Name: preparation of stable bicyclic aziridinium ions and their ring-opening for the synthesis of azaheterocycles
Uploaded: 2018-08-22T13:30:00.000+00:00
Duration: 11 min 45 s
Description: Watch this Scientific Journal Video about Preparation of Stable Bicyclic Aziridinium Ions and Their Ring-Opening for the Synthesis of Azaheterocycles at JoVE.com

这项工作得到韩国国家研究基金会 (NRF-2012M3A7B4049645 和 HUFS 研究基金 (2018) 的支持。

1. 合成 (6R)-1-[(R)-1-苯)-1-Azoniabicyclo [4.1. 0] 庚烷磺酸盐 (4)
<ol><li>4-(R)-[1-(r)-1-苯) aziridin 2-基] 丁基 4-磺酸盐 (2) 的合成<ol>
<li>添加100毫克 4-[(r)-1-(r)-1-苯) aziridin-2-基] 氨基正丁-1-ol (1)12 (0.46 毫摩尔, 1.0 equiv), 140 µL 的三乙胺 (Et3N, 1.0 毫摩尔, 2.2 equiv), 和一个磁搅拌棒成烤箱干25毫升双颈圆底烧瓶在氮气 (N2) 大气之下。</li>
		<li>用密闭注射器将无水二氯甲烷 (CH2氯2, 5 毫升) 加入到反应瓶中。</li>
		<li>冷却反应混合物在0°c 使用冰浴和搅动混合物5分钟。</li>
		<li>将对磺酸酐 (164 毫克, 0.50 毫摩尔, 1.10 equiv) 加入到反应混合物中, 再搅拌45分钟。</li>
		<li>将反应混合物加热室温 (RT), 搅拌30分钟。</li>
		<li>用薄层色谱 (TLC) 监测反应, 使用 hexanes: 乙酸乙酯 (EtOAc) (1:1 伏/v, 保留因子 Rf = 0.55) 作为淋洗。</li>
		<li>在开始的酒精的完全消耗量以后1, 淬火反应混合物与水 (5 毫升)。采用 CH2Cl2 (3 x 15 毫升) 提取异质混合物, 在无水硫酸钠 (Na2至4) 上干燥复合有机层, 用于10分钟, 并在真空中使用旋转蒸发器进行浓缩。</li>
		<li>用 hexanes 与闪光柱层析洗脱法提纯原油产品: EtOAc (2:1 至1:2 伏/v), 可负担165毫克 (0.44 毫摩尔, 96% 产量) 4-(R)-[1-(r)-1-苯) aziridin-2-基] 丁基 4-磺酸盐 (rf= 0.55, hexanes: EtOAc (1:1 伏/v)) 作为粘性液体。</li>
	</ol>
</li>
	<li>合成 (6R)-1-[(R)-1-苯)-1-azoniabicyclo [4.1. 0] 庚烷磺酸盐 (4)<ol>
<li>转移5毫克的新鲜准备2在核磁共振管和添加乙腈 d3 (CD3CN, 300 µL)。</li>
		<li>保持上述溶液在 RT 为24小时, 以达到完全转化为 (6R)-1-[(R)-1-苯)-1-azoniabicyclo [4.1. 0] 庚烷磺酸盐4。</li>
		<li>在 CD3CN 的不同时间点 (10 分钟、1、5、7和 24 h) 中, 通过核磁共振 (NMR) 频谱监测2到4的转换。</li>
	</ol>
</li>
</ol>2. 扩大 1-Azoniabicyclo [4.1. 0] 庚烷磺酸盐的一般程序
<ol><li>使用步骤 1.1.1 1.1.7 准备相应的磺酸盐2。</li>
	<li>将上述粗磺酸盐, 并将磁性搅拌棒放入烤箱干燥的25毫升圆底烧瓶中。</li>
	<li>使用密闭注射器将无水 CH3CN (4.0 毫升) 添加到反应瓶中。</li>
	<li>将相应的亲核试剂 (1.37 毫摩尔, 3.0 equiv) 添加到反应混合物中, 搅拌 8-15 h。</li>
	<li>淬火反应混合物与水 (5 毫升), 萃取物与 CH2Cl2 (3 x 15 毫升), 干燥的有机层在无水 Na2如此4 , 并集中在真空使用旋转蒸发器。</li>
	<li>用柱层析法提纯原油产品: EtOAc (19:1 至 7:3 hexanes), 以支付纯环膨胀产品。 注: 所有化合物均采用上述程序合成, 除6j (入口 j,表 1)。 注意: 干燥 CH3CN 是由氢化钙 (2) 在 N2大气中蒸馏而成。氰化钠在已知的最有毒物质中是有毒的, 在化学油烟机下使用适当的安全防护。用高锰酸钾 (KMnO4) 溶液对氰进行淬火。</li>
</ol>3. 合成 (S)-1-[(R)-1-苯] azepan 3 醇 (6j)
<ol><li>转移 4-(r)-[1-(r)-1-苯) aziridin 2-基] 丁基 4-磺酸盐 (100 毫克, 0.27 毫摩尔, 1.0 equiv), 和一个磁搅拌棒成烤箱干燥25毫升的圆底烧瓶装有回流冷凝器。</li>
	<li>用注射器将 14-二恶烷 (4 毫升) 加入到反应瓶中。</li>
	<li>加入0.4 毫升2.0 米氢氧化钠溶液 (氢氧化钠, 0.80 毫摩尔, 3.0 equiv) 到反应混合物和热回流为 2.0 h。</li>
