(4R)-4-chloro-6-iodohept-6-enal | 1583253-07-9

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: (4R)-4-chloro-6-iodohept-6-enal
• CAS: 1583253-07-9
• 化学式: C₇H₁₀ClIO
• 分子量: 272.513
• InChiKey: KICCGQAHGMKOQV-SSDOTTSWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  10
• 可旋转键数：
  5
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  17.1
• 氢给体数：
  0
• 氢受体数：
  1

反应信息

• 作为反应物：
  描述：

  (4R)-4-chloro-6-iodohept-6-enal 在 N-溴代丁二酰亚胺(NBS) 、 正丁基锂 、 碳酸氢钠 、 戴斯-马丁氧化剂 、 对甲苯磺酸 、 silver nitrate 作用下， 以 四氢呋喃 、 正己烷 、 二氯甲烷 、 丙酮 、 苯 为溶剂， 反应 19.0h， 生成 2-(2-bromoethynyl)-2-[(3R)-3-chloro-5-iodohex-5-enyl]-1,3-dioxane
  参考文献：
  名称：

  在 (Ni)/Cr 介导的反应中通过多卤化亲核试剂的选择性激活/偶联统一合成软海绵素的 C1-C19 构件

  摘要：

  软海绵素 AC 的 C1-C19 结构单元 8-10 的统一合成是从常见的合成中间体 26a,b 开发的。乙炔酮 26a、b 依次通过多卤化亲核试剂 23a、b 与醛 11 在 (Ni)/Cr 介导的偶联反应中的选择性活化/偶联合成。与乙烯基碘化物和醛的 Ni/Cr 介导的偶联相比，这种 (Ni)/Cr 介导的偶联表现出两个独特的特征。首先，发现以痕量或不添加镍催化剂进行偶联。其次，TES-Cl 是一种用于再生 Cr 催化剂的解离剂，被发现比 Zr(Cp)2Cl2 的产率更高。需要调整氧化态才能将炔酮 26a、b 分别转化为软海绵素 A 和 B 的 C1-C19 结构单元 8 和 9。在软海绵素 B 系列中，发现 E- 和 Z-β-烷氧基-烯酮 30 的羟基定向 (Me)4NBH(OAc)3 还原可以实现所需的转化，而 E-乙烯基酯 27 的 DMDO 氧化允许引入 C13 羟基在软海绵素

  DOI：

  10.1021/jacs.5b03499
• 作为产物：
  描述：

  tert-butyldimethyl(3-(oxiran-2-yl)propoxy)silane 在 吡啶 、 正丁基锂 、 Jacobsen's catalyst 、 甲基叔丁基醚 、 2,2,2-三氯乙酰胺 、 碳酸氢钠 、 potassium carbonate 、 戴斯-马丁氧化剂 、 溶剂黄146 、 三苯基膦 、 9-碘-9-硼杂二环[3.3.1]壬烷 作用下， 以 四氢呋喃 、 甲醇 、 正己烷 、 二氯甲烷 、 水 为溶剂， 反应 40.5h， 生成 (4R)-4-chloro-6-iodohept-6-enal
  参考文献：
  名称：

  Selective Activation/Coupling of Polyhalogenated Nucleophiles in Ni/Cr-Mediated Reactions: Synthesis of C1–C19 Building Block of Halichondrin Bs

