Name: efficient construction of drug-like bispirocyclic scaffolds via organocatalytic cycloadditions of &#945;-imino &#947;-lactones and alkylidene pyrazolones
Uploaded: 2019-02-07T15:00:00
Description: Watch this Scientific Journal Video about Efficient Construction of Drug-like Bispirocyclic Scaffolds Via Organocatalytic Cycloadditions of ÃŽÂ±-Imino ÃŽÂ³-Lactones and Alkylidene Pyrazolones at JoVE.

作者非常感谢国家自然科学基金 (第21708051至 x. c. 号) 的资助。

注意: 使用前请查阅所有相关材料安全数据表 (msds)。所使用的化学品和溶剂都是试剂级的, 使用时没有进一步的净化。所有涉及空气或对水分敏感的试剂或中间体的反应都是在氩气氛下进行的。
1. α-芳基吡唑酮的制备
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准备工作吡唑酮
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<li>在室温下从刻度缸中加入40毫升的冰醋酸, 加入250毫升的圆底烧瓶。在加入联氨 (1 当量, 1.58 摩尔) 和乙?...

<ol>
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双吡咯 [γ-丁基吡咯烷酮-4, 4 '-吡唑酮] 骨架的成功制备取决于许多因素。
这种一步不对称环加成工艺的关键步骤是双功能四酰胺催化剂对α-芳基吡唑酮1a 和环咪诺酯2a 的协同作用。它是通过催化剂作为氢键供体和两个反应基板之间形成多个分子间氢键来实现的。因此, 在大量的位阻下, c5 在所有的氢键供体双功能有机催化剂中表现出最佳的立体选择性...

在天然产物中发现的手性螺旋体化合物, 手性配体和有机金属配合物由于其结构复杂性和生物活性1,2, 已成为有吸引力的合成靶点。 (三)有什么问题吗？具体而言, 双环支架是许多具有重要生物活性4、5的天然产物中的结构子单元, 由三个环和两个刚性尖塔组成。因此, 在过去几十年中, 具有立体控制、光学纯双环骨架的化合物的构建引起了极大的关注。通过有机金属方法和有机催化方法成功合成了大量的螺旋体环化合物及其衍生物, 例如 1, 3-偶极极环加和狄勒-阿尔德等不对称环加。反应6,7,8。然而, 这些分子大多是单旋循环结构, 而双环结构的报道较少, 仅限于建立基于作物醇的双环。
为了获得结构更加多样化的双环化合物, 探讨了环加成合成子在螺旋体环中心不对称构造中的多功能性。特别是双功能的四酰胺有机催化剂, 偶氮胺 ylide12,13,14, 如α-两乙酮-内酯, 和双极体, 如烷基脂酰胺吡唑酮15,16 ,17, 能够经历一个简单的 1, 3-偶极环加成, 以构建具有多个立体中心的双吡咯环骨骼, 使它们成为完美的螺旋体环化合成子 (图 1)。经过有机催化剂和反应溶剂结构的优化, 该循环加成工艺有效地为所需产品提供了较高的产率和优良的对映体和环氧选择性。此外, 这种反应表现出相对较高的结构耐受性, 在广泛的环加成合成子与不同的功能群18。这种新方法通过简单的有机催化环加成, 在结构多样性导向中的应用, 为各种具有两个第四纪螺旋体的高功能化类似药物的化合物提供了有效的访问合成了这一类有趣的化合物。

