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Asymmetric Synthesis of 3,4-Disubstituted 2-(Trifluoromethyl)pyrrolidines through Rearrangement of Chiral 2-(2,2,2-Trifluoro-1-hydroxyethyl)azetidines

(2017) JOURNAL OF ORGANIC CHEMISTRY. 82(19). p.10092-10109
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Abstract
Enantiopure 4-formyl-beta-lactams were deployed as synthons for the diastereoselective formation of chiral 2-(2,2,2-trifluoro-1-hydroxyethypazetidines via trifluoromethylation through aldehyde modification followed by reductive removal of the beta-lactam carbonyl moiety. Subsequent treatment of the (in situ) activated 2-trifluoroethylated azetidines with a variety of nitrogen, oxygen, sulfur, and fluorine nucleophiles afforded chiral 3,4-disubstituted 2-(trifluoromethyl)pyrrolidines in good to excellent yields (45-99%) and high diastereoselectivities (dr >99/1, H-1 NMR) via interception of bicyclic aziridinium intermediates. Furthermore, representative pyrrolidines were N,O-debenzylated in a selective way and used for further synthetic elaboration to produce, for example, a CF3-substituted 2-oxa-4,7-diazabicyclo[3.3.0]octan-3-one system.
Keywords
DENSITY FUNCTIONALS, RING EXPANSION, NONCOVALENT INTERACTIONS, AMINO-ALCOHOLS, BETA-LACTAMS, TRIFLUOROMETHYLATION, PYRROLIDINES, DERIVATIVES, TRANSFORMATION, AZETIDINES

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MLA
Dolfen, Jeroen et al. “Asymmetric Synthesis of 3,4-Disubstituted 2-(Trifluoromethyl)pyrrolidines Through Rearrangement of Chiral 2-(2,2,2-Trifluoro-1-hydroxyethyl)azetidines.” JOURNAL OF ORGANIC CHEMISTRY 82.19 (2017): 10092–10109. Print.
APA
Dolfen, J., Boydas, E. B., Van Speybroeck, V., Catak, S., Van Hecke, K., & D’hooghe, M. (2017). Asymmetric Synthesis of 3,4-Disubstituted 2-(Trifluoromethyl)pyrrolidines through Rearrangement of Chiral 2-(2,2,2-Trifluoro-1-hydroxyethyl)azetidines. JOURNAL OF ORGANIC CHEMISTRY, 82(19), 10092–10109.
Chicago author-date
Dolfen, Jeroen, Esma Birsen Boydas, Veronique Van Speybroeck, Saron Catak, Kristof Van Hecke, and Matthias D’hooghe. 2017. “Asymmetric Synthesis of 3,4-Disubstituted 2-(Trifluoromethyl)pyrrolidines Through Rearrangement of Chiral 2-(2,2,2-Trifluoro-1-hydroxyethyl)azetidines.” Journal of Organic Chemistry 82 (19): 10092–10109.
Chicago author-date (all authors)
Dolfen, Jeroen, Esma Birsen Boydas, Veronique Van Speybroeck, Saron Catak, Kristof Van Hecke, and Matthias D’hooghe. 2017. “Asymmetric Synthesis of 3,4-Disubstituted 2-(Trifluoromethyl)pyrrolidines Through Rearrangement of Chiral 2-(2,2,2-Trifluoro-1-hydroxyethyl)azetidines.” Journal of Organic Chemistry 82 (19): 10092–10109.
Vancouver
1.
Dolfen J, Boydas EB, Van Speybroeck V, Catak S, Van Hecke K, D’hooghe M. Asymmetric Synthesis of 3,4-Disubstituted 2-(Trifluoromethyl)pyrrolidines through Rearrangement of Chiral 2-(2,2,2-Trifluoro-1-hydroxyethyl)azetidines. JOURNAL OF ORGANIC CHEMISTRY. American Chemical Society (ACS); 2017;82(19):10092–109.
IEEE
[1]
J. Dolfen, E. B. Boydas, V. Van Speybroeck, S. Catak, K. Van Hecke, and M. D’hooghe, “Asymmetric Synthesis of 3,4-Disubstituted 2-(Trifluoromethyl)pyrrolidines through Rearrangement of Chiral 2-(2,2,2-Trifluoro-1-hydroxyethyl)azetidines,” JOURNAL OF ORGANIC CHEMISTRY, vol. 82, no. 19, pp. 10092–10109, 2017.
@article{8537768,
  abstract     = {Enantiopure 4-formyl-beta-lactams were deployed as synthons for the diastereoselective formation of chiral 2-(2,2,2-trifluoro-1-hydroxyethypazetidines via trifluoromethylation through aldehyde modification followed by reductive removal of the beta-lactam carbonyl moiety. Subsequent treatment of the (in situ) activated 2-trifluoroethylated azetidines with a variety of nitrogen, oxygen, sulfur, and fluorine nucleophiles afforded chiral 3,4-disubstituted 2-(trifluoromethyl)pyrrolidines in good to excellent yields (45-99%) and high diastereoselectivities (dr >99/1, H-1 NMR) via interception of bicyclic aziridinium intermediates. Furthermore, representative pyrrolidines were N,O-debenzylated in a selective way and used for further synthetic elaboration to produce, for example, a CF3-substituted 2-oxa-4,7-diazabicyclo[3.3.0]octan-3-one system.},
  author       = {Dolfen, Jeroen and Boydas, Esma Birsen and Van Speybroeck, Veronique and Catak, Saron and Van Hecke, Kristof and D'hooghe, Matthias},
  issn         = {0022-3263},
  journal      = {JOURNAL OF ORGANIC CHEMISTRY},
  keywords     = {DENSITY FUNCTIONALS,RING EXPANSION,NONCOVALENT INTERACTIONS,AMINO-ALCOHOLS,BETA-LACTAMS,TRIFLUOROMETHYLATION,PYRROLIDINES,DERIVATIVES,TRANSFORMATION,AZETIDINES},
  language     = {eng},
  number       = {19},
  pages        = {10092--10109},
  publisher    = {American Chemical Society (ACS)},
  title        = {Asymmetric Synthesis of 3,4-Disubstituted 2-(Trifluoromethyl)pyrrolidines through Rearrangement of Chiral 2-(2,2,2-Trifluoro-1-hydroxyethyl)azetidines},
  url          = {http://dx.doi.org/10.1021/acs.joc.7b01241},
  volume       = {82},
  year         = {2017},
}

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