Enantioselective amine α-functionalization via palladium-catalysed C–H arylation of thioamides
Open accessAbstract
Saturated aza-heterocycles are highly privileged building blocks that are commonly encountered in bioactive compounds and approved therapeutic agents. These N-heterocycles are also incorporated as chiral auxiliaries and ligands in asymmetric synthesis. As such, the development of methods to functionalize the α-methylene C-H bonds of these systems enantioselectively is of great importance, especially in drug discovery. Currently, enantioselective lithiation with (-)-sparteine followed by Pd(0) catalysed cross-coupling to prepare α-arylated amines is largely limited to pyrrolidines. Here we report a Pd(II)-catalysed enantioselective α-C-H coupling of a wide range of amines, which include ethyl amines, azetidines, pyrrolidines, piperidines, azepanes, indolines and tetrahydroisoquinolines. Chiral phosphoric acids are demonstrated as effective anionic ligands for the enantioselective coupling of methylene C-H bonds with aryl boronic acids. This catalytic reaction not only affords high enantioselectivities, but also provides exclusive regioselectivity in the presence of two methylene groups in different steric environments.
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Several of the enantiopure fragment recognition groups deployed herein are poised for direct modification using synthetic methodologies such as C-H bond activation chemistry.
“Toward this end, we note that the enantioprobes offer a convenient target engagement assay for assessing competitive binding of elaborated analogues in cells, and that several of the enantiopure fragment recognition groups deployed herein are poised for direct modification using synthetic methodologies such as C-H bond activation chemistry44–46.”
From Expedited mapping of the ligandable proteome using fully functionalized enantiomeric probe pairs (2019) · cites this paper as [46]
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Expedited mapping of the ligandable proteome using fully functionalized enantiomeric probe pairs
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- Authors
- Jain, P., Verma, P., Xia, G., & Yu, J.-Q.
- Affiliations
- Scripps Research Institute (US)
- Corresponding author
- Yu, Jin-Quan
- Venue
- Nature Chemistry
- Published
- 2016-10-03
- Volume
- 9
- Issue
- 2
- Pages
- 140-144
- ISSN
- 1755-4330 (ISSN-L)
- 1755-4349
- PMC
- PMC5347480
- OpenAlex
- W2528441550
- Cited by
- 336
- References
- 35
- Citations by year
- 2026: 14 · 2025: 22 · 2024: 27 · 2023: 30 · 2022: 37 · 2021: 43 · 2020: 41 · 2019: 53 · 2018: 44 · 2017: 24 · 2016: 1
- FWCI
- 18.64
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute of General Medical Sciences (R01GM084019)
- Topics
- Physical Sciences › Chemistry › Organic Chemistry › Catalytic C–H Functionalization Methods
- Physical Sciences › Chemistry › Organic Chemistry › Asymmetric Synthesis and Catalysis
- Physical Sciences › Chemistry › Organic Chemistry › Catalytic Cross-Coupling Reactions
- Keywords
- palladium catalysis, thioamides, chiral phosphoric acid, arylboronic acids, regioselectivity, pyrrolidine, azetidines, piperidine, indolines, tetrahydroisoquinolines, chiral auxiliaries, asymmetric synthesis
- MeSH terms
- Amines, Boronic Acids, Carbon, Catalysis, Hydrogen, Ligands, Palladium, Phosphoric Acids, Stereoisomerism, Thioamides, Coordination Complexes
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