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DOI: https://doi.org/10.6023/A25050172

研究论文

铜催化不对称Kinugasa/Aldol反应构建手性螺环β-内酰胺

  • 张杰豪 ,
  • 徐明金 ,
  • 古满珍 ,
  • 马浩文 ,
  • 蔡倩
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  • a暨南大学药学院 广州 广东 510632
    b浙江师范大学化学与材料科学学院 金华 浙江 321004

收稿日期: 2025-05-15

  网络出版日期: 2025-06-25

基金资助

浙江省自然科学基金（ZCLZ25B0201）、浙江师范大学启动基金支持.

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Copper(I)-Catalyzed Asymmetric Kinugasa/Aldol Reactions for the Construction of Chiral Spiro β-Lactams

  • Jiehao Zhang ,
  • Mingjin Xu ,
  • Manzhen Gu ,
  • Haowen Ma ,
  • Qian Cai
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  • aCollege of Pharmacy, Jinan University, Guangzhou 510632
    bZhengjiang Normal University, Jinhua, Zhejiang Province 321004

Received date: 2025-05-15

  Online published: 2025-06-25

Supported by

Natural Science Foundation of Zhejiang Province (ZCLZ25B0201) and Zhejiang Normal University.

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摘要

β-内酰胺和螺β-内酰胺是多种天然产物和生物活性化合物中的关键骨架结构,因其重要的生物学意义而备受关注。Kinugasa反应,即铜催化末端炔烃与硝酮的环加成反应,是构建β-内酰胺最直接高效的方法之一。通过将Kinugasa反应与其他反应结合,已发展出多种串联或一锅法策略,用于合成多取代的手性β-内酰胺或螺β-内酰胺。在前期工作中,我们发展了铜催化N-(2-酰基芳基)丙炔酰胺与硝酮的不对称Kinugasa/Aldol串联反应,成功构建了手性螺环β-内酰胺-二氢喹啉酮。该反应中,碱促进的retro-aldol/aldol差向异构化过程发挥了关键作用,这一过程将次要非对映异构体转化为主要产物,实现了非对映体富集,显著提升了产物的非对映选择性。在本研究中,为进一步拓展反应适用范围,我们探索了线性烷基酮连接的丙炔酰胺与硝酮的反应。该类反应在PhCF3中进行,但由于反应条件下烷基醇产物的retro-aldol/aldol过程难以进行,导致级联反应的非对映选择性较低。为提高非对映选择性,我们在反应完成后引入极性溶剂DMF,成功促进了retro-aldol/aldol差向异构化过程,从而以中等收率合成了一系列具有高非对映选择性的手性螺环β-内酰胺产物。

关键词： 不对称反应; 铜催化; Kinugasa反应; Aldol反应; Retro-aldol/aldol过程

本文引用格式

张杰豪 , 徐明金 , 古满珍 , 马浩文 , 蔡倩 . 铜催化不对称Kinugasa/Aldol反应构建手性螺环β-内酰胺[J]. 化学学报, 0 : 25050172 . DOI: 10.6023/A25050172

Abstract

β-Lactams and spiro β-lactams represent privileged structural motifs that are prevalent in numerous natural products and pharmacologically active compounds. Due to their profound biological significance and versatile applications in medicinal chemistry, considerable research efforts have been devoted to developing efficient synthetic methodologies for these important scaffolds. Among various synthetic approaches, the copper(I)-catalyzed [3+2] cycloaddition between terminal alkynes and nitrones, commonly referred to as the Kinugasa reaction, has emerged as one of the most straightforward and efficient strategies for constructing the β-lactam core structure. By combining the Kinugasa reaction with subsequent transformations, researchers have established various cascade or one-pot processes that enable the synthesis of multisubstituted β-lactams and spiro β-lactam derivatives. In our previous investigations, we successfully developed an asymmetric copper(I)-catalyzed Kinugasa/aldol cascade reaction utilizing N-(2-acylaryl)propiolamides and nitrones as substrates. This methodology provided efficient access to chiral 1',4'-dihydro-2'H-spiro[azetidine-3,3'-quinoline]-2,2'-diones with excellent stereocontrol. The high diastereoselectivity observed in these reactions was attributed to a base-mediated retro-aldol/aldol epimerization process, which effectively converted the minor diastereomer into the thermodynamically favored major product, thereby enhancing the overall stereoselectivity of the transformation. To expand the substrate scope of this methodology, the current study focused on examining the reactivity of linear alkyl ketone-tethered propiolamides with nitrones. Initial experiments conducted in PhCF3 as solvent revealed that the retro-aldol/aldol process was significantly less efficient for alkyl alcohol products under standard reaction conditions, resulting in poor diastereoselectivity for the cascade reaction. To overcome this limitation, we implemented a strategic modification by introducing the polar aprotic solvent DMF after the initial reaction phase. This solvent switch proved crucial in promoting the retro-aldol/aldol epimerization process, ultimately leading to the desired products with substantially improved diastereoselectivity. The optimized reaction protocol involves several key steps: First, the alkyl ketone-tethered propiolamides, nitrones, Cu(OTf)2 catalyst, and chiral ligand are combined in PhCF3 solvent at 0 oC in the presence of tBuOLi as base, with stirring maintained for 12 hours to allow complete conversion. Following this initial phase, the solvent is carefully removed under reduced pressure, and DMF is introduced as the secondary solvent. The reaction mixture is then stirred for an additional 5 hours at ambient temperature to facilitate the epimerization process, during which the minor diastereomer is converted to the major product. This carefully optimized two-step procedure enables the synthesis of target compounds in moderate yields while achieving high diastereoselectivity, thereby significantly expanding the synthetic utility of this methodology for the preparation of structurally diverse β-lactam derivatives.

Key words： Asymmetric reaction; Copper-Catalyzed; Kinugasa reaction; Aldol reaction; Retro-aldol/aldol process

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