1. Catalytic Enantioselective Fluorination
Teerawat Songsichan
1st June 2017
Laboratory of Synthesis and Natural Products (LSPN)

2. Content 1. Introduction 2. Electrophilic Fluorination
2.1 Metal-Catalyzed Fluorination Involving Enolates
2.2 Metal-Catalyzed Fluorination Not Involving Enolates
2.3 Organocatalytic Electrophilic Fluorination
2.4 Fluorination Using Multiple Catalysts
2.5 One-Pot and Tandem Processes
3. Nucleophilic Fluorination
4. Summary and Outlook
- Catalytic Enantioselective Trifluoromethylation and Perfluoroalkylation
- Catalytic Enantioselective Monofluoromethylation
- Catalytic Enantioselective Difluoromethylation
- Catalytic Enantioselective Trifluoromethylthiolation

3. Introduction Impact of Fluorine in Pharmaceuticals
It is well known that fluorine’s electronegativity, size, omniphobicity/lipophilicity, and electrostatic interactions can dramatically influence chemical reactivity.
One of the major effects of fluorination is a modulation of acidity and basicity of a parent compound. This can strongly influence binding affinity, pharmacokinetic properties, and bioavailability of a given drug candidate.
In general, about one-third of the top-performing drugs, currently on the market, contain fluorine atoms in their structures.
Atorvastatin (Lipitor)
treatment of high cholesterol
Fluticasone propionate
anti-inflammatory drug
Ciprofloxacin (Ciprobay)
antibacterial drug
Fustero, S.; Soloshonok, V. A.; Liu, H. Chem. Rev. 2013, 114, 2432.

4. Introduction Common Fluorinating reagents Electrophilic reagents
- Elemental fluorine (F2)
- Fluoroxyltrifluoromethane (CF3OF)
- N-Fluoropyridinium salts
- Selectfluor
- N-Fluorobenzenesulfonimide (NFSI)
Nucleophilic reagents
- Ammonium fluoride (e.g. tetrabutylammonium fluoride, TBAF)
- Pyridinium poly(hydrogen fluoride), PPHF (Olah’s reagent)
- DAST [Et2NSF3] / Deoxofluor [(MeOCH2CH2)2NSF3]

5. Electrophilic Fluorination
Metal-Catalyzed Fluorination Involving Enolates
Ti/TADDOL Catalysts
Togni, A. Angew. Chem., Int. Ed. 2000, 39, 4359.

6. Electrophilic Fluorination
Metal-Catalyzed Fluorination Involving Enolates
Ti/TADDOL Catalysts
Togni, A. Beilstein J. Org. Chem. 2011, 7, 1421.

7. Electrophilic Fluorination
Metal-Catalyzed Fluorination Involving Enolates
Ti/TADDOL Catalysts
Togni, A. Org. Lett. 2003, 5, 1709.
Togni, A. Tetrahedron 2006, 62, 7180.

8. Electrophilic Fluorination
Metal-Catalyzed Fluorination Involving Enolates
Pd/BINAP Catalysts
Sodeoka, M. J. Am. Chem. Soc. 2002, 124,

9. Electrophilic Fluorination
Metal-Catalyzed Fluorination Involving Enolates
Pd/BINAP Catalysts
Sodeoka, M. Tetrahedron 2006, 62, 7168.

10. Electrophilic Fluorination
Metal-Catalyzed Fluorination Involving Enolates
Pd/BINAP Catalysts
Sodeoka, M. J. Am. Chem. Soc. 2005, 127,

11. Electrophilic Fluorination
Metal-Catalyzed Fluorination Involving Enolates
Pd/BINAP Catalysts
Kim, D. Y. Tetrahedron Lett. 2005, 46, 3115.
Kim, A. Y. Org. Lett. 2005, 7, 2309.
Kim, S. Y. Tetrahedron Lett. 2013, 54, 3359.

12. Electrophilic Fluorination
Metal-Catalyzed Fluorination Involving Enolates
Ni/BINAP Catalysts
Sodeoka, M. Angew. Chem., Int. Ed. 2007, 46, 5435.

13. Electrophilic Fluorination
Metal-Catalyzed Fluorination Involving Enolates
Cu/Bis(oxazoline) [Box] Catalysts
Cahard, D. Tetrahedron: Asymmetry 2004, 15, 1007.

14. Electrophilic Fluorination
Metal-Catalyzed Fluorination Involving Enolates
Cu and Ni/Bis(oxazoline) [Box] Catalysts
Shibata, N.; Toru, T. Synlett 2004, 10, 1703.