	<li>淬火反应混合物与水 (4 毫升), 萃取物与 CH2Cl2 (4 x 15 毫升), 干燥的有机层在无水 Na2如此4 , 并集中在真空使用旋转蒸发器。</li>
	<li>用 hexanes 的柱层析洗脱法提纯原油产品: EtOAc (2:1 至 1:1 (v/v)) (Rf = 0.60, hexanes: EtOAc (1:1 (v/v)), 可负担46毫克 (S)-1-[(R)-1-苯] azepan 3 醇 (0.21 毫摩尔, 79% 产量)。</li>
</ol>4. 合成 [(2R, 3r, 4r)-34-双 (苄)-1-(S)-1-苯) 哌-2-基] 乙酸甲酯 (8):
<ol><li>转移 (3r, 4r)-34-双 (苄)-4-[(R)-1-(S)-1-苯) aziridin-2-基] 氨基正丁-1-ol (7) (220 毫克, 0.51 毫摩尔, 1.0 equiv), 180 µL Et3N (1.27 毫摩尔, 2.5 equiv), 和一个磁性搅拌棒成烤箱干燥25毫升双颈圆底烧瓶在 N2的气氛下。</li>
	<li>使用密闭注射器将无水 CH2氯2 (4 毫升) 添加到反应瓶中。</li>
	<li>冷却反应混合物在0°c 和搅动5分钟。</li>
	<li>将对磺酸酐 (200 毫克, 0.61 毫摩尔, 1.20 equiv) 加入到反应混合物中, 再搅拌45分钟。</li>
	<li>将反应混合物加热至 RT, 搅拌30分钟。</li>
	<li>用 hexanes: EtOAc (7:3 伏/五, Rf = 0.60) 作为淋洗, 监测反应的进展。</li>
	<li>在酒精的完全消耗量7以后, 淬火反应混合物与水 (5 毫升), 萃取物与 CH2Cl2 (3 x 15 毫升), 干燥联合有机层数在无水 Na2如此4和集中在真空使用旋转蒸发器。</li>
	<li>将上述粗磺酸盐, 并将磁性搅拌棒放入烤箱干燥的25毫升圆底烧瓶中。</li>
	<li>使用密闭注射器将无水 CH3CN (4 毫升) 添加到反应瓶中。</li>
	<li>将125毫克醋酸钠 (NaOAc, 1.53 毫摩尔, 3.0 equiv) 加入到反应混合物中, 搅拌12小时。</li>
	<li>淬火反应混合物与水 (5 毫升), 萃取物与 CH2Cl2 (3 x 15 毫升), 干燥的有机层在无水 Na2如此4 , 并集中在真空使用旋转蒸发器。</li>
	<li>用柱层析法提纯粗产品: EtOAc (9:1 至4:1 伏/v), 以 hexanes 纯化合物 8 (200 毫克, 83% 产量)。</li>
</ol>5. 合成 (3R, 4r)-3-叠氮基-1-[(R)-1-苯] azepan-4-Ol (14):
<ol><li>转移 (r)-1-[(S)-1-(r)-1-苯) aziridin 2-基] 丁烷-14-二醇 (13) (235 毫克, 1.0 毫摩尔, 1.0 equiv), 0.35 毫升 Et3N (2.50 毫摩尔, 2.5 equiv), 和一个磁搅拌棒成烤箱干25毫升双颈圆底烧瓶在氮气气氛下。</li>
	<li>用密闭注射器将无水 CH2Cl2 (8 毫升, 0.12 米) 添加到反应瓶中。</li>
	<li>冷却反应混合物在0°c 和搅动5分钟。</li>
	<li>将对磺酸酐 (359 毫克, 1.10 毫摩尔, 1.10 equiv) 加入到反应混合物中, 再搅拌45分钟。</li>
	<li>用 hexanes: EtOAc (1:1 伏/五, Rf = 0.40) 作为淋洗, 监测反应的进展。</li>
	<li>在开始酒精的完全消耗量以后13, 淬火反应混合物与水 (10 毫升), 萃取物与 CH2Cl2 (3 x 15 毫升), 干燥联合有机层数在无水 Na2如此4和集中在真空使用旋转蒸发器。</li>
	<li>将上述粗磺酸盐, 并将磁性搅拌棒放入烤箱干燥的25毫升圆底烧瓶中。</li>
	<li>使用密闭注射器将无水 CH3CN (8 毫升, 0.12 米) 添加到反应瓶中。</li>
	<li>加入214毫克的 NaOAc (3.30 毫摩尔, 3.30 equiv) 的反应混合物和搅拌 12 h。</li>
	<li>将反应混合物与水 (10 毫升) 淬火, 萃取物与 CH2Cl2 (15 毫升 x 3 倍), 干燥的有机层在无水 Na2如此4 , 并集中在真空使用旋转蒸发器。</li>
	<li>用柱层析法提纯粗产品: EtOAc (9:1 至4:1 伏/v), 以 hexanes 纯化合物14 (133 毫克, 51% 产量)。</li>
</ol>6. 所有产品的特性
<ol><li>用1H、 13C 核磁共振波谱和高分辨率质谱 (HRMS) 表征了所有新化合物。</li>
</ol>

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作者声明没有竞争的财政利益。

哌啶和 azepane 是 azaheterocycles 许多救生药物和抗生素中最丰富的两种, 包括各种生物活性天然产物16。为了获得 enantiopure 哌啶 (5) 和 azepane (6) 与不同的取代基, 我们得以一个有效的合成方法通过形成 1-azoniabicyclo [4.1. 0] 庚烷磺酸盐从 entiopure 2-(4-丁基)aziridne 其次是 regiospecific 亲核攻击在桥梁或在桥头碳。在乙腈中溶解相应的 2-(4-tosyloxybutyl) 氮丙啶, 容易制备...

