被确定为（S）。通过固相肽合成来合成环化前体3a。利用MNBA- DMAPO对3a进行大分子内酯化，然后形成环氧化物，然后得到destruxinE 。其非对映异构体Epi- destruxin E（2）也以相同的方式合成。此外，生物学评估表明，destruxin E的V-ATPase抑制活性比Epi- destruxin E的高10倍。
• Solid-Phase Combinatorial Synthesis and Biological Evaluation of Destruxin E Analogues
  作者：Masahito Yoshida、Yoshitaka Ishida、Kenta Adachi、Hayato Murase、Hiroshi Nakagawa、Takayuki Doi

  DOI：10.1002/chem.201502970

  日期：2015.12.7

  gave 18 member destruxin E analogues 6. Biological evaluation of analogues 6 indicated that the N‐MeAla residue was crucial to the induction of morphological changes in osteoclast‐like multinuclear cells (OCLs). Based on structure–activity relationships, azido‐containing analogues 15 were then designed for use as a molecular probe. The synthesis and biological evaluation of analogues 15 revealed that

  已经证明了环二肽destruxin E的固相组合合成。环化前体8的组合合成是通过在SynPhase Lanterns上使用拆分和合并方法实现的。通过使用2-甲基-6-硝基苯甲酸酐和4-（二甲基氨基）吡啶N-氧化物成功地将它们在溶液相中进行大分子内酯化，得到大内酯9，随后在侧链中形成环氧化物，得到18个成员destruxin E类似物6。对类似物6的生物学评估表明，N-MeAla残留对于诱导破骨细胞样多核细胞（OCL）的形态变化至关重要。基于结构-活性关系，然后设计了含叠氮基的类似物15用作分子探针。类似物15的合成和生物学评估表明，15 b（其中Ile残基被Lys（N 3）残基替代，在足够浓度下诱导OCL的形态发生变化，并且Ile残基周围的修饰可被允许附着）化学标签对目的蛋白destruxin E（1）的识别。
• Scalable Solution-Phase Synthesis of the Biologically Active Cyclodepsipeptide Destruxin E, a Potent Negative Regulator of Osteoclast Morphology
  作者：Masahito Yoshida、Hiroshi Sato、Yoshitaka Ishida、Hiroshi Nakagawa、Takayuki Doi

  DOI：10.1021/jo402437z

  日期：2014.1.3

  The scalable solution-phase synthesis of the cyclodepsipeptide destruxin E (1) has been achieved. Diastereoselective dihydroxylation of the terminal alkene in a 2-alkoxy-4-pentenoic amide, 7, was successfully accomplished utilizing (DHQD)(2)PHAL as the chiral ligand, and it was found that the use of the L-proline moiety in the substrate as a chiral auxiliary was essential for the induction of high diastereoselectivity to afford the key compound 4 on a gram scale. MNBA-mediated macrolactonization of 3 was also performed without formation of the dimerized product even under higher-dilution conditions, and it is noteworthy that the internal hydrogen bonds and s-cis configuration of the amide bond between N-methylalanine and N-methylvaline in the cyclization precursor 3 would assist in the macrolactonization to provide the macrolactone 2 without forming a dimerized product. Finally, epoxide formation in the side chain afforded destruxin E (1) on a gram scale in high purity (>98%).