<table border="0" cellpadding="0" cellspacing="0" style="width:993px;" width="992">
	<tbody>
		<tr height="21">
			<td height="21" style="height:21px;width:361px;">Acetonitrile, anhydrous, 99.9%</td>
			<td style="width:213px;">Innochem (China)</td>
			<td style="width:213px;">A0080</td>
			<td style="width:205px;"></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:361px;">&#945;-amino-&#947;-butyrolactone hydrobromide, 98%</td>
			<td style="width:213px;">Alfa Aesar</td>
			<td style="width:213px;">B23148</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:361px;">3,5-bis(trifluoromethyl)aniline, 98+%</td>
			<td style="width:213px;">Adamas</td>
			<td style="width:213px;">48611B</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:361px;">Dichloromethane, 99.5%</td>
			<td style="width:213px;">Greagent&#160;</td>
			<td style="width:213px;">G81014H</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:361px;">3,4-dimethoxycyclobut-3-ene-1,2-dione, 98+%</td>
			<td style="width:213px;">Leyan (China)</td>
			<td style="width:213px;">1062550</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:361px;">Ethanol, 99.5%</td>
			<td style="width:213px;">Greagent&#160;</td>
			<td style="width:213px;">G73537B</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:361px;">Ethyl acetate, 99.5%</td>
			<td style="width:213px;">Greagent&#160;</td>
			<td style="width:213px;">G23272L</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:361px;">Ethyl ether,anhydrous,99.5%</td>
			<td style="width:213px;">Greagent</td>
			<td style="width:213px;">G69159B</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:361px;">Ethyl 3-oxobutanoate, 98%</td>
			<td style="width:213px;">TCI</td>
			<td style="width:213px;">A0649</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:361px;">4-fluorobenzaldehyde, 98%</td>
			<td style="width:213px;">Innochem (China)</td>
			<td style="width:213px;">A24295</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:361px;">&#160;Glacial acetic acid, 99.5%</td>
			<td style="width:213px;">Greagent&#160;</td>
			<td style="width:213px;">G73562B</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:361px;">Magnesium oxide, 99+%</td>
			<td style="width:213px;">Alfa Aesar</td>
			<td style="width:213px;">44733</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:361px;">Magnesium sulfate, 98%</td>
			<td style="width:213px;">Greagent</td>
			<td style="width:213px;">G80872C</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:361px;">Methanol, 99.5%</td>
			<td style="width:213px;">Greagent</td>
			<td style="width:213px;">G75851A</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:361px;">Petroleum ether</td>
			<td style="width:213px;">Greagent&#160;</td>
			<td style="width:213px;">G84208D</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:361px;">Phenylhydrazine, 98%</td>
			<td style="width:213px;">Innochem (China)</td>
			<td style="width:213px;">A57671</td>
			<td></td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:361px;">(S)-(6-methoxyquinolin-4-yl)((1S,2R,4S,5R)-5-vinylquinuclidin-2-yl)methanamine</td>
			<td style="width:213px;">DAICEL Group</td>
			<td style="width:213px;">111240</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:361px;">Sodium sulfate,anhydrous,99%</td>
			<td style="width:213px;">Greagent</td>
			<td style="width:213px;">G82667A</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:361px;">Thiophene-2-carbaldehyde, 98%</td>
			<td style="width:213px;">J &#38; K scientific (China)</td>
			<td style="width:213px;">124605</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:361px;">Triethylamine, 99%</td>
			<td style="width:213px;">J &#38; k scientific (China)</td>
			<td style="width:213px;">432915</td>
			<td></td>
		</tr>
	</tbody>
</table>

efficient construction of drug-like bispirocyclic scaffolds via organocatalytic cycloadditions of &#945;-imino &#947;-lactones and alkylidene pyrazolones

双环支架是许多自然产品中重要的结构子单元之一, 具有多样化和吸引力的生物活性。最近, 我们开发了一种高效的有机催化策略, 为人们提供了一种简便的富对映体双吡咯烷酮 [γ-丁基-吡咯烷酮-4, 4 '-吡唑酮] 骨骼。本文通过有机催化剂 1, 3-偶极环加成反应, 证明了用两个螺旋体环碳中心不对称合成类似药物的双环化合物的详细协议。首先制备了α-氨基γ-内酯和烷基化物吡唑酮, 然后在双功能四酰胺有机催化剂的存在下进行环加成反应, 以提供所需的双硫磷高产量和出色的立体选择性。采用手性高效液相色谱法 (hplc) 测定产物的对映体纯度, 用质子核磁共振 (1h nmr) 检测其 d. r. 值。产品的绝对结构是根据 x 射线晶体学分析分配的。这种合成策略使科学家能够在高产量和优良的非对映体和对映性中制备多种双环支架。

在25°c 时, 在二氯甲烷 (dcm) 有机催化剂的存在下, 对各种氢键供体双功能有机催化剂进行了检测 (表 1)。具有代表性的有机催化剂合成过程如图 1所示。通过对不同有机催化剂的筛选 (表 1, 第1-6 项), c5 具有优异的立体选择性 (94% ee, & gt;20:1 d. r., 第5个条目) 和最佳产率 (85% 收率)。溶剂的进一步优化 (表 1, 条目 7-11) ?...

Watch this Scientific Journal Video about Efficient Construction of Drug-like Bispirocyclic Scaffolds Via Organocatalytic Cycloadditions of ÃŽÂ±-Imino ÃŽÂ³-Lactones and Alkylidene Pyrazolones at JoVE.

Efficient Construction of Drug-like Bispirocyclic Scaffolds Via Organocatalytic Cycloadditions of ÃƒÅ½Ã‚Â±-Imino ÃƒÅ½Ã‚Â³-Lactones and Alkylidene Pyrazolones

通过简单的有机催化 1, 3-偶极极环加成反应, 不对称地合成了富聚物的双吡咯烷酮----吡咯烷酮] 骨架。

α-伊米诺γ-乳胶酮和阿基地利酮吡唑酮有机催化环加花法高效构建药物样双环脚手架

Bispirocyclic scaffolds are one of the important structural subunits in many natural products that exhibit diverse and attractive biological activities. ...

