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Chemistry

用于区域选择性开环反应的连续双氮丙啶的制备

Published: July 28, 2022
doi:
10.3791/64019
, , ,
1Department of Energy Science,Sungkyunkwan University, 2Department of Chemistry,Hankuk University of Foreign Studies

Summary

通过不对称有机催化氮丙啶合成含有未活化和活化氮杂环啶的连续双氮丙啶，然后在酸性或碱性条件下进行化学选择性开环反应。在酸性条件下，未活化的氮丙啶环以较少的反应性亲核试剂打开，而活化的氮丙啶环在碱性条件下以反应性较高的亲核试剂打开。

Abstract

氮丙啶是一类含有三元环的反应性有机分子，是通过C-取代的氮丙啶的区域控制开环合成多种功能化含氮目标化合物的重要合成子。尽管在过去十年中氮丙啶合成取得了巨大进展，但有效地获得连续的双氮丙啶仍然很困难。因此，我们有兴趣合成具有电子多样化N-取代基集的连续双氮丙啶，而不是单个氮丙啶主链，用于与不同亲核试剂的区域选择性开环反应。本研究以（2 S）-[二苯基（三甲基硅氧基）甲基]吡咯烷为手性有机催化剂，以N-Ts-O-甲苯磺酰基或N-Boc-O-甲苯磺酰基羟胺为氮源，以（2 S）-[二苯基（三甲基硅氧基）甲基]吡咯烷为有机催化剂，以（E）-3-（（S）-1-（（R）-1-苯基乙基）氮丙啶-2-基丙烯醛为有机催化不对称氮化制备手性连续双氮丙啶。这里还展示了连续双氮丙啶与多种亲核试剂（如硫、氮、碳和氧）的区域选择性开环反应的代表性实例，以及连续双氮丙啶在通过Pd催化加氢合成多取代手性吡咯烷中的应用。

Introduction

合理设计具有不同反应位点的有机小分子，精确控制产物选择性是现代有机合成和绿色化学1，2，3，4，5，6，7，8的关键目标。为了实现这一目标，我们对氮丙啶的模块化合成感兴趣。大多数有机化学家都对氮丙啶感兴趣，因为它们的结构重要框架9具有电子多样化的N-取代基集，可导致与多个亲核试剂10，11，12，13，14，15，16，17，18的区域选择性开环反应，19，以及各种药理活性，如抗肿瘤，抗菌和抗菌特性。尽管氮丙啶化学取得了进展，但未活化的氮丙啶和活化的氮丙啶在文献中具有独立的合成和开环反应20。

因此，我们旨在合成由非活化和活化氮丙啶组成的连续双氮丙啶。这些连续的双氮丙啶可用于系统地合理化化学选择性开环模式，基于两种不同氮丙啶的以下电子特性及其对亲核试剂的反应性20，21，22，23，24：a）活化的氮杂环丙啶，其中吸电子取代基共轭稳定氮上的负电荷，容易与多种亲核试剂反应至 允许开环产品;b）非活化的氮杂环丁烷，其中氮与供电子取代基结合，对亲核试剂相当惰性;因此，需要使用合适的活化剂（主要是Brønsted或Lewis酸）进行预活化步骤，以提供高产率20，21，25，26的开环产物。

本研究描述了通过无过渡金属有机催化 将 连续双氮丙啶作为手性构建单元的合理设计，以及利用预测建模工具合成各种富氮分子的双氮丙啶开环反应。本研究旨在促进富氮生物活性化合物和天然产物的构建以及氮丙啶聚合的实用方法的进步。

Protocol

所有合成产物（1-5）的详细信息，包括结构、完整的NMR波谱、光学纯度和HRMS-MALDI数据，在 补充文件1中提供。 1. 3-（氮丙啶-2-基）丙烯酸醛的合成（1a） 在真空条件下用火焰干燥装有搅拌棒和隔膜的 50 mL 圆底烧瓶。冷却至室温，同时填充氩气。 向烧瓶中加入无水甲苯（19mL）和（R）-1-（（R）-1-苯乙基）氮丙?…

Representative Results

为了研究制备连续双氮丙啶的可实现性，首先按照步骤1（图1）28中提到的程序合成了（E）-3-（（S）-1-（（R）-1-苯基乙基）氮丙啶-2-基）丙烯醛（1a）。 图 1：合成 1a 作为模型?…

Discussion

当使用N-Boc-O-甲苯磺酰基或N-Ts-O-甲苯磺酰基羟胺作为氮源时，在手性3-[1-（1-苯乙基）氮杂环啶-2-基]丙烯醛的有机催化氮丙啶过程中，偶尔观察到非对映异构体不可分离混合物的形成。此外，当作为催化剂的二芳基甲硅烷基醚脯氨醇的用量从7摩尔%增加到20mol%时，连续双氮杂环啶产物的收率降低47，48，49</…

Disclosures

The authors have nothing to disclose.

