Accessing acyclic vicinal tetrasubstituted stereocenters via biomimetic Cu/squaramide cooperative catalysed asymmetric Mannich reactions

Wen-Run Zhu, Ze-Long Ouyang, Xuzhao Du, Yun-Zhe Li, Xiao-Yi Deng, Yu-Jie Xue, Jian-Xin Zhou, Peiyuan Yu (), Gui Lu (), Albert S. C. Chan and Jiang Weng ()
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Wen-Run Zhu: Sun Yat-sen University
Ze-Long Ouyang: Sun Yat-sen University
Xuzhao Du: Southern University of Science and Technology
Yun-Zhe Li: Sun Yat-sen University
Xiao-Yi Deng: Sun Yat-sen University
Yu-Jie Xue: Guangdong Pharmaceutical University
Jian-Xin Zhou: Guangdong Pharmaceutical University
Peiyuan Yu: Southern University of Science and Technology
Gui Lu: Sun Yat-sen University
Albert S. C. Chan: Sun Yat-sen University
Jiang Weng: Sun Yat-sen University

Nature Communications, 2025, vol. 16, issue 1, 1-11

Abstract: Abstract The catalytic asymmetric Mannich reaction offers efficient approaches for the simultaneous construction of a C–C bond and two adjacent stereocenters in a single step. However, employing the Mannich reaction to create two neighboring, fully substituted carbon stereocenters in acyclic systems presents significant challenges and remains largely unexplored. Inspired by class II aldolases found in nature, we report here a biomimetic copper/squaramide cooperative catalysis strategy for asymmetric Mannich reactions between challenging acyclic ketimines and α-substituted β-keto esters. The highly functionalized Mannich adducts featuring vicinal and acyclic tetrasubstituted stereocenters are obtained, and exhibit good yields and excellent stereoselectivities (up to >19:1 dr and 99% ee). The versatile utility of these enantioenriched products is further highlighted by their diverse transformations with complete diastereocontrol. Mechanistic studies and DFT calculations support the novel cooperative roles of copper and squaramide in substrate activation and stereoselectivity control.

Date: 2025
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DOI: 10.1038/s41467-025-63919-9

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