  摘要：

  The C1-C19 building block 46 of halichondrin Bs was synthesized via a selective activation/coupling of beta-bromoenone 34 with aldehyde 35 in a Ni/Cr-mediated reaction. The first phase of study was a method development to effect a coupling of a naked vinylogous anion with an aldehyde. The study with the coupling of 9 + 10 -> 11 revealed: (1) beta-bromoenone 9b is a better nucleophile than the corresponding beta-iodo- and beta-chloroenones 9a,c; (2) (Me)(2)Phen(OMe)(2)center dot NiCl2 13b is a better Ni-catalyst than (Me)(2)Phen(H)(2)center dot NiCl2 13a; and (3) a low Ni-catalyst loading, for example, 0.05-0.1 mol % Ni-catalyst against 10 mol % Cr-catalyst, is crucial for an effective coupling. The second phase of study was a method development to realize a selective activation/coupling of polyhalogenated nucleophiles such as 34. The competition experiment of 10 + 9b over 10 + 31a-c revealed: (1) (Me)(2)Phen(OMe)(2)center dot NiCl2 13b is more effective than (Me)(2)Phen(H)(2)center dot NiCl2 13a for the required selective activation/coupling; (2) a low Ni-catalyst loading, for example, 0.05-0.1 mol % Ni-catalyst against 10 mol % Cr-catalyst, is crucial for discriminating beta-bromoenone 9b from the three types of vinyl iodides 31a-c. The third phase of study was an application of the developed method to execute the proposed coupling of 34 + 35 -> 36. For this application, a polyether-type Ni-catalyst 37c, readily soluble in the reaction medium, was introduced to achieve the selective activation/coupling with higher efficiency. With use of ion-exchange resin-based device, the coupling product 36 was transformed to the C1-C19 building block 46 of halichondrin Bs without purification/separation of the intermediates.

  DOI：

  10.1021/jacs.5b03498

文献信息

• [EN] SYNTHESIS OF HALICHONDRIN ANALOGS AND USES THEREOF<br/>[FR] SYNTHÈSE D'ANALOGUES D'HALOCHONDRINES ET LEURS UTILISATIONS
  申请人：HARVARD COLLEGE

  公开号：WO2016003975A1

  公开（公告）日：2016-01-07

  The present invention provides halichondrin analogs, such as compounds of Formula (I). The compounds may bind to microtubule sites, thereby inhibiting microtubule dynamics. Also provided are methods of synthesis, pharmaceutical compositions, kits, methods of treatment, and uses that involve the compounds for treatment of a proliferative disease (e.g., cancer). Compounds of the present invention are particularly useful for the treatment of metastatic breast cancer, non-small cell lung cancer, prostate cancer, and sarcoma. The included methods of synthesis are useful for the preparation of compounds of Formula (I)-(III) along with naturally occurring halicondrins (e.g., halichondrin B & C, norhalichondrin A, B, & C, and homohalichondrin A, B, & C). Also included are methods for interconverting between the halichondrins, norhalichondrins, and homohalichondrins and their unnatural epimers at the C38 ketal stereocenter through the use of an acid-mediated equilibration.

  本发明提供了半龙胆碱类似物，如化合物的结构式(I)所示。这些化合物可能结合到微管位点，从而抑制微管动力学。还提供了合成方法、药物组合物、试剂盒、治疗方法和利用这些化合物治疗增生性疾病（例如癌症）的用途。本发明的化合物特别适用于转移性乳腺癌、非小细胞肺癌、前列腺癌和肉瘤的治疗。所包括的合成方法适用于制备结构式(I)-(III)化合物以及天然存在的半龙胆碱（例如半龙胆碱B和C、诺半龙胆碱A、B和C以及同半龙胆碱A、B和C）。还包括通过使用酸介导的平衡方法在C38酮缩醛立体中心之间相互转化半龙胆碱、诺半龙胆碱和同半龙胆碱及其不自然对映体的方法。
• Total Synthesis of Halichondrin A, the Missing Member in the Halichondrin Class of Natural Products
  作者：Atsushi Ueda、Akihiko Yamamoto、Daisuke Kato、Yoshito Kishi

  DOI：10.1021/ja5013307

  日期：2014.4.2

  A total synthesis of halichondrin A, the phantom member in the halichondrin class of natural products, is reported. The highlights of synthesis include: (1) synthesis of C1-C19 building block 6b via a catalytic asymmetric Cr-mediated coupling of 12 and 13b; (2) synthesis of the right-half of 19 via an asymmetric Ni/Cr-mediated coupling, followed by base-induced furan formation, and Shiina macrolactonization;

  据报道，软软骨素 A 是天然产物软软骨素类中的幻影成员。合成的亮点包括：（1）通过催化不对称Cr介导的12和13b偶联合成C1-C19结构单元6b；(2) 通过不对称 Ni/Cr 介导的偶联合成 19 的右半部分，然后是碱诱导的呋喃形成和椎名大环内酯化；(3) 通过 Ni/Cr 介导的 5 与 19 偶联合成烯酮 20，然后氧化；(4) 从 20 合成软海绵素 A，使用新发现的高选择性 TMSOTf 介导的 C38-epi-软海绵素 A 与软海绵素 A 的平衡。明确提出了两个证据来确定由此合成的软海绵素 A 的结构: 一种是从 19 和 23 合成去甲软海绵素 A (24)，
• Chromium-mediated coupling and application to the synthesis of halichondrins
  申请人：President and Fellows of Harvard College