在三元循环化合物中, 氮丙啶具有类似的环应变能, 如丙烷和环氧乙烷, 可通过环形开口1、2、3来承受各种含氮循环和非环状化合物。然而, 氮丙啶的特性和反应性取决于环氮的取代基。氮丙啶与一个电子撤退的小组在圆环氮气4, 被叫 "激活的氮丙啶", 被激活与接踵而来的亲核试剂反应, 不用任何另外的活化试剂。另一方面, "非活化氮丙啶" 与电子捐赠取代基在氮气是相当稳定和惰性的亲核试剂, 除非它被激活作为一个 aziridinium 离子作为Ia (图 1a)5,6,7. 非活化氮丙啶环的开启取决于各种因素, 如 C2 的取代基和氮丙啶的 C3 碳、亲电性激活氮丙啶环和传入的亲核试剂。由于亲核试剂对开环反应的高反应性, aziridinium 离子的分离和表征是不可能的, 但它的形成和特征 spectroscopically 与非亲核反负离子5,8,9,10. aziridinium 离子的立体环开放反应由适当的亲核试剂产生含氮非循环有价值分子 (pi和pii)5, 6,7,8,9,10。
同样, 笼 aziridinium 离子 (Ib) 可能是通过去除组内的氮丙啶环氮的亲核攻击而产生的 (图 1b)。然后, 该中间体通过环应变的释放与传入亲核试剂进行环形扩展。笼 aziridinium 离子的形成和稳定性取决于许多因素, 如取代基、环的大小和溶剂介质9。氮丙啶环扩展的立体选择性是其综合效用的一个关键方面, 它依赖于起始基板的取代性和应用亲核试剂的特性。
在我们早期的研究中, 我们成功地准备了 1-azoniabicyclo [3.1. 0] 己烷磺酸盐Ib (n = 1), 其随后的环扩张导致了吡咯烷和哌啶的形成 (piii和piv, n= 1,图 1)8。作为我们继续研究笼 aziridinium 离子化学的一部分, 我们在这里描述了 1-azoniabicyclo [4.1. 0] 庚烷磺酸盐Ib (n = 2) 的形成, 作为一个代表性的例子。这是由 2-(4-toluensulfonyloxybutyl) 氮丙啶和它的圆环扩展被触发由亲核试剂负担得起价值的哌啶和 azepane (pi和pii, n = 2,图 1) 以各种各样的取代在圆环11附近。enantiopure 氮丙啶 4-[(r)-1 (r)-1-苯) aziridin 2 基] 氨基正丁-1-ol (1) 的扩环导致取代 azaheterocycles 的不对称合成, 适用于生物具有哌啶和 azepane 骨架的活性分子。该合成协议已应用于各种化合物, 从简单的 2-cyanomethylpiperidine 5f, 2-acetyloxymethylpiperidine 5h和 3-hydroxyazepane 6j到更复杂的分子, 包括自然产品如 fagomine (9), febrifugine 模拟 (12) 和 balanol (15) 在光学纯净的形式11。

