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C–H Bond Functionalization: New Strategies for the Synthesis of
Complex Natural Products and Pharmaceuticals
Phil Knutson
Ferreira Group
12/3/2015
New strategies in organic synthesis
nsf-cchf.com
What is C–H Functionalization?
D. Sames, et al. Science 2006, 312, 67-72.
What is C–H Functionalization?
D. Sames, et al. Science 2006, 312, 67-72.
Friedel-Crafts acylation/alkylation
Oxidative phenol-phenol coupling
Allylic oxidation via SeO2 or other stoichiometric transition metal
Ortho- or remote-metalation via stoichiometric strong bases
What is not C–H Functionalization?
K. Itami, et al. Angew. Chem. Int. Ed. 2012, 51, 8960-9009.
Examples in complex molecule synthesis
Two Total Syntheses Utilizing C–H Functionalization
Content
C-C Bond Formation C–Heteroatom Bond Formation
Aromatic C–H Arylation C–H Amination (C–H Insertion of Nitrenes)
C(sp2)–H Alkenylation and Alkylation C–H Amination (C–H Insertion of Metal Nitrenoids)
Pd-cat. Directed C(sp3)–H Functionalization C–H Allylic Oxidation
C–H Insertion of Metal Carbenoids C–H Borylation
C–H Halogenation
C-C Bond Formation
Aromatic C–H Arylation
Types of C–H Functionalization
K. Fagnou, et al. J. Org. Chem. 2008, 73, 5022.
Aromatic C–H Arylation
D. Trauner, et al. Org. Lett. 2005, 7, 5207-5209.
Aromatic C–H Arylation
D. Trauner, et al. Org. Lett. 2005, 7, 5207-5209.
C-C Bond Formation
Aromatic C–H Arylation
C(sp2)–H Alkenylation and Alkylation
Types of C–H Functionalization
C(sp2)–H Alkenylation and Alkylation
R.G. Bergman, J.A. Ellman, et al. J. Am. Chem. Soc. 2005, 127, 13496-13497.
C(sp2)–H Alkenylation and Alkylation
R.G. Bergman, J.A. Ellman, et al. J. Am. Chem. Soc. 2005, 127, 13496-13497.
C(sp2)–H Alkenylation and Alkylation
R.G. Bergman, J.A. Ellman, et al. J. Am. Chem. Soc. 2005, 127, 13496-13497.
C-C Bond Formation
Aromatic C–H Arylation
C(sp2)–H Alkenylation and Alkylation
Directed C(sp3)–H Functionalization
Types of C–H Functionalization
Directed C(sp3)–H Functionalization
D. Sames, et al. J. Am. Chem. Soc. 2002, 124, 11856-11857.
C-C Bond Formation
Aromatic C–H Arylation
C(sp2)–H Alkenylation and Alkylation
Directed C(sp3)–H Functionalization
C–H Insertion Metal Carbenoids
Types of C–H Functionalization
C–H Insertion of Metal Carbenoids
X. Lei, et al. J. Am. Chem. Soc. 2015, 137, 11946−11949.
C-C Bond Formation
Aromatic C–H Arylation
C(sp2)–H Alkenylation and Alkylation
Directed C(sp3)–H Functionalization
C–H Insertion of Metal Carbenoids
C–Heteroatom Bond Formation
C–H Amination (C–H Insertion of Nitrenes)
Types of C–H Functionalization
C–H Amination (Nitrene Insertion)
H. Tokuyama, et al. Angew. Chem. Int. Ed. 2010, 49, 5925 –5929.
C-C Bond Formation
Aromatic C–H Arylation
C(sp2)–H Alkenylation and Alkylation
Directed C(sp3)–H Functionalization
C–H Insertion of Metal Carbenoids
C–Heteroatom Bond Formation
C–H Amination (C–H Insertion of Nitrenes)
C–H Amination (C–H Insertion of Metal Nitrenoids)
Types of C–H Functionalization
C–H Amination (C–H Insertion of Metal Nitrenoids)
J. Du Bois, et al. J. Am. Chem. Soc. 2003, 125, 11510-11511.
C-C Bond Formation
Aromatic C–H Arylation
C(sp2)–H Alkenylation and Alkylation
Directed C(sp3)–H Functionalization
C–H Insertion of Metal Carbenoids
C–Heteroatom Bond Formation
C–H Amination (C–H Insertion of Nitrenes)
C–H Amination (C–H Insertion of Metal Nitrenoids)
C–H Allylic Oxidation (Pd-Catalyzed)
