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Enantioselective Synthesis of α-(Hetero)aryl Piperidines Through Asymmetric Hydrogenation of Pyridinium Salts and Its Mechanistic Insights

Authors :
Keith R. Fandrick
Daniel Rivalti
Nizar Haddad
Marisa C. Kozlowski
Olga V. Zatolochnaya
Suttipol Radomkit
Scott Pennino
Nathan K. Yee
Keith McKellop
Dmitry Kurouski
Jean-Nicolas Desrosiers
Heewon Lee
Chris H. Senanayake
Soumik Biswas
Shuklendu D. Karyakarte
Jinhua J. Song
Bo Qu
Sonia Rodriguez
Hari P. R. Mangunuru
Sergei Tcyrulnikov
Joshua D. Sieber
Publication Year :
2018

Abstract

Enantioselective synthesis of α-aryl and α-heteroaryl piperidines is reported. The key step is an iridium-catalyzed asymmetric hydrogenation of substituted N-benzyl pyridinium salts. High levels of enantioselectivity up to 99.3:0.7 er were obtained for a range of α-heteroaryl piperidines. DFT calculations support an outer-sphere dissociative mechanism for the pyridinium reduction. Notably, initial protonation of the final enamine intermediate determines the stereochemical outcome of the transformation rather than hydride reduction of the resultant iminium intermediate.

Details

Language :
English
Database :
OpenAIRE
Accession number :
edsair.doi.dedup.....ea58d5693fceeb4c744ba3de80f4c7e0