Recently, a collaborative team from Shanghai Jiao Tong University, led by Guoqiang Yang, Wanbin Zhang, and Jianming Zhang, reported an asymmetric bimetallic synergistic CuAPS (copper-catalyzed propargyl substitution reaction) strategy. By activating the propargyl electrophile and the α-cyano ester nucleophile respectively using a chiral Cu(I)–BOX complex catalyst, and through a transient binuclear catalytic mechanism, they achieved the tandem cyclization of asymmetric propargyl substitution and the Pinner reaction to construct chiral cyclic imine esters. The article was published as an open access Research Article in CCS Chemistry, the flagship journal of the Chinese Chemical Society.
Background information:
Copper-catalyzed asymmetric propargyl substitution (CuAPS) is an important strategy for constructing chiral propargyl skeletons, but the activation modes of existing catalytic systems remain insufficiently understood. Chiral cyclic imides have potential applications in ligand design and the discovery of bioactive molecules; however, their asymmetric synthetic methods, especially the techniques for directly preparing N-unprotected chiral imides, are still immature. To address this, the collaborative team of Guoqiang Yang, Wanbin Zhang, and Jianming Zhang at Shanghai Jiao Tong University proposed a tandem reaction of propargyl substitution and Pinner reaction through a dual copper catalytic system based on a transient binuclear asymmetric synergistic catalysis concept , in order to efficiently synthesize chiral N-unprotected cyclic imine esters, and explored their antiviral activity.
Highlights of this article:
1. Strategic Innovation: In the key bonding step, the reaction forms a quasi-C₂ symmetric binuclear complex transiently assembled from two chiral copper centers: one side is a Cu-propynyl intermediate, and the other side is a Cu-stable deprotonated α-cyano ester. The two achieve efficient and stereooriented C–C bond construction through conformational locking induced by H···π stacking .
2. Excellent stereoselectivity: The reaction achieves excellent stereoselectivity control under mild conditions, with an enantioselectivity of up to 94% and high diastereoselectivity, providing a reliable method for constructing N-unprotected cyclic imine esters .
3. Good substrate universality: This strategy shows good compatibility with propargyl carbonates and α-cyano esters with different substituents, and can efficiently prepare structurally diverse N-unprotected cyclic imine esters, expanding the chemical space of such advantageous skeletons.
4. Flexible subsequent derivatization: By derivatizing the N-H and alkynyl groups in the product (such as N-alkylation, Sonogashira reaction), a variety of chiral imine ester derivatives can be rapidly constructed, demonstrating the application potential of this method in medicinal chemistry.
5. Outstanding antiviral activity: In a feline calicivirus (FCV) infection model, some compounds showed significant inhibitory activity, which was superior to the positive control drug nitrozonide.
Summary and Outlook:
In summary, this study developed a highly efficient dual-copper catalyzed asymmetric tandem reaction, achieving highly enantioselective synthesis of chiral N-unprotected cyclic imine esters and revealing a transient binuclear synergistic catalytic mechanism. This system possesses advantages such as high catalytic activity (S/C up to 2000), a broad substrate applicability, and strong product derivatization potential. Furthermore, some products exhibit significant antiviral activity, providing new insights for the application of chiral imine esters in drug development.
The research findings were published as a Research Article in CCS Chemistry. The research was supported by the Fundamental Research Funds for the Central Universities and the Research Start-up Fund of Shanghai Jiao Tong University.
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About the journal: CCS Chemistry is the Chinese Chemical Society's flagship publication, established to serve as the preeminent international chemistry journal published in China. It is an English language journal that covers all areas of chemistry and the chemical sciences, including groundbreaking concepts, mechanisms, methods, materials, reactions, and applications. All articles are diamond open access, with no fees for authors or readers. More information can be found at https://www.chinesechemsoc.org/journal/ccschem .
About the Chinese Chemical Society: The Chinese Chemical Society (CCS) is an academic organization formed by Chinese chemists of their own accord with the purpose of uniting Chinese chemists at home and abroad to promote the development of chemistry in China. The CCS was founded during a meeting of preeminent chemists in Nanjing on August 4, 1932. It currently has more than 120,000 individual members and 184 organizational members. There are 7 Divisions covering the major areas of chemistry: physical, inorganic, organic, polymer, analytical, applied and chemical education, as well as 31 Commissions, including catalysis, computational chemistry, photochemistry, electrochemistry, organic solid chemistry, environmental chemistry, and many other sub-fields of the chemical sciences. The CCS also has 10 committees, including the Woman's Chemists Committee and Young Chemists Committee. More information can be found at https://www.chinesechemsoc.org/ .
