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Catalytic Enantioselective Fluorination

Catalytic Enantioselective Fluorination. Teerawat Songsichan 1 st June 2017. Laboratory of Synthesis and Natural Products (LSPN). Content. 1. Introduction 2. Electrophilic Fluorination 2.1 Metal-Catalyzed Fluorination Involving Enolates

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Catalytic Enantioselective Fluorination

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  1. Catalytic Enantioselective Fluorination TeerawatSongsichan 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. Tetrahedron2006, 62, 7180.

  8. Electrophilic Fluorination • Metal-Catalyzed Fluorination Involving Enolates • Pd/BINAP Catalysts Sodeoka, M. J.Am. Chem. Soc. 2002, 124, 14530.

  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, 10164.

  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: Asymmetry2004, 15, 1007.

  14. Electrophilic Fluorination • Metal-Catalyzed Fluorination Involving Enolates • Cu and Ni/Bis(oxazoline) [Box] Catalysts Shibata, N.; Toru, T. Synlett2004, 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 product 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, 10359.

  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, 13299. 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, 16001.

  29. Nucleophilic Fluorination • Cooperative Catalysis in the Enantioselective Fluorination of Aziridines Doyle, A. G. Tetrahedron2013, 69, 5702.

  30. Nucleophilic Fluorination • Palladium-Catalyzed Asymmetric Synthesis of Allylic Fluorides Doyle, A. G. J. Am. Chem. Soc. 2010, 132, 17402. Doyle, A. G. J. Am. Chem. Soc. 2011, 133, 15902.

  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.

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