2-[(2R,4aR,6S,7R,8aS)-7-methyl-2-phenyl-7-trimethylsilyloxy-4a,6,8,8a-tetrahydro-4H-pyrano[3,2-d][1,3]dioxin-6-yl]acetaldehyde | 1021700-94-6

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 2-[(2R,4aR,6S,7R,8aS)-7-methyl-2-phenyl-7-trimethylsilyloxy-4a,6,8,8a-tetrahydro-4H-pyrano[3,2-d][1,3]dioxin-6-yl]acetaldehyde
• CAS: 1021700-94-6
• 化学式: C₁₉H₂₈O₅Si
• 分子量: 364.514
• InChiKey: ODJYYNKFHQIDBQ-ZWJWXYIHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.46
• 重原子数：
  25
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.63
• 拓扑面积：
  54
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  2-[(2R,4aR,6S,7R,8aS)-7-methyl-2-phenyl-7-trimethylsilyloxy-4a,6,8,8a-tetrahydro-4H-pyrano[3,2-d][1,3]dioxin-6-yl]acetaldehyde 在 四丁基氟化铵 、 sodium hexamethyldisilazane 作用下， 以 四氢呋喃 为溶剂， 反应 3.0h， 生成
  参考文献：
  名称：

  Design and Synthesis of Skeletal Analogues of Gambierol: Attenuation of Amyloid-β and Tau Pathology with Voltage-Gated Potassium Channel and N-Methyl-d-aspartate Receptor Implications

  摘要：

  Gambierol is a potent neurotoxin that belongs to the family of marine polycyclic ether natural products and primarily targets voltage-gated potassium channels (K-v channels) in excitable membranes. Previous work in the chemistry of marine polycyclic ethers has suggested the critical importance of the full length of polycyclic ether skeleton for potent biological activity. Although we have previously investigated structure-activity relationships (SARs) of the peripheral functionalities of gambierol, it remained unclear whether the whole polycyclic ether skeleton is needed for its cellular activity. In this work, we designed and synthesized two truncated skeletal analogues of gambierol comprising the EFGH- and BCDEFGH-rings of the parent compound, both of which surprisingly showed similar potency to gambierol on voltage gated potassium channels (K-v) inhibition. Moreover, we examined the effect of these compounds in an in vitro model of Alzheimer's disease (AD) obtained from triple transgenic (3xTg-AD) mice, which expresses amyloid beta (A beta) accumulation and tau hyperphosphorylation. In vitro preincubation of the cells with the compounds resulted in significant inhibition of K+ currents, a reduction in the extra- and intracellular levels of A beta, and a decrease in the levels of hyperphosphorylated tau. In addition, pretreatment with these compounds reduced the steady-state level of the N-methyl-D-aspartate (NMDA) receptor subunit 2A without affecting the 2B subunit. The involvement of glutamate receptors was further suggested by the blockage of the effect of gambierol on tau hyperphosphorylation by glutamate receptor antagonists. The present study constitutes the first discovery of skeletally simplified, designed polycyclic ethers with potent cellular activity and demonstrates the utility of gambierol and its synthetic analogues as chemical probes for understanding the function of K-v channels as well as the molecular mechanism of A beta metabolism modulated by NMDA receptors.

  DOI：

  10.1021/ja300565t
• 作为产物：
  描述：

  在 二异丁基氢化铝 作用下， 以 正己烷 、 甲苯 为溶剂， 反应 0.25h， 生成 2-[(2R,4aR,6S,7R,8aS)-7-methyl-2-phenyl-7-trimethylsilyloxy-4a,6,8,8a-tetrahydro-4H-pyrano[3,2-d][1,3]dioxin-6-yl]acetaldehyde
  参考文献：
  名称：

  麦芽毒素的合成研究。2. WXYZA'-环系统的立体选择性合成。

  摘要：

  麦托毒素的WXYZA'-环系统的立体选择性合成已通过线性合成方法完成，其中关键反应是SmI 2诱导的β-烷氧基丙烯酸酯的环化反应，以构建A'-，Y-和X- Z环和W环的羟基环和6-乙烯基环氧基的6-内环化。

  DOI：

  10.1021/ol800268c

文献信息

• Total Synthesis and Biological Evaluation of (+)-Gambieric Acid A and Its Analogues
  作者：Kazuya Ishigai、Haruhiko Fuwa、Keisuke Hashizume、Ryo Fukazawa、Yuko Cho、Mari Yotsu-Yamashita、Makoto Sasaki

  DOI：10.1002/chem.201204303

  日期：2013.4.22

  thus obtained closed the F‐ring and completed the polycyclic ether skeleton. Finally, the J‐ring side chain was introduced by using a Julia–Kocienski olefination in the presence of CeCl3 to complete the total synthesis of gambieric acid A (1), thereby unambiguously establishing its complete stereostructure. The present total synthesis enabled us to evaluate the antifungal and antiproliferative activities

