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

• DOI: 10.1021/acs.orglett.8b00067
• Publication Date: 2018-02-20T18:07:52Z
• Authors: Bo Qu; Hari P. R. Mangunuru; Sergei Tcyrulnikov; Daniel Rivalti; Olga V. Zatolochnaya; Dmitry Kurouski; Suttipol Radomkit; Soumik Biswas; Shuklendu Karyakarte; Keith R. Fandrick; Joshua D. Sieber; Sonia Rodriguez; Jean-Nicolas Desr...; Nizar Haddad; Keith McKellop; Scott Pennino; Heewon Lee; Nathan K. Yee; Jinhua J. Song; Marisa C. Kozlowski; Chris H. Senanayake
• Keywords: Models, Chemical; Molecular Structure; Piperidines; Pyridinium Compounds; Stereoisomerism; Hydrogenation; Iridium; Oxidation-Reduction; 01 natural sciences; Catalysis; 0104 chemical sciences

Enantioselective synthesis of α-aryl and α-heteroaryl piperidines is reported. The key step is an iridium-catalyzed asymmetric hydrogenation of substituted N-benzylpyridinium 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 outersphere 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.