  公开号：US10344038B2

  公开（公告）日：2019-07-09

  The present invention provides unified synthesis of the CI-CI 9 building blocks of halichondrins and analogs thereof using selective coupling of poly-halogenated nucleophiles in chromium-mediated coupling reactions. The present invention also provides a practical and efficient synthesis of C20-C38 building blocks of halichondrins and analogs thereof. Also provided herein are general methods of selective activation and coupling of poly-halogenated analogs with an aldehyde. The provided coupling reactions are selective for halo-enone and halo-acetylenic ketal over vinyl halide and halide attached to a sp hydridized carbon. The provided efficient selective coupling reactions can allow easy access to the CI-CI 9 building blocks and C20-C38 building blocks of halichondrins and analogs thereof with limited or no purification or separation of the intermediates.

  本发明提供了在铬介导的偶联反应中利用多卤代亲核物的选择性偶联来统一合成卤代姜黄素及其类似物的 CI-CI 9 结构单元。本发明还提供了一种实用高效的卤代龙毒素及其类似物的 C20-C38 结构单元的合成方法。本发明还提供了选择性活化多卤代类似物并将其与醛偶联的一般方法。所提供的偶联反应对卤代烯酮和卤代乙炔缩酮具有选择性，而对乙烯基卤化物和连接到 sp 水化物碳上的卤化物则没有选择性。所提供的高效选择性偶联反应可以方便地获得卤代烯酮及其类似物的 CI-CI 9 结构单元和 C20-C38 结构单元，中间产物的纯化或分离程度有限或根本不需要。
• Synthesis of halichondrin analogs and uses thereof
  申请人：President and Fellows of Harvard College

  公开号：US10556910B2

  公开（公告）日：2020-02-11

  The present invention provides halichondrin analogs, such as compounds of Formula (I). The compounds may bind to microtubule sites, thereby inhibiting microtubule dynamics. Also provided are methods of synthesis, pharmaceutical compositions, kits, methods of treatment, and uses that involve the compounds for treatment of a proliferative disease (e.g., cancer). Compounds of the present invention are particularly useful for the treatment of metastatic breast cancer, non-small cell lung cancer, prostate cancer, and sarcoma. The included methods of synthesis are useful for the preparation of compounds of Formula (I)-(III) along with naturally occurring halicondrins (e.g., halichondrin B & C, norhalichondrin A, B, & C, and homohalichondrin A, B, & C). Also included are methods for interconverting between the halichondrins, norhalichondrins, and homohalichondrins and their unnatural epimers at the C38 ketal stereocenter through the use of an acid-mediated equilibration.

  本发明提供了卤虫菊酯类似物，如式（I）化合物。这些化合物可与微管位点结合，从而抑制微管动力学。本发明还提供了化合物的合成方法、药物组合物、试剂盒、治疗方法以及用于治疗增殖性疾病（如癌症）的用途。本发明的化合物尤其适用于治疗转移性乳腺癌、非小细胞肺癌、前列腺癌和肉瘤。本发明所包含的合成方法可用于制备式（I）-（III）化合物以及天然卤化膦（例如，卤化膦 B 和 C，去卤化膦 A、B 和 C，同卤化膦 A、B 和 C）。此外，还包括通过使用酸介导的平衡，在 C38 酮立体中心实现卤化琼脂、去卤化琼脂和高卤化琼脂及其非天然表聚物之间相互转化的方法。
• [EN] CHROMIUM-MEDIATED COUPLING AND APPLICATION TO THE SYNTHESIS OF HALICHONDRINS<br/>[FR] COUPLAGE INDUIT PAR CHROME ET APPLICATION À LA SYNTHÈSE D'HALICHONDRINES
  申请人：HARVARD COLLEGE

  公开号：WO2016176560A8

  公开（公告）日：2017-06-22