<table><tbody><tr><td>Thin Layer Chromatography (TLC)</td><td>Merck</td><td>100390</td><td></td></tr><tr><td>UV light</td><td>Sigma-Aldrich</td><td>Z169625-1EA</td><td></td></tr><tr><td>Bruker AVANCE III HD (400 MHz) spectrometer</td><td>Bruker</td><td>NA</td><td></td></tr><tr><td>JASCO P-2000</td><td>JASCO</td><td>P-2000</td><td>For optical rotation</td></tr><tr><td>High resolution mass spectra/ MALDI-TOF/TOF Mass Spectrometry</td><td>AB SCIEX</td><td>4800 Plus&amp;nbsp;</td><td>High resolution mass spectra</td></tr><tr><td>(2R)-1-[(1R)-1-Phenylethyl]-2-aziridinecarboxylic acid (&amp;ndash;)-menthol ester, 98%</td><td>Sigma-Aldrich</td><td>57,054-0</td><td></td></tr><tr><td>(2S)-1-[(1R)-1-Phenylethyl]-2-aziridinecarboxylic acid (&amp;ndash;)-menthol ester</td><td>Sigma-Aldrich</td><td>57,051-6</td><td></td></tr><tr><td>Triethylethylamine</td><td>DAEJUNG</td><td>8556-4400-1L</td><td>CAS No: 121-44-8</td></tr><tr><td>Dichloromethane</td><td>SAMCHUN</td><td>M0822-18L</td><td>CAS No: 75-09-2</td></tr><tr><td>p-Toluenesulfonic anhydride</td><td>Sigma-Aldrich</td><td>259764-25G</td><td>CAS No: 4124-41-8</td></tr><tr><td>n-Hexane</td><td>SAMCHUN</td><td>H0114-18L</td><td>CAS No: 110-54-3</td></tr><tr><td>Ethyl acetate</td><td>SAMCHUN</td><td>E0191-18L</td><td>CAS No: 141-78-6</td></tr><tr><td>Sodium sulfate</td><td>SAMCHUN</td><td>S1011-1kg</td><td>CAS No: 7757-82-6</td></tr><tr><td>Acetonitrile-d3</td><td>Cambridge Isotope Laboratories, Inc</td><td>15G-744-25g</td><td>CAS No: 2206-26-0</td></tr><tr><td>Acetonitrile</td><td>SAMCHUN</td><td>A0127-18L</td><td>CAS No: 75-05-8</td></tr><tr><td>1,4-Dioxane</td><td>SAMCHUN</td><td>D0654-1kg</td><td>CAS No: 123-91-1</td></tr><tr><td>Sodium hydroxide</td><td>DUKSAN</td><td>A31226-1kg</td><td>CAS No: 1310-73-2</td></tr><tr><td>Sodium acetate</td><td>Alfa Aesar</td><td>11554-250g</td><td>CAS No: 127-09-3</td></tr><tr><td>Lithium aluminum hydride</td><td>TCI</td><td>L0203-100g</td><td>CAS No: 16853-85-3</td></tr><tr><td>Tetrahydrofuran</td><td>SAMCHUN</td><td>T0148-18L</td><td>CAS No: 109-99-9</td></tr><tr><td>Sodium azide</td><td>D.S.P</td><td>703301-500g</td><td>CAS No: 26628-22-8</td></tr><tr><td>Cesium fluoride</td><td>aldrich</td><td>18951-0250-25g</td><td>CAS No: 13400-13-0</td></tr><tr><td>Tetrabutylammonium bromide</td><td>aldrich</td><td>426288-25g</td><td>CAS No: 1643-19-2</td></tr><tr><td>Sodium iodide</td><td>aldrich</td><td>383112-100g</td><td>CAS No: 7681-82-5</td></tr><tr><td>Sodium cyanide</td><td>Acros Organics</td><td>424301000-100g</td><td>CAS No: 143-33-9</td></tr><tr><td>Sodium thiocyanate</td><td>aldrich</td><td>467871-250g</td><td>CAS No: 540-72-7</td></tr><tr><td>Sodium methoxide</td><td>aldrich</td><td>156256-1L</td><td>CAS No: 124-41-4</td></tr><tr><td>Benzylamine</td><td>Alfa Aesar</td><td>A10997-1000g</td><td>CAS No: 100-46-9</td></tr><tr><td>Phenol</td><td>TCI</td><td>P1610-500g</td><td>CAS No: 108-95-2</td></tr><tr><td>Sodium benzoate</td><td>Alfa Aesar</td><td>A15946-250g</td><td>CAS No: 532-32-1</td></tr><tr><td>Chloroform-d</td><td>Cambridge Isotope Laboratories, Inc</td><td>DLM-7TB-100S/16H-239, 100g</td><td>CAS No: 865-49-6</td></tr><tr><td>Dimethyl sulfoxide-d6</td><td>Cambridge Isotope Laboratories, Inc</td><td>DLM-10-25, 25g</td><td>CAS No: 2206-27-1</td></tr><tr><td>Methanol</td><td>SAMCHUN</td><td>M0585-18L</td><td>CAS No: 67-56-1</td></tr><tr><td>Ninhydrin</td><td>Alfa Aesar</td><td>A10409-250g</td><td>CAS No: 485-47-2</td></tr><tr><td>Phosphomolybdic acid hydrate</td><td>TCI</td><td>P1910-100g</td><td>CAS No: 51429-74-4</td></tr><tr><td>p-Anisaldehyde</td><td>aldrich</td><td>A88107-5g</td><td>CAS No: 123-11-5</td></tr></tbody></table>

preparation of stable bicyclic aziridinium ions and their ring-opening for the synthesis of azaheterocycles

笼 aziridinium 离子是通过在氮丙啶环中的氮原子的内部亲核攻击去除适当的离开群而产生的。笼 aziridinium 离子的效用, 特别是 1-azoniabicyclo [3.1. 0] 己烷和 1-azoniabicyclo [4.1. 0] 庚烷磺酸盐突出在氮丙啶环开口由亲核试剂与释放环应变产生相应的环扩张 azaheterocycles, 如吡咯烷, 哌啶和 azepane 与不同的取代基在环上的范围-和立体方式。在此, 我们报告了一个简单和方便的方法, 以制备稳定的 1-杂双环 [4.1. 0] 庚烷磺酸盐后, 选择性环开口通过亲核攻击无论是在桥梁或在桥头碳产生哌啶和 azepane环, 分别。这一综合策略使我们能够高效地制备含有哌啶和 azepane 的生物活性天然产物, 包括 sedamine、allosedamine、fagomine 和 balanol。

4-[(r)-1-(r)-1-苯) aziridin-2-基] 氨基正丁-1 醇 (1)12与p-磺酸酐和三乙胺的反应在 CH2Cl2在室温为 1.0 h 产生了相应的 2-(4-tosyloxybutyl) 氮丙啶2在96% 产量11。1在不同时间间隔内, 在 CD3CN 中, 2的 H NMR (400 兆赫) 频谱显示了 2-(4-tosyloxybutyl) 氮丙啶2到...