Types of C–H Functionalization
M. White, et al. J. Am. Chem. Soc., 2005, 127, 6970-6971.
M. White, et al. Nature Chem. 2009, 125, 547-551.
C–H Allylic Oxidation (Pd-Catalyzed)
M. White, et al. Nature Chem. 2009, 125, 547-551.
C–H Allylic Oxidation (Pd-Catalyzed)
M. White, et al. Nature Chem. 2009, 125, 547-551.
C–H Allylic Oxidation (Pd-Catalyzed)
M. White, et al. Nature Chem. 2009, 125, 547-551.
C–H Allylic Oxidation (Pd-Catalyzed)
M. White, et al. Nature Chem. 2009, 125, 547-551.
C-C Bond Formation
Aromatic C–H Arylation
C(sp2)–H Alkenylation and Alkylation
Directed C(sp3)–H Functionalization
C–H Insertion of Metal Carbenoids
C–Heteroatom Bond Formation
C–H Amination (C–H Insertion of Nitrenes)
C–H Amination (C–H Insertion of Metal Nitrenoids)
C–H Allylic Oxidation (Pd-Catalyzed)
C–H Borylation
Types of C–H Functionalization
C–H Borylation
J. F. Hartwig, et al. J. Am. Chem. Soc. 2011, 133, 2088–2091.
C-C Bond Formation
Aromatic C–H Arylation
C(sp2)–H Alkenylation and Alkylation
Directed C(sp3)–H Functionalization
C–H Insertion of Metal Carbenoids
C–Heteroatom Bond Formation
C–H Amination (C–H Insertion of Nitrenes)
C–H Amination (C–H Insertion of Metal Nitrenoids)
C–H Allylic Amination/Oxidation (Pd-Catalyzed)
C–H Borylation
C–H Halogenation (Metal-Catalyzed)
Types of C–H Functionalization
C–H Halogenation
K. Itami, et al. Angew. Chem. Int. Ed. 2012, 51, 8960-9009.
Examples in complex molecule synthesis
Two Total Syntheses Utilizing C–H Functionalization
Content
C-C Bond Formation C–Heteroatom Bond Formation
Aromatic C–H Arylation C–H Amination (C–H Insertion of Nitrenes)
C(sp2)–H Alkenylation and Alkylation C–H Amination (C–H Insertion of Metal Nitrenoids)
Pd-cat. Directed C(sp3)–H Functionalization C–H Allylic Oxidation
C–H Insertion of Metal Carbenoids C–H Borylation
C–H Halogenation
(+)-Austamide
Y. Kishi, et al. J. Am. Chem. Soc. 1979, 101, 6786-6788.
E. J. Corey, J. Am. Chem. Soc. 2002, 124, 7904-7905.
(+)-Austamide
E. J. Corey, J. Am. Chem. Soc. 2002, 124, 7904-7905.
(+)-Austamide
E. J. Corey, J. Am. Chem. Soc. 2002, 124, 7904-7905.
(+)-Austamide
E. J. Corey, J. Am. Chem. Soc. 2002, 124, 7904-7905.
Dragmacidin D
B. M. Stoltz, et al. J. Am. Chem. Soc. 2002, 124, 13179-13184.
K. Itami, et al. J. Am. Chem. Soc. 2011, 133, 19660–19663.
Dragmacidin D
K. Itami, et al. J. Am. Chem. Soc. 2011, 133, 19660–19663.
Dragmacidin D
K. Itami, et al. J. Am. Chem. Soc. 2011, 133, 19660–19663.
Dragmacidin D
K. Itami, et al. J. Am. Chem. Soc. 2011, 133, 19660–19663.
Dragmacidin D
K. Itami, et al. J. Am. Chem. Soc. 2011, 133, 19660–19663.
Dragmacidin D
K. Itami, et al. J. Am. Chem. Soc. 2011, 133, 19660–19663.
Comparing total syntheses
K. Itami, et al. Angew. Chem. Int. Ed. 2012, 51, 8960-9009.
Examples in complex molecule synthesis
Two Total Syntheses Utilizing C–H Functionalization
Summary
C-C Bond Formation C–Heteroatom Bond Formation
Aromatic C–H Arylation C–H Amination (C–H Insertion of Nitrenes)
C(sp2)–H Alkenylation and Alkylation C–H Amination (C–H Insertion of Metal Nitrenoids)
Pd-cat. Directed C(sp3)–H Functionalization C–H Allylic Oxidation
C–H Insertion of Metal Carbenoids C–H Borylation
C–H Halogenation