阐明 [3 + 2] 环加成的机理和选择性:对 6-丁氧基-5,6-二氢-4H-1,2-恶嗪 2-氧化物与马来酸二甲酯反应的 DFT 和分子对接研究

IF 2.1 4区 化学 Q3 CHEMISTRY, MULTIDISCIPLINARY Structural Chemistry Pub Date : 2024-09-04 DOI:10.1007/s11224-024-02373-7
Haydar Mohammad-Salim, Jesus Vicente de Julián-Ortiz, Kholood A. Dahlous, Mohammad Shahidul Islam, Tahani Mazyad Almutairi, Sofiane Benmetir
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引用次数: 0

摘要

本研究考察了涉及 6-丁氧基-5,6-二氢-4H-1,2-恶嗪 2-氧化物和马来酸二甲酯的[3 + 2]环加成(32CA)反应。在 M06-2X/6-311G(d,p) 水平上应用了分子电子密度理论 (MEDT),并结合了 D3 色散校正。通过对电子定位功能(ELF)的分析,确定了硝酸 1 物为齐聚物。该 32CA 反应遵循异步单步机理。利用 DFT 概念指数将马来酸二甲酯归类为亲电成分,将硝酸酯归类为亲核成分。外向和内向途径的活化自由能分别为 - 23.6 和 - 11.4 kcal.mol-1,这表明 [3 + 2] 环加成过程主要受动力学控制,与实验结果一致。尽管试剂具有亲核性和亲电性,但在 TS 处发生的全局电子密度转移表明 32CA 反应具有很强的极性。在碳原子 C3 和 C4 上开始形成一个伪四极中心。随后对环加合物 3 和 4 与 SARS-CoV-2 的主要蛋白酶(6LU7)以及共晶体配体进行了对接分析。分析结果表明,与共晶体配体相比,环加合物 3 表现出更高的结合能,而环加合物 4 表现出更低的结合能。结果证实,异噁唑烷环的存在增加了产物 3 的亲和力。
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Elucidating the mechanism and selectivity of [3 + 2] cycloaddition: a DFT and molecular docking investigation of the reaction of 6-butoxy-5,6-dihydro-4H-1,2-oxazine 2-oxide with dimethyl maleate

The [3 + 2] cycloaddition (32CA) reactions involving 6-butoxy-5,6-dihydro-4H-1,2-oxazine 2-oxide and dimethyl maleate are examined in this study. Molecular electron density theory (MEDT) is applied at the M06-2X/6-311G(d,p) level, coupled with the D3 dispersion correction. The nitronate 1 species are identified as zwitterionic entities through an analysis of the electron localization function (ELF). This 32CA reaction follows an asynchronous one-step mechanism. Conceptual DFT indices are utilized to classify dimethyl maleate as the electrophilic component and the nitronate as the nucleophilic counterpart. The [3 + 2] cycloaddition processes are predominantly governed by kinetic control, as indicated by activation free energies of − 23.6 and − 11.4 kcal.mol−1 for the exo and endo pathways, respectively, aligning with experimental findings. Despite the nucleophilic and electrophilic character of the reagents, the global electron density transfer at the TSs indicates rather polar 32CA reactions. The formation of a pseudoradical center initiates at carbon atoms C3 and C4. A subsequent docking analysis is conducted on cycloadducts 3 and 4 in relation to the main protease of SARS-CoV-2 (6LU7), alongside the co-crystal ligand. The results of this analysis reveal that cycloadducts 3 exhibit higher binding energy, while cycloadducts 4 display lower binding energy compared to the co-crystal ligand. The results confirm that the presence of isoxazolidine ring increases the affinity of the product 3.

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来源期刊
Structural Chemistry
Structural Chemistry 化学-化学综合
CiteScore
3.80
自引率
11.80%
发文量
227
审稿时长
3.7 months
期刊介绍: Structural Chemistry is an international forum for the publication of peer-reviewed original research papers that cover the condensed and gaseous states of matter and involve numerous techniques for the determination of structure and energetics, their results, and the conclusions derived from these studies. The journal overcomes the unnatural separation in the current literature among the areas of structure determination, energetics, and applications, as well as builds a bridge to other chemical disciplines. Ist comprehensive coverage encompasses broad discussion of results, observation of relationships among various properties, and the description and application of structure and energy information in all domains of chemistry. We welcome the broadest range of accounts of research in structural chemistry involving the discussion of methodologies and structures,experimental, theoretical, and computational, and their combinations. We encourage discussions of structural information collected for their chemicaland biological significance.
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