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Chiral Piperidines from Acyclic Amines Via Enantioselective, Radical-Mediated δ C-H Cyanation

194 Pages Posted: 1 Aug 2019 Sneak Peek Status: Published

See all articles by Zuxiao Zhang

Zuxiao Zhang

Ohio State University (OSU) - Department of Chemistry and Biochemistry

Xin Zhang

Ohio State University (OSU) - Department of Chemistry and Biochemistry

David A. Nagib

Ohio State University (OSU) - Department of Chemistry and Biochemistry

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Abstract

Piperidines are the most prevalent heterocyclic core found in medicines. Yet, while these structures often contain chiral substituents, there are no robust methods for the synthesis of enantioenriched, substituted piperidines. Current approaches rely on the reduction of pyridines or C-H functionalizations to afford racemic mixtures that must then be resolved. To solve this challenge, we proposed an adaptation of the century-old Hofmann-Löffler-Freytag (HLF) reaction may afford this privileged heterocycle. This approach would require interruption of the regioselective δ C-H amination of acyclic amines to instead incorporate a carbonyl equivalent at the δ position. Moreover, this C-C bond would need to be installed with high stereoselectivity (>90% enantiomeric excess) for the first time. To this end, a catalytic method for remote, enantioselective C-C formation has been developed. This δ C-H cyanation of amines is enabled by a chiral Cu catalyst, which both initiates and terminates an intramolecular hydrogen atom transfer (HAT) mechanism. The broad scope and utility of this catalytic method for enantioselective δ C-C formation by an N-centered radical relay is presented, as well as the conversion of the resulting enantioenriched d amino nitriles to a family of chiral piperidines. Experiments probing the chemo-, regio-, and enantio-selectivity of this HAT mechanism are also included to enable extension to other δ C-H functionalizations in a stereoselective fashion.

Keywords: radical chemistry, asymmetric catalysis, heterocycle synthesis

Suggested Citation

Zhang, Zuxiao and Zhang, Xin and Nagib, David A., Chiral Piperidines from Acyclic Amines Via Enantioselective, Radical-Mediated δ C-H Cyanation (July 30, 2019). CHEMJOURNAL-D-19-00763. Available at SSRN: https://ssrn.com/abstract=3429297 or http://dx.doi.org/10.2139/ssrn.3429297
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Zuxiao Zhang

Ohio State University (OSU) - Department of Chemistry and Biochemistry ( email )

Blankenship Hall-2010
901 Woody Hayes Drive
Columbus, OH 43210
United States

Xin Zhang

Ohio State University (OSU) - Department of Chemistry and Biochemistry

Blankenship Hall-2010
901 Woody Hayes Drive
Columbus, OH 43210
United States

David A. Nagib (Contact Author)

Ohio State University (OSU) - Department of Chemistry and Biochemistry ( email )

Blankenship Hall-2010
901 Woody Hayes Drive
Columbus, OH 43210
United States

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