Watch this Scientific Journal Video about Preparation of Stable Bicyclic Aziridinium Ions and Their Ring-Opening for the Synthesis of Azaheterocycles at JoVE.com

Preparation of Stable Bicyclic Aziridinium Ions and Their Ring-Opening for the Synthesis of Azaheterocycles

稳定笼 Aziridinium 离子的制备及其开环 Azaheterocycles 的合成

笼 aziridinium 离子, 如 1-azoniabicyclo [4.1. 0] 庚烷磺酸盐是由 2-[4-tolenesulfonyloxybutyl] 氮丙啶, 用于制备替代的 piperidines 和 azepanes 通过地-和立体环形膨胀与各种亲核试剂。这一高效的协议允许我们准备各种 azaheterocycles, 包括自然产品, 如 fagomine, febrifugine 模拟和 balanol。

Bicyclic aziridinium ions were generated by the removal of an appropriate leaving group through internal nucleophilic attack by nitrogen atom in the ...

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Organic Chemistry

Chemistry

Unit 1

Nucleophilic Substitution and Elimination Reactions of Alkyl Halides

SCIENTISTS IN ACTION

8.3K 次观看.  North Eastern Regional Institute of Science and Technology. 笼 aziridinium 离子, 如 1-azoniabicyclo [4.1. 0] 庚烷磺酸盐是由 2-[4-tolenesulfonyloxybutyl] 氮丙啶, 用于制备替代的 piperidines 和 azepanes 通过地-和立体环形膨胀与各种亲核试剂。这一高效的协议允许我们准备各种 azaheterocycles, 包括自然产品, 如 fagomine, febrifugine 模拟和 balanol。

视频: Preparation of Stable Bicyclic Aziridinium Ions and Their Ring-Opening for the Synthesis of Azaheterocycles

Synthesis of Hypervalent Iodonium Alkynyl Triflates for the Application of Generating Cyanocarbenes

The procedures described in this article involve the synthesis and isolation of hypervalent iodonium alkynyl triflates (HIATs) and their subsequent reactions with azides to form cyanocarbene intermediates. The synthesis of hypervalent iodonium alkynyl triflates can be facile, but difficulties stem from their isolation and reactivity. In particular, the necessity to use filtration under inert atmosphere at -45 &deg;C for some HIATs requires special care and equipment. Once isolated, the compounds can be stored and used in reactions with azides to form cyanocarbene intermediates. 
The evidence for cyanocarbene generation is shown by visible extrusion of dinitrogen as well as the characterization of products that occur from O-H insertion, sulfoxide complexation, and cyclopropanation. A side reaction of the cyanocarbene formation is the generation of a vinylidene-carbene and the conditions to control this process are discussed. There is also potential to form a hypervalent iodonium alkenyl triflate and the means of isolation and control of its generation are provided. The O-H insertion reaction involves using a HIAT, sodium azide or tetrabutylammonium azide, and methanol as solvent/substrate. The sulfoxide complexation reaction uses a HIAT, sodium azide or tetrabutylammonium azide, and dimethyl sulfoxide as solvent. The cyclopropanations can be performed with or without the use of solvent. The azide source must be tetrabutylammonium azide and the substrate shown is styrene.

Herein is described the synthesis, isolation, and reactions of hypervalent iodonium alkynyl triflates (HIATs) with azides to generate cyanocarbenes. The procedures will involve air-sensitive and cryogen techniques, including cold filtration under an inert atmosphere. Handling and safety of the synthesized compounds will also be discussed.

高价碘鎓炔基三氟甲磺酸酯的生成Cyanocarbenes的合成应用

The procedures described in this article involve the synthesis and isolation of hypervalent iodonium alkynyl triflates (HIATs) and their subsequent ...

科研

化学

Synthesis of 1,2-Azaborines and the Preparation of Their Protein Complexes with T4 Lysozyme Mutants

We describe a general synthesis of 1,2-azaborines using standard air-free techniques and protein complex preparation with T4 lysozyme mutants by vapor diffusion. Oxygen- and moisture-sensitive compounds are prepared and isolated under an inert atmosphere (N2) using either a vacuum gas manifold or a glove box. As an example of azaborine synthesis, we demonstrate the synthesis and purification of the volatile N-H-B-ethyl-1,2-azaborine by a five-step sequence involving distillation and column chromatography for the isolation of products. T4 lysozyme mutants L99A and L99A/M102Q are expressed with Escherichia coli RR1 strain. Standard protocols for chemical cell lysis followed by purification using carboxymethyl ion exchange column affords protein of sufficiently high purity for crystallization. Protein crystallization is performed in various concentrations of precipitant at different pH ranges using the hanging drop vapor diffusion method. Complex preparation with the small molecules is carried out by vapor diffusion method under an inert atmosphere. X-ray diffraction analysis of the crystal complex provides unambiguous structural evidence of binding interactions between the protein binding site and 1,2-azaborines.

A protocol for the synthesis of 1,2-azaborines and the preparation of their protein complexes with T4 lysozyme mutants is presented.