这一个，三双极性细胞加载提供容易访问高度功能化双螺旋环化合物。这种化合物含有重要的脚手架，在许多自然产品中已经发现，表现出重要的生物活动。我们可以应用这种有机解囊肿，准备或压缩双螺旋环脚手架，其中包含两个手性螺旋中心，只需一步。这种反应避免了高产量和出色的立体选择性。在开始反应之前，确保所有试剂和溶剂都干燥至关重要。此外，在阿贡或氮气中应进行循环反应。演示这个程序的将是我实验室的研究生程亚平。为了准备，丙酮将45毫升的冰川醋酸加入含有磁性搅拌棒的250毫升圆形底部烧瓶中。在室温下搅拌溶液，同时添加一个等效的氢化物和乙酰乙酰乙酸酯。然后，为烧瓶配备回流冷凝器。在油浴中将反应瓶加热至120摄氏度，同时搅拌3小时。将烧瓶冷却到环境温度后，使用搅拌棒猎犬取出磁搅拌棒。使用旋转蒸发器在60摄氏度下集中反应混合物。接下来，在反应瓶中加入20毫升的去水，并将溶液转移到分离漏斗中。用30毫升乙酸乙酯提取水层三次。将分离漏斗中的有机层混合，用50毫升盐水洗涤两次。将组合的有机层在无水硫酸钠上干燥一小时。然后，通过重力过滤去除硫酸钠。在35摄氏度的减压下，在旋转蒸发器上去除溶剂，以分离丙酮。要准备α-丙烯苯丙酮，在氮气下将一个相当于丙酮、一个相当于苯甲醛、0.6个相当于氧化镁和磁搅拌棒的苯丙烯酮添加到烤箱干燥的100毫升圆形底瓶中。使用气密注射器，加入40毫升无水乙酰气，并装备反应瓶与反流冷凝器。在油浴中将反应瓶加热至120摄氏度，同时搅拌12小时。使用石油醚和乙酸乙酯的二对一混合物（TLC）监测反应的进度。在完全食用丙酮后，将反应瓶冷却至室温。然后，使用硅石塞过滤掉氧化镁。在 35 摄氏度的低压下使用旋转蒸发器，去除多余的乙酰气。通过硅胶柱色谱净化残留物。用石油醚和乙酸乙酯来购买原油。将粗制产品加入100毫升的Erlenmeyer烧瓶中，并加入一个磁性搅拌棒，并加入95%的乙醇最小体积。将烧瓶放在热盘上，轻轻煮沸搅拌，直到整个固体刚刚溶解。然后，从热板中取下烧瓶，缓慢冷却，无需任何搅拌，即可将α-二甲二烯产品形成纯晶体。要准备α-imino伽马-乳酮，在氮气下将α-imino-伽马-丁醇酮氢溴化物、硫酸镁、三乙胺和磁搅拌棒和磁搅拌棒添加一个等效物。使用气密注射器，在反应瓶中加入36毫升无水二氯甲烷，并在室温下搅拌反应混合物一小时。然后，在溶液中加入1.1个当量所需的硫磷二甲醛，再搅拌12小时。使用石油醚和乙酸乙酯的四对一混合物来监测TLC的反应进展，直到乳酮物种完全消耗。然后，使用倾水尺寸为 30 到 50 微米的滤纸过滤掉反应。接下来，在产生的混合物中加入五毫升的去层水，并将有机层与水相分离。用30毫升二氯甲烷萃取水相两次。将分离漏斗中的有机层混合，用50毫升盐水洗涤两次。将组合的有机层在无水硫酸钠上干燥一小时。通过重力过滤去除硫酸钠。然后，在35摄氏度的低压下，在旋转蒸发器上去除溶剂。在氮气下，将一个相当于α-丙烯酰丙酮1.2等价的α-imino-伽马-拉酮和磁搅拌棒加入烤箱干燥的15毫升圆形底部烧瓶中。使用气密注射器在反应瓶中加入10毫升无水乙醚。然后将相当于双功能四边形催化剂的0.1等量加入溶液中，并在40摄氏度下搅拌反应混合物。通过 TLC 监控反应的进度。使用石油乙醚和乙酸乙酯的四对一混合物作为紫水晶。反应完成后，使用旋转蒸发器在40摄氏度下浓缩混合物。用四比一的石油醚和乙酸乙酯混合物纯化残留物，以提供最终产品。使用 400 兆赫 NMR 光谱仪以质子和碳 NMR 光谱为最终产品进行特征化。使用奇性 HPLC 列确定产品的抗异体过量。此处显示了双功能四酰催化剂的代表性合成工艺。对不同有机催化剂的筛选使C5具有优异的立体选择性和最高的产量。溶剂的进一步优化表明，乙醚在合成工艺中更可取。利用优化的模型反应条件，成功测试了两个不同功能组两个螺旋环化合成器的各种替代体，提供了所需的双螺旋循环，具有优异的产量和立体选择性。双螺旋环产品的结构得到质子和碳N NMR光谱的确认。具有代表性的 HPLC 色谱图具有种族和奇性化合物 3E 显示在这里。化合物3E的X射线晶体显示绝对配置为5S、6R、7R、13R。此处显示了 3E 的单晶结构。在开始反应之前，确保所有试剂和溶剂都干燥。此外，反应应在阿贡或氮气中进行。通过这种药物样双螺旋环生产，我们可以调查它们的生物活性，以探讨它们对蛋白质和细胞水平的潜在影响，以及它们在药物发现中的应用。通过新的策略，研究人员能够探索这些双螺旋环化合物的可能生物功能，它们对蛋白质和细胞活动的影响以及交叉结合机制。

