byWilliam Schulz Bechara

Charette/Collins Charette/Collins LiteratureLiterature Meeting MeetingApril 8April 8thth, 2014, 2014

14 MARCH 2014

a) Neufeldt, S. R.; Sanford, M. S. Acc. Chem. Res. 2012, 45, 936. b) Engle, K. M.; Mei, T.-S.; Wasa, M.; Yu, J.-Q. Acc. Chem. Res. 2012, 45, 788.

Controlling Site Selectivity in C-H Functionalization

Catalyst-based control Substrate-based control

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a) Neufeldt, S. R.; Sanford, M. S. Acc. Chem. Res. 2012, 45, 936. b) Engle, K. M.; Mei, T.-S.; Wasa, M.; Yu, J.-Q. Acc. Chem. Res. 2012, 45, 788. c) Colby, D. A.; Tsay, A.-S.; Bergman, R. G.; Ellman, J. A. Acc. Chem. Res. 2012, 45, 814. d) Zaitsev, V. G.; Shabashov, D.; Daugulis, O. J. Am. Chem. Soc. 2005, 127, 13154. e) Shabashov, D.; Daugulis, O. J. Am. Chem. Soc. 2010, 132, 3965. f) Rouquet, G.; Chatani, N. Angew. Chem. Int. Ed. 2013, 52, 11726. g) Shi Chem. Sci. 2013, 4, 3712.

Directing Groups in Substrate-Based Control With Pd

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Monodentate Bidentate Tridentate

Catalytic Manifolds in Pd-Catalyzed C-H Functionalization

4Engle, K. M.; Mei, T.-S.; Wasa, M.; Yu, J.-Q. Acc. Chem. Res. 2012, 45, 788.

Jin-Quan Yu

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Education :

• East China Normal University - Shanghai, China : 1982 - 1987B.Sc. in Chemistry - Top 5% of national examination for admission to SIOC

• Shanghai Institute of Organic Chemistry (SIOC) - Shanghai, China : 1987 - 1988Coursework for M.Sc. degree

• Guangzhou Institute of Chemistry - Guangzhou, China : 1988 - 1990M.Sc. in Chemistry with S.D. Xiao

• University of Cambridge - Cambridge, UK : 1994 - 1999Ph.D. in Chemistry with Jonathan Spencer

• University of Cambridge - Cambridge, UK : 1999 - 2003Junior Research Fellow (JRF) of St. John's College

• Harvard University - Cambridge, MA, USA : 2001 - 2002Postdoctoral Fellow, supervisor: E.J. Corey

Academic Positions :

• University of Cambridge - Cambridge, UK Royal Society Research Fellow : 2003 - 2004

• Brandeis University - Waltham, MA, USAAssistant Professor of Chemistry : 2004 - 2007

• Scripps Research Institute - La Jolla, CA, USA Associate Professor of Chemistry : 2007 – 2010 Professor of Chemistry : 2010 – 2012 Frank and Bertha Hupp Professor of Chemistry : 2012 - present

20 (or 16) years ofacademic studies!!

Pd(0)-Catalyzed Intermolecular Arylation of C(sp3)-H Bonds

6Wasa, M.; Engle, K. M.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131, 9886.

Pd(II)-Catalyzed Olefination of C(sp3)-H Bonds

7Wasa, M.; Engle, K. M.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 3680.

Key Features of the Weak Coordinating “N-ArF” DG Auxiliary

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- Low pKa : Faster deprotonation. Lower pKa is instrumental for the presence of a larger population of the reactive deprotonated amide.

- Weak coordination : EWG group coordinated to the N center pushes the hybridization toward a N(sp2) center and weakens the coordination to the Pd center (relative to other N(sp3)).

- PES (potential energy surface/DFT studies) of the reaction is slightly flatter in presence of ArF compared to fully H-substituted. Reductive elimination step is slightly more favorable.

- Weak coordination has been successfully exploited to control the reactivity and selectivity of Pd-cat. C-H functionalization.

Figg, T. M.; Wasa, M.; Yu, J.-Q.; Musaev, D. G. J. Am. Chem. Soc. 2013, 135, 14206.

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Can one apply the Pd(II)-catalyzed C-H activation for the -functionalization of Alanine based SM?

Synthesis of Unnatural Chiral -Amino Acids

Synthesis of Unnatural Chiral -Amino Acids

a) Chen, K.; Hu, F.; Zhang, S.-Q.; Shi, B.-F. Chem. Sci. 2013, 4, 3906. b) Zhang, Q.; Chen, K.; Rao, W.; Zhang, Y.; Chen, F.-J.; Shi, B.-F. Angew. Chem. Int. Ed. 2013, 52, 13588. c) Tran, L. D.; Daugulis, O. Angew. Chem., Int. Ed. 2012, 51, 5188. 10

General Limitations

- Long reaction time- Di-arylation- Low yields- Different N-Aux for mono- or di-arylation- Racemization- Limited to electron-rich Ar-X- No one-pot di-arylation with 2 different substituents

Pd-Catalyzed Arylation of Primary C(sp3)-H Bonds

11a) He, J.; Li, S.; Deng, Y.; Fu, H.; Laforteza, B. N.; Spangler, J. E.l Homs, A.; Yu, J.-Q. Science. 2014, 343, 1216. b) M. Wasa et al., J. Am. Chem. Soc. 2012, 134, 18570.