1,2- Azaborines的合成及其蛋白复合物的用T4溶菌酶突变体的制备

We describe a general synthesis of 1,2-azaborines using standard air-free techniques and protein complex preparation with T4 lysozyme mutants by vapor ...

生物化学

Synthesis and Purification of Iodoaziridines Involving Quantitative Selection of the Optimal Stationary Phase for Chromatography

The highly diastereoselective preparation of cis-N-Ts-iodoaziridines through reaction of diiodomethyllithium with N-Ts aldimines is described. Diiodomethyllithium is prepared by the deprotonation of diiodomethane with LiHMDS, in a THF/diethyl ether mixture, at -78 &#176;C in the dark. These conditions are essential for the stability of the LiCHI2 reagent generated. The subsequent dropwise addition of N-Ts aldimines to the preformed diiodomethyllithium solution affords an amino-diiodide intermediate, which is not isolated. Rapid warming of the reaction mixture to 0 &#176;C promotes cyclization to afford iodoaziridines with exclusive cis-diastereoselectivity. The addition and cyclization stages of the reaction are mediated in one reaction flask by careful temperature control.
Due to the sensitivity of the iodoaziridines to purification, assessment of suitable methods of purification is required. A protocol to assess the stability of sensitive compounds to stationary phases for column chromatography is described. This method is suitable to apply to new iodoaziridines, or other potentially sensitive novel compounds. Consequently this method may find application in range of synthetic projects. The procedure involves firstly the assessment of the reaction yield, prior to purification, by 1H NMR spectroscopy with comparison to an internal standard. Portions of impure product mixture are then exposed to slurries of various stationary phases appropriate for chromatography, in a solvent system suitable as the eluent in flash chromatography. After stirring for 30 min to mimic chromatography, followed by filtering, the samples are analyzed by 1H NMR spectroscopy. Calculated yields for each stationary phase are then compared to that initially obtained from the crude reaction mixture. The results obtained provide a quantitative assessment of the stability of the compound to the different stationary phases; hence the optimal can be selected. The choice of basic alumina, modified to activity IV, as a suitable stationary phase has allowed isolation of certain iodoaziridines in excellent yield and purity.

A protocol for the diastereoselective one-pot preparation of cis-N-Ts-iodoaziridines is described. The generation of diiodomethyllithium, addition to N-Ts aldimines and cyclization of the amino gem-diiodide intermediate to iodoaziridines is demonstrated. Also included is a protocol to rapidly and quantitatively assess the most appropriate stationary phase for purification by chromatography.

合成和Iodoaziridines纯化涉及定量选择最优固定相的色谱

The highly diastereoselective preparation of cis-N-Ts-iodoaziridines through reaction of diiodomethyllithium with N-Ts aldimines is described. ...

Solid-phase Synthesis of [4.4] Spirocyclic Oximes

A convenient synthetic route for spirocyclic heterocycles is well sought after due to the molecule&#39;s potential use in biological systems. By means of solid-phase synthesis, regenerating Michael (REM) linker strategies, and 1,3-dipolar cycloaddition, a library of structurally similar heterocycles, both with and without a spirocyclic center, can be constructed. The main advantages of the solid-support synthesis are as follows: first, each reaction step can be driven to completion using a large excess of reagents resulting in high yields; next, the use of commercially available starting materials and reagents keep the costs low; finally, the reaction steps are easy to purify via simple filtration. The REM linker strategy is attractive because of its recyclability and traceless nature. Once a reaction scheme is completed, the linker can be reused multiple times. In a typical solid-phase synthesis, the product contains either a part of or the whole linker, which can prove undesirable. The REM linker is &#34;traceless&#34; and the point of attachment between the product and the polymer is indistinguishable. The high diastereoselectivity of the intramolecular 1,3-dipolar cycloaddition is well documented. Limited by the insolubility of the solid support, the reaction progression can only be monitored by a change in the functional groups (if any) via infrared (IR) spectroscopy. Thus, the structural identification of intermediates cannot be characterized by conventional nuclear magnetic resonance (NMR) spectroscopy. Other limitations to this method stem from the compatibilities of the polymer/linker to the desired chemical reaction scheme. Herein we report a protocol that allows for the convenient production of spirocyclic heterocycles that, with simple modifications, can be automated with high-throughput techniques.

Here we present a protocol to demonstrate an efficient method for the synthesis of spirocyclic heterocycles. The five-step process utilizes solid-phase synthesis and regenerating Michael linker strategies. Generally difficult to synthesize, we present a customizable method for the synthesis of spirocyclic molecules otherwise inaccessible to other modern approaches.

[4.4] 刺环氧基的固相合成

A convenient synthetic route for spirocyclic heterocycles is well sought after due to the molecule&#39;s potential use in biological systems. By means of ...

