Enantioselective Nucleophile-Catalyzed Synthesis of Tertiary Alkyl Fluorides via the α‑Fluorination of Ketenes: Synthetic and Mechanistic Studies
Abstract
The catalytic asymmetric synthesis of alkyl fluorides, particularly α-fluorocarbonyl compounds, has been the focus of substantial effort in recent years. While significant progress has been described in the formation of enantioenriched secondary alkyl fluorides, advances in the generation of tertiary alkyl fluorides have been more limited. Here, we describe a method for the catalytic asymmetric coupling of aryl alkyl ketenes with commercially available N-fluorodibenzenesulfonimide (NFSI) and C_6F_5ONa to furnish tertiary α-fluoroesters. Mechanistic studies are consistent with the hypothesis that the addition of an external nucleophile (C_6F_5ONa) is critical for turnover, releasing the catalyst (PPY*) from an N-acylated intermediate. The available data can be explained by a reaction pathway wherein the enantioselectivity is determined in the turnover-limiting transfer of fluorine from NFSI to a chiral enolate derived from the addition of PPY* to the ketene. The structure and the reactivity of the product of this proposed elementary step, an α-fluoro-N-acylpyridinium salt, have been examined.
Additional Information
© 2014 American Chemical Society. ACS AuthorChoice - This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes. Received: May 2, 2014. Publication Date (Web): June 12, 2014. Support has been provided by the National Institutes of Health (National Institute of General Medical Sciences R01-GM57034) and the Deutsche Forschungsgemeinschaft (fellowship to S.N.). We thank Trixia M. Buscagan, Dr. Nathan D. Schley, Dr. Michael K. Takase (X-ray Crystallography Facility; a Bruker KAPPA APEX II X-ray diffractometer was purchased via NSF CRIF:MU award CHE-0639094 to the California Institute of Technology), Dr. David VanderVelde (NMR Facility), and Dr. Scott C. Virgil (Caltech Center for Catalysis and Chemical Synthesis, supported by the Gordon and Betty Moore Foundation) for assistance.Attached Files
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Supplemental Material - ja5044209_si_002.cif
Supplemental Material - ja5044209_si_003.cif
Supplemental Material - ja5044209_si_004.pdf
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Additional details
- PMCID
- PMC4091276
- Eprint ID
- 46273
- Resolver ID
- CaltechAUTHORS:20140616-085001666
- NIH National Institute of General Medical Sciences
- R01-GM57034
- Deutsche Forschungsgemeinschaft (DFG)
- NSF CRIF:MU Award
- CHE-0639094
- Gordon and Betty Moore Foundation
- Created
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2014-06-16Created from EPrint's datestamp field
- Updated
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2021-11-10Created from EPrint's last_modified field