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Synthetic versatility of 2-substituted-6-methyl 2,3-dihydropyridinones in the synthesis of polyfunctional piperidine-based compounds and related β amino acid derivatives

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Abstract

Chiral 2-substituted-6-methyl 2,3-dihydropyidinones 9, which can be facilely obtained from an asymmetric vinylogous Mannich reaction (VMR) with 1,3-bis-trimethysily enol ether, were used as versatile intermediates in constructing chiral polyfunctional piperidine-based compounds. The 6-methyl group of such compounds can be conveniently functionalized via alkylation and acylation reactions to provide efficient entries to the synthesis of a variety of chiral multi-substituted piperidine-based compounds. Further elaboration of the corresponding intermediates also provided access to polyfunctional indolizidine-based compounds. These methods were showcased in an asymmetric synthesis of 2,6-di-substituted piperidine compound 13, reported as the key intermediate in the synthesis of (+)-calvine and a natural alkaloid (−)-indolizidine 209D. Furthermore, selective C5 iodination of compound 9 enabled the installation of additional functional groups at this position. Finally, we demonstrated that the oxidative cleavage of 2-substituted-6-methyl-2,3-dihydropyidinones is a practical and efficient method for the enantioselective synthesis of β-amino acids, which can undergo further intra-molecular cyclization to give the corresponding chiral four-membered β-lactam derivatives.

Graphical abstract: Synthetic versatility of 2-substituted-6-methyl 2,3-dihydropyridinones in the synthesis of polyfunctional piperidine-based compounds and related β amino acid derivatives

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Publication details

The article was received on 05 Aug 2017, accepted on 25 Sep 2017 and first published on 25 Sep 2017


Article type: Paper
DOI: 10.1039/C7OB01948C
Citation: Org. Biomol. Chem., 2017, Advance Article
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    Synthetic versatility of 2-substituted-6-methyl 2,3-dihydropyridinones in the synthesis of polyfunctional piperidine-based compounds and related β amino acid derivatives

    Y. Yang and C. Hardman, Org. Biomol. Chem., 2017, Advance Article , DOI: 10.1039/C7OB01948C

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