Cu/chiral phosphoric acid-catalyzed asymmetric (3 + 2) cycloaddition of donor–acceptor aziridines with aldehydes: synthesis of enantioenriched oxazolidines as potential antitumor agents

Abstract

Chiral oxazolidines are pivotal structural motifs commonly found in natural products, medicinally important compounds, and chiral ligands. Among various synthetic strategies, the asymmetric formal (3 + 2) annulation of donor–acceptor (D–A) aziridines with dipolarophiles has emerged as a powerful method for constructing enantioenriched five-membered azaheterocycles with potential bioactivity. Herein, we present a Cu(II)/chiral phosphoric acid (CPA) cooperative catalytic system for the asymmetric intermolecular (3 + 2) cycloaddition of D–A aziridines with aldehydes via C–C bond cleavage. This approach enables the efficient and highly enantioselective synthesis of cis-(2S,5S)-1,3-oxazolidines with excellent atom economy, as well as exceptional chemo-, enantio-, and diastereoselectivities. This novel activation model, distinct from existing catalytic methodologies, serves as a complementary approach that significantly broadens the scope of asymmetric (3 + 2) cycloaddition of D–A aziridines. Moreover, the resulting chiral oxazolidines exhibited significant anti-proliferative activity against various human cancer cell lines, highlighting their potential for further advancement in medicinal chemistry.

Graphical abstract: Cu/chiral phosphoric acid-catalyzed asymmetric (3 + 2) cycloaddition of donor–acceptor aziridines with aldehydes: synthesis of enantioenriched oxazolidines as potential antitumor agents

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Article information

Article type
Research Article
Submitted
08 May 2025
Accepted
17 Jun 2025
First published
20 Jun 2025

Org. Chem. Front., 2025, Advance Article

Cu/chiral phosphoric acid-catalyzed asymmetric (3 + 2) cycloaddition of donor–acceptor aziridines with aldehydes: synthesis of enantioenriched oxazolidines as potential antitumor agents

Z. Shi, T. Fan, J. Lin, W. Xie, F. Zhan, Z. Wang, Q. Zuo, H. Fu, X. Zhang, Q. Huang and Y. Jiang, Org. Chem. Front., 2025, Advance Article , DOI: 10.1039/D5QO00729A

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