Modular access to chiral bridged piperidine-γ-butyrolactones via catalytic asymmetric allylation/aza-Prins cyclization/lactonization sequences

Cong Fu, Ling He, Hui Xu, Zongpeng Zhang, Xin Chang, Yanfeng Dang (), Xiu-Qin Dong () and Chun-Jiang Wang ()
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Cong Fu: Wuhan University
Ling He: Wuhan University
Hui Xu: Tianjin University
Zongpeng Zhang: Wuhan University
Xin Chang: Wuhan University
Yanfeng Dang: Tianjin University
Xiu-Qin Dong: Wuhan University
Chun-Jiang Wang: Wuhan University

Nature Communications, 2024, vol. 15, issue 1, 1-11

Abstract: Abstract Chiral functionalized piperidine and lactone heterocycles are widely spread in natural products and drug candidates with promising pharmacological properties. However, there remains no general asymmetric methodologies that enable rapid assemble both critical biologically important units into one three-dimensional chiral molecule. Herein, we describe a straightforward relay strategy for the construction of enantioenriched bridged piperidine-γ-butyrolactone skeletons incorporating three skipped stereocenters via asymmetric allylic alkylation and aza-Prins cyclization/lactonization sequences. The excellent enantioselectivity control in asymmetric allylation with the simplest allylic precursor is enabled by the synergistic Cu/Ir-catalyzed protocol; the success of aza-Prins cyclization/lactonization can be attributed to the pivotal role of the ester substituent, which acts as a preferential intramolecular nucleophile to terminate the aza-Prins intermediacy of piperid-4-yl cation species. The resulting chiral piperidine-γ-butyrolactone bridged-heterocyclic products show impressive preliminary biological activities against a panel of cancer cell lines.

Date: 2024
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DOI: 10.1038/s41467-023-44336-2

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