Volume 5, Issue 7 p. 2332-2336
Full Paper

Cascade Reductive Rearrangement for the Stereoselective Synthesis of Multifunctional Piperidinones: A Combined Experimental and Computational Study

Guoxun Zhu

Guoxun Zhu

School of Chemical Engineering and Technology, Sun Yat-sen University 135 Xin Gang West Road, Guangzhou, 510275 P.R. China

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Lei Ma

Lei Ma

Key Laboratory of Molecular Target and Clinical Pharmacology & the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, 511436 P. R. China

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Kaixin Zhang

Kaixin Zhang

School of Chemical Engineering and Technology, Sun Yat-sen University 135 Xin Gang West Road, Guangzhou, 510275 P.R. China

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Zhi Zhou

Corresponding Author

Zhi Zhou

Key Laboratory of Molecular Target and Clinical Pharmacology & the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, 511436 P. R. China

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Huacan Song

Corresponding Author

Huacan Song

School of Chemical Engineering and Technology, Sun Yat-sen University 135 Xin Gang West Road, Guangzhou, 510275 P.R. China

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Prof. Dr. Wei Yi

Corresponding Author

Prof. Dr. Wei Yi

School of Chemical Engineering and Technology, Sun Yat-sen University 135 Xin Gang West Road, Guangzhou, 510275 P.R. China

Key Laboratory of Molecular Target and Clinical Pharmacology & the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, 511436 P. R. China

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First published: 19 February 2020

Graphical Abstract

A unprecedented cascade ring-opening/reduction/annulation process of amino-substituted dihydropyrano[3,2-c]chromen-5(2H)-one framework has been realized for the stereoselective synthesis of the multifunctional piperidinones. Combined experimental and computational studies revealed the the plaussible mechanism. Scale-up synthesis, one-pot multi-step synthesis and biological studies proved the synthetic utility of this approach.

Abstract

An efficient and practical reductive rearrangement reaction has been developed for the stereoselective synthesis of diverse piperidinones. This transformation features mild conditions, good substrate/functional group compatibility and large-scale synthetic potential. Subsequent combined DFT and experimental studies revealed a reduction triggered cascade pathway in which the active imine species was involved as the key intermediate. The biological application of the products has also been demonstrated by acting as the potent antitumor agents, which further strengthens the synthetic utility of this approach.