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A Modular and Diastereoselective 5+1 Cyclization Approach to N-(Hetero)Aryl Piperidines

preprint
submitted on 04.12.2019 and posted on 12.12.2019 by Matthew Larsen, Elisabeth Hennessy, Madeleine Deem, Yu-hong Lam, Josep Saurí, Aaron Sather
A new general de novo synthesis of pharmaceutically important N-(hetero)aryl piperidines is reported. This protocol uses a robustly diastereoselective reductive amination/aza-Michael reaction sequence to achieve rapid construction of complex polysubstituted ring systems starting from widely available heterocyclic amine nucleophiles and carbonyl electrophiles. Notably, the diastereoselectivity of this process is enhanced by the presence of water, and DFT calculations support a stereochemical model involving a facially selective protonation of a water-coordinated enol intermediate.

History

Email Address of Submitting Author

aaron.sather@merck.com

Institution

Department of Process Research and Development, Merck & Co., Inc.

Country

USA

ORCID For Submitting Author

0000-0002-1737-7512

Declaration of Conflict of Interest

None

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