Iridium-catalyzed asymmetric hydrogenation of 5-hydroxypicolinate pyridinium salts under batch and flow: stereodefined access to cis -configurated hydroxypiperidine esters

The stereoselective synthesis of 2,5-disubstituted piperidines, which are common structural motifs in bioactive compounds and organocatalysts, remains a challenging task and is relatively rare. Herein, we report a novel iridium-catalyzed asymmetric hydrogenation of 5-hydroxypicolinate pyridinium sal...

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Veröffentlicht in:Organic Chemistry Frontiers 2024-05, Vol.11 (11), p.3225-3233
Hauptverfasser: Yang, Zhi, Luan, Shangxian, Wan, Linxi, Chen, Jingxi, Wei, Xiaofang, Tang, Pei, Chen, Fen-Er
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Sprache:eng
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Zusammenfassung:The stereoselective synthesis of 2,5-disubstituted piperidines, which are common structural motifs in bioactive compounds and organocatalysts, remains a challenging task and is relatively rare. Herein, we report a novel iridium-catalyzed asymmetric hydrogenation of 5-hydroxypicolinate pyridinium salts for the first time. This asymmetric dearomatization strategy exhibits a broad substrate scope, enabling the synthesis of valuable cis -configurated hydroxypiperidine esters with distinct functionalities (ester, amino and hydroxy groups) in excellent yield and with excellent enantioselectivity and diastereoselectivity (up to 96% yield, 97% ee and >20 : 1 dr). The synthetic potential of this reaction is explored through gram-scale reactions and subsequent diverse transformations, leading to the generation of chiral amine scaffolds with substantial synthetic significance (such as crucial building blocks in the manufacturing of diazabicyclooctane β-lactamase inhibitors). The successful implementation of this approach in a continuous flow manner has additionally expanded its practical applicability. Consequently, this method expands the realm of catalytic asymmetric hydrogenation for N-heteroarenes.
ISSN:2052-4129
2052-4110
2052-4129
2052-4110
DOI:10.1039/D4QO00322E