Substituted pyridine ligands can match the weak coordination of the amide auxiliary (CONHArF)

Pd-Catalyzed Arylation of Primary C(sp3)-H Bonds

12He, J.; Li, S.; Deng, Y.; Fu, H.; Laforteza, B. N.; Spangler, J. E.l Homs, A.; Yu, J.-Q. Science. 2014, 343, 1216. *Gram-scale reaction.

Pd-Catalyzed Arylation of Primary C(sp3)-H Bonds

13He, J.; Li, S.; Deng, Y.; Fu, H.; Laforteza, B. N.; Spangler, J. E.l Homs, A.; Yu, J.-Q. Science. 2014, 343, 1216. *Gram-scale reaction.

Determination of Enantiomeric Purity

14He, J.; Li, S.; Deng, Y.; Fu, H.; Laforteza, B. N.; Spangler, J. E.l Homs, A.; Yu, J.-Q. Science. 2014, 343, 1216.

Pd-Catalyzed Arylation of Secondary C(sp3)-H Bonds

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Better yields using electron-donating 2-alkoxylpyridines.The conformation of the lone pairs on the oxygen atom (in L10) is rigidified

to favor -conjugation with the pyridine ring.a) He, J.; Li, S.; Deng, Y.; Fu, H.; Laforteza, B. N.; Spangler, J. E.l Homs, A.; Yu, J.-Q. Science. 2014, 343, 1216. b) M. Wasa et al., J. Am. Chem. Soc. 2012, 134, 18570.

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Pd-Catalyzed Arylation of Secondary C(sp3)-H Bonds

He, J.; Li, S.; Deng, Y.; Fu, H.; Laforteza, B. N.; Spangler, J. E.l Homs, A.; Yu, J.-Q. Science. 2014, 343, 1216.

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Pd-Catalyzed Arylation of Secondary C(sp3)-H Bonds

He, J.; Li, S.; Deng, Y.; Fu, H.; Laforteza, B. N.; Spangler, J. E.l Homs, A.; Yu, J.-Q. Science. 2014, 343, 1216.

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Pd-Catalyzed Arylation of Secondary C(sp3)-H Bonds

He, J.; Li, S.; Deng, Y.; Fu, H.; Laforteza, B. N.; Spangler, J. E.l Homs, A.; Yu, J.-Q. Science. 2014, 343, 1216.

Synthesis of Amino Acids via Sequential C(sp3)–H Arylation in One Pot

19He, J.; Li, S.; Deng, Y.; Fu, H.; Laforteza, B. N.; Spangler, J. E.l Homs, A.; Yu, J.-Q. Science. 2014, 343, 1216.

20He, J.; Li, S.; Deng, Y.; Fu, H.; Laforteza, B. N.; Spangler, J. E.l Homs, A.; Yu, J.-Q. Science. 2014, 343, 1216.

Synthesis of Amino Acids via Sequential C(sp3)–H Arylation in One Pot

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Ligand-Enabled C(sp3)–H Arylation With Heteroaryl Iodides

He, J.; Li, S.; Deng, Y.; Fu, H.; Laforteza, B. N.; Spangler, J. E.l Homs, A.; Yu, J.-Q. Science. 2014, 343, 1216.

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Synthesis of N-Fmoc-Protected Unnatural Amino Acid

He, J.; Li, S.; Deng, Y.; Fu, H.; Laforteza, B. N.; Spangler, J. E.l Homs, A.; Yu, J.-Q. Science. 2014, 343, 1216.

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C(sp3)–H Olefination of Alanine Derivatives (PdII/Pd0)

He, J.; Li, S.; Deng, Y.; Fu, H.; Laforteza, B. N.; Spangler, J. E.l Homs, A.; Yu, J.-Q. Science. 2014, 343, 1216.

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Unnatural –Amino Acid Elaboration

He, J.; Li, S.; Deng, Y.; Fu, H.; Laforteza, B. N.; Spangler, J. E.l Homs, A.; Yu, J.-Q. Science. 2014, 343, 1216.

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Crystallography of Primary C(sp3)–H Activation Intermediate

He, J.; Li, S.; Deng, Y.; Fu, H.; Laforteza, B. N.; Spangler, J. E.l Homs, A.; Yu, J.-Q. Science. 2014, 343, 1216.

Crystallography of Secondary C(sp3)–H Activation Intermediate

26He, J.; Li, S.; Deng, Y.; Fu, H.; Laforteza, B. N.; Spangler, J. E.l Homs, A.; Yu, J.-Q. Science. 2014, 343, 1216.

Catalytic Reactivity of Intermediates A and B

27He, J.; Li, S.; Deng, Y.; Fu, H.; Laforteza, B. N.; Spangler, J. E.l Homs, A.; Yu, J.-Q. Science. 2014, 343, 1216.

- TFA is required for this transformation, presumably to facilitate the dissociation of one of the pyridine ligands.

Intramolecular Kinetic Isotope Effect

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Proposed Mechanism for Pd(II)/Pd(IV) Catalysis

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CsF or AgCO3 help scavenge the I from Pd

by forming clusters*

* M. Wasa et al., J. Am. Chem. Soc. 2012, 134, 18570.

- These rare and valuable C(sp3)–H insertion intermediates (A and B) provide a promising platform for further kinetic and computational

study of elementary steps in a well-defined manner.

Future Work

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Thank You

Questions?