Acknowledgements

这项研究得到了教育部资助的韩国基础科学研究所（国家研究设施和设备中心）资助（2022R1A6C101A751）。这项工作还得到了韩国国家研究基金会（NRF）资助（2020R1A2C1007102和2021R1A5A6002803）的支持。

Materials

(R)-(+)-α,α-Diphenyl-2-pyrrolidinemethanol trimethylsilyl ether Sigma-Aldrich 677191 reagent
(R)-1-((R)-1-phenylethyl)aziridine-2-carbaldehyde Imagene Co.,Ltd. reagent
(S)-(–)-α,α-Diphenyl-2-pyrrolidinemethanol trimethylsilyl ether Sigma-Aldrich 677183 reagent
(S)-2-(diphenyl((trim ethylsilyl)oxy)methyl)pyrrolidine Sigma-Aldrich 677183 reagent
(Triphenylphosphoranylidene) acetaldehyde Sigma-Aldrich 280933 reagent
1,2-Dichloroethane Sigma-Aldrich 284505 solvent
AB Sciex 4800 Plus MALDI TOFTM (2,5-dihydroxybenzoic acid (DHB) matrix Sciex High resolution mass spectra
Acetic acid Sigma-Aldrich A6283 reagent
Ammonium chloride Sigma-Aldrich 254134 reagent
aniline Sigma-Aldrich 132934 reagent
Autopol III digital polarimeter Rudolph Research Analytical polarimeter
AVANCE III HD (400 MHz) spectrometer Bruker NMR spectrometer
Bruker Ascend 500 (500 MHz) Bruker NMR spectrometer
Celite 535 Sigma-Aldrich 22138 For Celite pad
Dichloromethane Sigma-Aldrich 270997 solvent
Di-tert-butyl dicarbonate Sigma-Aldrich 361941 reagent
Ethyl Acetate Sigma-Aldrich 270989 solvent
Ethyl nitroacetate Sigma-Aldrich 192333 reagent
Imidazole Sigma-Aldrich I2399 reagent
INOVA 400WB (400 MHz) Varian NMR spectrometer
JMS-700 JEOL High resolution mass spectra
Methanol Sigma-Aldrich 322415 solvent
N-Boc-O-tosylhydroxylamine Sigma-Aldrich 775037 reagent
P-2000 JASCO polarimeter
Palladium hydroxide on carbon Sigma-Aldrich 212911 reagent
Phenyl-1H-tetrazole-5-thiol TCI P0640 reagent
Silica gel Sigma-Aldrich 227196 For flash clromatography
Silica gel on TLC plates Merck 60768 TLC plate
Sodium acetate Sigma-Aldrich S8750 reagent
Sodium azide Sigma-Aldrich S2002 reagent
Sodium borohydride Sigma-Aldrich 452882 reagent
Sodium carbonate Sigma-Aldrich S2127 reagent
tert-Butyldimethylsilyl chloride Sigma-Aldrich 190500 reagent
Tetrahydrofuran Sigma-Aldrich 401757 solvent
Toluene Sigma-Aldrich 244511 solvent
Zinc bromide Sigma-Aldrich 230022 reagent
Zinc chloride Sigma-Aldrich 429430 reagent
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Tags

BisaziridineRegioselective Ring-openingNitrogen-rich MoleculesBioactive CompoundsNatural ProductsSodium BorohydrideAldehyde ReductionEthyl AlcoholNMR Characterization
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Lee, Y., Byeon, H., Ha, H., Yang, J. W. Preparation of Contiguous Bisaziridines for Regioselective Ring-Opening Reactions. J. Vis. Exp. (185), e64019, doi:10.3791/64019 (2022).
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