15. Electrophilic Fluorination
Metal-Catalyzed Fluorination Involving Enolates
Zn/Bis(oxazoline) [Box] Catalysts
Shibata, N.; Toru, T. Angew. Chem., Int. Ed. 2008, 47, 164.

16. Electrophilic Fluorination
Metal-Catalyzed Fluorination Involving Enolates
Metal/Bis(oxazoline) [Box] Catalysts
Other substrates:
Other ligands:

17. Electrophilic Fluorination
Metal-Catalyzed Fluorination Not Involving Enolates
Platinum-Catalyzed Enantioselective Cyclization and C3-Fluorination of Polyenes
Substrate
product
minor
Gagne, M. R. J. Am. Chem. Soc. 2013, 135, 628.

18. Electrophilic Fluorination
Metal-Catalyzed Fluorination Not Involving Enolates
Palladium-Catalyzed Three-component Coupling of Selectfluor, Styrenes, and Boronic Acids
Toste, F. D. J. Am. Chem. Soc. 2014, 136, 4104.

19. Electrophilic Fluorination
Organocatalytic Electrophilic Fluorination
Tertiary Amine Catalysis
Shibata, N.; Toru, T. J. Fluorine Chem. 2006, 127, 548.

20. Electrophilic Fluorination
Organocatalytic Electrophilic Fluorination
Tertiary Amine Catalysis
Shibata, N.; Toru, T. Angew. Chem., Int. Ed. 2008, 47, 4157.
Gouverneur, V. Angew. Chem., Int. Ed. 2011, 50, 8105.

21. Electrophilic Fluorination
Organocatalytic Electrophilic Fluorination
Enamine Catalysis
Jørgensen, K. A. Angew. Chem., Int. Ed. 2005, 44, 3703.

22. Electrophilic Fluorination
Organocatalytic Electrophilic Fluorination
Enamine Catalysis
Brenner-Moyer, S. E. Org. Lett. 2010, 12, 3356.

23. Electrophilic Fluorination
Organocatalytic Electrophilic Fluorination
Enamine Catalysis
MacMillan, D. W. C. J. Am. Chem. Soc. 2011, 133, 1738.
Houk, K. N. J. Am. Chem. Soc. 2014, 136, 9556.

24. Electrophilic Fluorination
Organocatalytic Electrophilic Fluorination
NHC Catalysis
Lin, Z.; Sun, J. Angew. Chem., Int. Ed. 2012, 51,

25. Electrophilic Fluorination
Organocatalytic Electrophilic Fluorination
Thiourea-Catalyzed Enantioselective Fluorination
Chiral Phosphoric Acid-Catalyzed Enantioselective Fluorination
Hu, Y. Adv. Synth. Catal. 2012, 254, 515.
Akiyama, T. Chem. Lett. 2014, 43, 137.

26. Electrophilic Fluorination
Fluorination Using Multiple Catalysts
Combination of Chiral Anion Phase-Transfer Catalysis and Enamine Catalysis
Toste, F. D. J. Am. Chem. Soc. 2014, 136, 5225.

27. Electrophilic Fluorination
One-Pot and Tandem Processes
Asymmetric Synthesis of Fluorinated Flavanone Derivatives
Diastereo- and Enantioselective Tandem 1,4-Addition/Fluorination
Transitionstate model for the oxa-Michael addition step.
(Re face attack)
Zhao, G. Chem.–Eur. J. 2009, 15,
Ma, J.-A. Angew. Chem., Int. Ed. 2011, 50, 9442.

28. Nucleophilic Fluorination
Cooperative Catalysis in the Enantioselective Fluorination of Epoxides
Doyle, A. G. J. Am. Chem. Soc. 2010, 132, 3268.
Doyle, A. G. J. Am. Chem. Soc. 2011, 133,

29. Nucleophilic Fluorination
Cooperative Catalysis in the Enantioselective Fluorination of Aziridines
Doyle, A. G. Tetrahedron 2013, 69, 5702.

30. Nucleophilic Fluorination
Palladium-Catalyzed Asymmetric Synthesis of Allylic Fluorides
Doyle, A. G. J. Am. Chem. Soc. 2010, 132,
Doyle, A. G. J. Am. Chem. Soc. 2011, 133,

31. Summary and Outlook
There has been remarkable progress in the past decade toward catalytic asymmetric methods for the introduction of fluorine atom into small molecules.
Both transition metal catalysis and organocatalysis were applied as the strategies for the catalytic enantioselective fluorination.
Various types of products were obtained.
Reviews:
Toste, F. D. Chem. Rev. 2015, 115, 826.
Cahard, D. Chem. Rev. 2008, 108, PR1.
Cahard, D. Chem. Rev. 2004, 104, 6119.