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

Bispirocyclic scaffolds are one of the important structural subunits in many natural products that exhibit diverse and attractive biological activities. Recently, we have developed an efficient organocatalytic strategy, which provides facile access to a variety of enantiomerically enriched bispiro[&#947;-butyrolactone-pyrrolidin-4,4&#39;-pyrazolone] skeletons. In this paper, we demonstrate a detailed protocol for the asymmetric synthesis of drug-like bispirocyclic compounds with two spirocyclic carbon centers via an organocatyltic 1,3-dipolar cycloaddition reaction. Spirocyclization synthons &#945;-imino &#947;-lactones and alkylidene pyrazolones are prepared first, which are then subjected to a cycloaddition reaction in the presence of a bifunctional squaramide organocatalyst to afford the desired bispirocycles in high yields and excellent stereoselectivities. Chiral high-performance liquid chromatography (HPLC) is carried out to determine the enantiomeric purity of the products, and the d.r. value is examined by proton nuclear magnetic resonance (1H NMR). The absolute configuration of the product is assigned according to an X-ray crystallographic analysis. This synthetic strategy allows scientists to prepare a diversity of bispirocyclic scaffolds in high yields and excellent diastereo- and enantioselectivities.

Enantiomerically enriched bispiro[&#947;-butyrolactone-pyrrolidin-4,4&#39;-pyrazolone] skeletons are asymmetrically synthesized through a simple organocatalytic 1,3-dipolar cycloaddition reaction.

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. ...

Cercosporin-Photocatalyzed [4+1]- and [4+2]-Annulations of Azoalkenes Under Mild Conditions

The interest on nitrogen-containing heterocycles has expanded rapidly in the synthetic community since they are important motifs for new drugs. Traditionally, they were synthesized through thermal cycloaddition reactions, whereas today, photocatalysis is preferred due to the mild and efficient conditions. With this focus, a new photocatalytic method for the synthesis of nitrogen-containing heterocycles is highly desired. Here, we report a protocol for the biosynthesis of cercosporin, which could function as a metal-free photocatalyst. We then illustrate cercosporin-photocatalyzed protocols for the synthesis of nitrogen-containing heterocycles 1,2,3-thiadiazoles through annulation of azoalkenes with KSCN, and synthesis of 1,4,5,6-tetrahydropyridazines [4+2] through cyclodimerization of azoalkenes under mild conditions, respectively. As a result, there is a new bridge between the microbial fermentation method and organic synthesis in a mild, cost-effective, environmentally friendly and sustainable manner.

New routes for the synthesis of nitrogen-containing heterocycles utilizing cercosporin as a metal-free photocatalyst were developed.

神经素-光催化 [4]1]- 和 [4]2]- 在轻度条件下对阿佐尔克内斯的无效

The interest on nitrogen-containing heterocycles has expanded rapidly in the synthetic community since they are important motifs for new drugs. ...

Preparation of Enantiopure Non-Activated Aziridines and Synthesis of Biemamide B, D, and epiallo-Isomuscarine

Nitrogen-containing heterocycle aziridines are synthetically very valuable for the preparation of azacyclic and acyclic molecules. However, it is very difficult and laborious to make aziridines in optically pure forms on a large scale to apply asymmetric synthesis of aza compounds. Fortunately, we successfully achieved both enantiomers (2R)- and (2S)-aziridine-2-carboxylates with the electron-donating &#945;-methylbenzyl group at the ring nitrogen as non-activated aziridines. These starting aziridines have two distinct functional groups-highly reactive three-membered ring and versatile carboxylate. They are applicable in ring-opening or ring-transformation with aziridine and in functional group transformation to others from carboxylate. Both of these enantiomers were utilized in the preparation of biologically important amino acyclic and/or aza-heterocyclic compounds in an asymmetric manner. Specifically, this report describes the first expedient asymmetric synthesis of both enantiomers of 5, 6-dihydrouracil-type marine natural products biemamide B and D as potential TGF-&#946; inhibitors. This synthesis consisted of regio- and the stereoselective ring-opening reaction of aziridine-2-carboxylate and subsequent formation of 4-aminoteterahydropyrimidine-2,4-dione. One more example in this protocol dealt a highly stereoselective Mukaiyama reaction of aziridine-2-carboxylate and silyl enol ether, following intramolecular aziridine ring-opening to provide easy and facile access to (-)-epiallo-isomuscarine.

Preparation of Enantiopure Non-Activated Aziridines and Synthesis of Biemamide B, D, and epiallo-Isomuscarine

In this study, we prepare both enantiomers of aziridine-2-carboxylate, which are used in the asymmetric synthesis of alkaloids, including biemamide B and D, and (-)-epiallo-isomuscarine.

对映草非活化氮丙啶的制备及比咪咪唑B、D和 表皮异毒羯碱的合成

Nitrogen-containing heterocycle aziridines are synthetically very valuable for the preparation of azacyclic and acyclic molecules. However, it is very ...

Preparation of Contiguous Bisaziridines for Regioselective Ring-Opening Reactions

Aziridines, a class of reactive organic molecules containing a three-membered ring, are important synthons for the synthesis of a large variety of functionalized nitrogen-containing target compounds through the regiocontrolled ring-opening of C-substituted aziridines. Despite the tremendous progress in aziridine synthesis over the past decade, accessing contiguous bisaziridines efficiently remains difficult. Therefore, we were interested in synthesizing contiguous bisaziridines bearing an electronically diverse set of N-substituents beyond the single aziridine backbone for regioselective ring-opening reactions with diverse nucleophiles. In this study, chiral contiguous bisaziridines were prepared by organocatalytic asymmetric aziridination of chiral (E)-3-((S)-1-((R)-1-phenylethyl)aziridin-2-yl)acrylaldehyde with N-Ts-O-tosyl or N-Boc-O-tosyl hydroxylamine as the nitrogen source in the presence of (2S)-[diphenyl(trimethylsilyloxy)methyl]pyrrolidine as a chiral organocatalyst. Also demonstrated here are representative examples of regioselective ring-opening reactions of contiguous bisaziridines with a variety of nucleophiles such as sulfur, nitrogen, carbon, and oxygen, and the application of contiguous bisaziridines to the synthesis of multi-substituted chiral pyrrolidines by Pd-catalyzed hydrogenation.