Research

JoVE Journal

Chemistry

Efficient Construction of Drug-like Bispirocyclic Scaffolds Via Organocatalytic Cycloadditions of &#945;-Imino &#947;-Lactones and Alkylidene Pyrazolones

Facile and Efficient Preparation of Tri-component Fluorescent Glycopolymers via RAFT-controlled Polymerization

通过RAFT控制聚合轻便和高效制备三组分荧光Glycopolymers

Synthetic glycopolymers are instrumental and versatile tools used in various biochemical and biomedical research fields. An example of a facile and ...

科研

化学

Construction and Systematical Symmetric Studies of a Series of Supramolecular Clusters with Binary or Ternary Ammonium Triphenylacetates

建筑和超分子集群与二元或三元铵Triphenylacetates一系列的体制性对称研究

Functions of clusters in nano or sub-nano scale significantly depend on not only kinds of their components but also arrangements, or symmetry, of their ...

Construction of Models for Nondestructive Prediction of Ingredient Contents in Blueberries by Near-infrared Spectroscopy Based on HPLC Measurements

基于HPLC测量通过近红外光谱对在蓝莓成分的含量无损预测模型的构建

Nondestructive prediction of ingredient contents of farm products is useful to ship and sell the products with guaranteed qualities. Here, near-infrared ...

Synthesis of Protein Bioconjugates via Cysteine-maleimide Chemistry

Synthesis of Protein Bioconjugates via Cysteine-maleimide Chemistry

蛋白质生物缀合物的合成<em&gt;通过</em&gt;半胱氨酸马来酰亚胺化学

The chemical linking or bioconjugation of proteins to fluorescent dyes, drugs, polymers and other proteins has a broad range of applications, such as the ...

The Preparation and Properties of Thermo-reversibly Cross-linked Rubber Via Diels-Alder Chemistry

热可逆交联橡胶通过的Diels-Alder反应的化学制备与性能

A method for using Diels Alder thermo-reversible chemistry as cross-linking tool for rubber products is demonstrated. In this work, a commercial ...

A Simple and Efficient Protocol for the Catalytic Insertion Polymerization of Functional Norbornenes

功能性降冰片烯的催化聚合插入一种简单高效的协议

Norbornene can be polymerized by a variety of mechanisms, including insertion polymerization whereby the double bond is polymerized and the bicyclic ...

Fabrication and Testing of Catalytic Aerogels Prepared Via Rapid Supercritical Extraction

快速超临界萃取制备催化气凝胶的制备与试验研究

Protocols for preparing and testing catalytic aerogels by incorporating metal species into silica and alumina aerogel platforms are presented. Three ...

Synthesis of Substrate-Bound Au Nanowires Via an Active Surface Growth Mechanism

通过活性表面生长机制合成基片束缚金纳米线

Advancing synthetic capabilities is important for the development of nanoscience and nanotechnology. The synthesis of nanowires has always been a ...

Synthesis of Esters Via a Greener Steglich Esterification in Acetonitrile

乙腈绿色 Steglich 酯化合成酯的研究

The Steglich esterification is a widely-used reaction for the synthesis of esters from carboxylic acids and alcohols. While efficient and mild, the ...

Experimental Methods for Efficient Solar Hydrogen Production in Microgravity Environment

微重力环境下高效太阳能氢气生产的实验方法

Long-term space flights and cis-lunar research platforms require a sustainable and light life-support hardware which can be reliably employed outside the ...