  在这项研究中，我们详细报告了冈比亚酸A（一种有效的抗真菌多环醚代谢物）的首次总合成和完整的立体结构。A / B环外环烯醇醚32是通过B环乙烯基碘18与烷基硼酸酯33的Suzuki-Miyaura偶联反应制备的，随后通过使用非对映选择性溴醚化作为关键转化来封闭A环。Suzuki-Miyaura将32与乙酸酯衍生的烯醇磷酸酯49偶联，然后将衍生的二烯进行开环易位，产生了D环。随后通过混合硫代缩醛化作用封闭C环，完成了A / BCD环片段的合成8。A / BCD和F'GHIJ环片段（即8和9）是通过Suzuki-Miyaura偶合组装的。通过利用七元F'环的内在构象特性，对C25立体生成中心进行了阐述。F'环被氧化裂解后，E环形成为环状混合硫缩醛（即70），然后使用糖基化化学方法进行立体选择性烯丙基化。由此获得的二烯3的闭环复分解反应关闭了F环并完成了多环醚骨架。最后，在存在CeCl 3的情况下
• Studies toward the Total Synthesis of Gambieric Acids: Stereocontrolled Synthesis of a DEFG-Ring Model Compound
  作者：Haruhiko Fuwa、Sayaka Noji、Makoto Sasaki

  DOI：10.1021/jo1008146

  日期：2010.8.6

  A stereocontrolled convergent synthesis of a DEFG-ring model compound of gambieric acids, highly potent antifungal marine polycyclic ether natural products, has been achieved based on Suzuki—Miyaura coupling. Conformational analysis of the model compound revealed that the nine-membered F-ring exists exclusively as a single stable conformer, as opposed to that of ciguatoxins.

  基于铃木-Miyaura偶联，已经完成了冈比亚酸DEFG环模型化合物（高效抗真菌海洋多环醚天然产物）的立体控制收敛性合成。对模型化合物的构象分析表明，与雪茄毒素相反，该九元F环仅作为一个稳定的构象体存在。
• Synthetic Studies on Maitotoxin. 2. Stereoselective Synthesis of the WXYZA′-Ring System
  作者：Masayuki Morita、Tasuku Haketa、Hiroyuki Koshino、Tadashi Nakata

  DOI：10.1021/ol800268c

  日期：2008.5.1

  The stereoselective synthesis of the WXYZA'-ring system of maitotoxin has been accomplished via a linear synthetic approach, in which key reactions were SmI 2-induced cyclization of beta-alkoxyacrylate for the construction of the A'-, Y-, and X-rings and 6- endo cyclization of hydroxy vinylepoxide for that of the Z- and W-rings.

  麦托毒素的WXYZA'-环系统的立体选择性合成已通过线性合成方法完成，其中关键反应是SmI 2诱导的β-烷氧基丙烯酸酯的环化反应，以构建A'-，Y-和X- Z环和W环的羟基环和6-乙烯基环氧基的6-内环化。
• Design and Synthesis of Skeletal Analogues of Gambierol: Attenuation of Amyloid-β and Tau Pathology with Voltage-Gated Potassium Channel and <i>N</i>-Methyl-<scp>d</scp>-aspartate Receptor Implications
  作者：Eva Alonso、Haruhiko Fuwa、Carmen Vale、Yuto Suga、Tomomi Goto、Yu Konno、Makoto Sasaki、Frank M. LaFerla、Mercedes R. Vieytes、Lydia Giménez-Llort、Luis M. Botana

  DOI：10.1021/ja300565t

  日期：2012.5.2

  Gambierol is a potent neurotoxin that belongs to the family of marine polycyclic ether natural products and primarily targets voltage-gated potassium channels (K-v channels) in excitable membranes. Previous work in the chemistry of marine polycyclic ethers has suggested the critical importance of the full length of polycyclic ether skeleton for potent biological activity. Although we have previously investigated structure-activity relationships (SARs) of the peripheral functionalities of gambierol, it remained unclear whether the whole polycyclic ether skeleton is needed for its cellular activity. In this work, we designed and synthesized two truncated skeletal analogues of gambierol comprising the EFGH- and BCDEFGH-rings of the parent compound, both of which surprisingly showed similar potency to gambierol on voltage gated potassium channels (K-v) inhibition. Moreover, we examined the effect of these compounds in an in vitro model of Alzheimer's disease (AD) obtained from triple transgenic (3xTg-AD) mice, which expresses amyloid beta (A beta) accumulation and tau hyperphosphorylation. In vitro preincubation of the cells with the compounds resulted in significant inhibition of K+ currents, a reduction in the extra- and intracellular levels of A beta, and a decrease in the levels of hyperphosphorylated tau. In addition, pretreatment with these compounds reduced the steady-state level of the N-methyl-D-aspartate (NMDA) receptor subunit 2A without affecting the 2B subunit. The involvement of glutamate receptors was further suggested by the blockage of the effect of gambierol on tau hyperphosphorylation by glutamate receptor antagonists. The present study constitutes the first discovery of skeletally simplified, designed polycyclic ethers with potent cellular activity and demonstrates the utility of gambierol and its synthetic analogues as chemical probes for understanding the function of K-v channels as well as the molecular mechanism of A beta metabolism modulated by NMDA receptors.