1. Enantioselective Synthesis of α-(Hetero)aryl Piperidines Through Asymmetric Hydrogenation of Pyridinium Salts and Its Mechanistic Insights
- Author
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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, and Joshua D. Sieber
- Subjects
Protonation ,Pyridinium Compounds ,010402 general chemistry ,Iridium ,01 natural sciences ,Biochemistry ,Medicinal chemistry ,Article ,Catalysis ,Enamine ,chemistry.chemical_compound ,Piperidines ,Physical and Theoretical Chemistry ,Molecular Structure ,010405 organic chemistry ,Hydride ,Aryl ,Organic Chemistry ,Asymmetric hydrogenation ,Enantioselective synthesis ,Iminium ,Stereoisomerism ,0104 chemical sciences ,chemistry ,Models, Chemical ,Pyridinium ,Hydrogenation ,Oxidation-Reduction - 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.
- Published
- 2018