Contiguous bisaziridines containing non-activated and activated aziridines were synthesized by asymmetric organocatalytic aziridinations and then subjected to chemoselective ring-opening reactions under acidic or basic conditions. The non-activated aziridine ring opens with less reactive nucleophiles under acidic conditions, whereas the activated aziridine ring opens with more reactive nucleophiles under basic conditions.

用于区域选择性开环反应的连续双氮丙啶的制备

Aziridines, a class of reactive organic molecules containing a three-membered ring, are important synthons for the synthesis of a large variety of ...

Functionalized Spirocyclic Heterocycle Synthesis and Cytotoxicity Assay

Spirocyclic heterocycles have recently been reported in literature to be potential drugs for cancer therapy. The synthesis of these novel orthogonal ring systems is challenging. An efficient methodology to synthesize these compounds was recently published that described the solid phase synthesis in four steps rather than the previously reported five steps. The advantage of this shorter synthesis is the elimination of the use of toxic reagents. Low-loading Regenerating Michael (REM) linker-based resin was found to be crucial in the synthesis as high-loading versions prevented the addition of reagents containing bulky phenyl and aromatic side chains. The colorimetric 3-(4&#8242;,5&#8242;-dimethylthiazol-2&#8242;-yl)-2,5- diphenyltetrazolium bromide (MTT) assay was used to examine the cytotoxicity of micromolar concentrations of these novel spirocyclic molecules in vitro. MTT is readily available commercially and produces relatively fast, reliable results, making this assay ideal for these spirocyclic heterocycles. Orthogonal ring structures as well as furfurylamine (a precursor in the synthesis method containing a similar 5-member ring motif) were tested.

Here, we describe a bioassay using 3-(4&#8242;,5&#8242;-dimethylthiazol-2&#8242;-yl)-2,5- diphenyltetrazolium bromide (MTT) to test previously synthesized spirocyclic oximes.

功能化螺环杂环合成和细胞毒性测定

Spirocyclic heterocycles have recently been reported in literature to be potential drugs for cancer therapy. The synthesis of these novel orthogonal ring ...

生物学

Preparation of 1&deg; Amines: Azide Synthesis

Direct alkylation of ammonia produces polyalkylated amines, along with a quaternary ammonium salt. To exclusively prepare primary amines, the azide synthesis method can be used.
Azide ions act as good nucleophiles and react with unhindered alkyl halides to form alkyl azides. Alkyl azides do not participate in further nucleophilic substitution reactions, thereby eliminating the chances of polyalkylated products. Alkyl azides are reduced by hydride-based reducing agents, like lithium aluminum hydride, or by catalytic hydrogenation to primary amines. The driving force for such reactions is the elimination of nitrogen gas.
Azide synthesis also works with other electrophiles like epoxides to produce amino alcohols through stereoselective ring-opening reactions. Alkyl azides have an explosive nature and must be carefully handled.

Preparation of 1&amp;deg; Amines: Azide Synthesis

1°胺的制备:叠氮化物合成

Direct alkylation of ammonia produces polyalkylated amines, along with a quaternary ammonium salt. To exclusively prepare primary amines, the azide ...

稳定笼 Aziridinium 离子的制备及其开环 Azaheterocycles 的合成

摘要

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高价碘鎓炔基三氟甲磺酸酯的生成Cyanocarbenes的合成应用

1,2- Azaborines的合成及其蛋白复合物的用T4溶菌酶突变体的制备

合成和Iodoaziridines纯化涉及定量选择最优固定相的色谱

[4.4] 刺环氧基的固相合成

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

神经素-光催化 [4]1]- 和 [4]2]- 在轻度条件下对阿佐尔克内斯的无效

对映草非活化氮丙啶的制备及比咪咪唑B、D和表皮异毒羯碱的合成

用于区域选择性开环反应的连续双氮丙啶的制备

功能化螺环杂环合成和细胞毒性测定

1°胺的制备:叠氮化物合成

稳定笼 Aziridinium 离子的制备及其开环 Azaheterocycles 的合成

摘要

探索更多视频

此视频中的章节

高价碘鎓炔基三氟甲磺酸酯的生成Cyanocarbenes的合成应用

1,2- Azaborines的合成及其蛋白复合物的用T4溶菌酶突变体的制备

合成和Iodoaziridines纯化涉及定量选择最优固定相的色谱

[4.4] 刺环氧基的固相合成

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

神经素-光催化 [4]1]- 和 [4]2]- 在轻度条件下对阿佐尔克内斯的无效

对映草非活化氮丙啶的制备及比咪咪唑B、D和 表皮异毒羯碱的合成

用于区域选择性开环反应的连续双氮丙啶的制备

功能化螺环杂环合成和细胞毒性测定

1°胺的制备:叠氮化物合成

对映草非活化氮丙啶的制备及比咪咪唑B、D和表皮异毒羯碱的合成