Lewis Basic Chiral Phosphine Organocatalysis

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Lewis Basic Chiral Phosphine Organocatalysis

• John Feltenberger
• Hsung Group
• University of Wisconsin Madison
• January 29, 2009

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Lewis Basic Organocatalysis
Lewis base catalysis is the process by which an
electron pair donor increases the rate of a given
chemical reaction by interacting with an acceptor
atom in one of the reagents or substrates.
Furthermore, the Lewis base should not be
consumed or altered during the course of the
reaction.
The binding event may
enhance either the electrophilic or nucleophilic
character of the bound species.
n-p interactions
Denmark, S. E. Beutner, G. L. Angew. Chem. Int.
Ed. 2008, 47, 1560.
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Mode of Activation n-p

• 1,2-addition to carbonyls

• Michael-type additions

Enhances electrophilic character
Enhances nucleophilic character
Masks electrophilic character
Denmark, S. E. Beutner, G. L. Angew. Chem. Int.
Ed. 2008, 47, 1560.
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Why Use Phosphines as Organocatalysts?
Highly Tunable Electronics Sterics
Source of Chirality Within groups attached to
P P-Chirality
Phosphorus Ligands in Asymmetric Catalysis
Börner, A., Ed. Wiley-VCH Weinheim ,2008
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Structure Amines and Phosphines

• Barrier to inversion

• Acyclic phosphines retain chirality at room temp

• Trigonal pyramidal structure

• Non-bonded lone pair of electrons

Rapid inversion
No inversion at room temp
Kölmel, C. Ochsenfeld, C. Ahlrichs, R. Theor.
Chim. Acta 1991, 82, 271.
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Nucleophilicity vs. Basicity
nMeI log(kY/kMeOH) where kY is the rate of
reaction of Y with MeI in methanol at 25 C
Methot, J. L. Roush, W. R. Adv. Synth. Catal.
2004, 346, 1035. Pearson, R. G. Songstad, J. J.
Am. Chem. Soc. 1967, 89, 1827.
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Phosphine Reactivity

• Soft nucleophile easily polarizable
• Trialkyl phosphines are more nucleophilic, but
  air sensitive
• Triaryl phosphines are less nucleophilic, but
  typically cheap and air stable

Methot, J. L. Roush, W. R. Adv. Synth. Catal.
2004, 346, 1035. Pearson, R. G. Songstad, J. J.
Am. Chem. Soc. 1967, 89, 1827.
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Typical Uses of Phosphines
Nucleophile Wittig Olefination
Reducing Agent Mitsunobu Reaction
Ligand Asymmetric Hydrogenation
High yields, ee
Wittig, G. Schollkopf, U. Chem. Ber. 1954, 97,
1318. Mitsunobu, O., Yamada, M. Bull. Chem. Soc.
Jpn. 1967, 40, 2380. Kitamura, M., Ohkuma, T.,
Inoue, S., Sayo, N., Kumobayashi, H., Akutagawa,
S., Ohta, T., Takaya, H., Noyori, R. J. Am. Chem.
Soc. 1988, 110, 629.
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Michael-Type Reactions

• Michael-Type
• Enones
• Morita-Baylis-Hillman
• Aza-MBH
• Ynones and Allenones
• Umpolung ?- addition
• 3 2 Cycloaddition
• 4 2 Annulation

• Michael-Type
• Enones
• Morita-Baylis-Hillman
• Aza-MBH
• Ynones and Allenones
• Umpolung ?- addition
• 3 2 Cycloaddition
• 4 2 Annulation

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Morita-Baylis-Hillman Reaction
Discovery by Morita, 1968
Proposed Mechanism
Morita, K. Suzuki, Z. Hirose, H. Bull. Chem.
Soc. Jpn. 1968, 41, 2815.
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First Chiral Phosphine MBH Reaction

• Low yield and ee

• Long reaction time

• Atmospheric Pressure

Hayase, T. Shibata, T. Soai, K. Wakatsuki, Y.
Chem. Commun. 1998, 1271.
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Chiral Amine Catalyzed MBH
High pressures necessary for higher
enantioselectivity
Bifunctional catalyst improved
enantioselectivity
Oishi, T. Oguri, H. Hirama, M. Tetrahedron
Asymmetry, 1995, 6, 1241-1244. Iwabuchi, Y.
Nakatani, M. Yokoyama, N. Hatakeyama, S. J. Am.
Chem. Soc. 1999, 121, 10219-10220.
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Bifunctional Phosphine Activated Aza-MBH
with MS 4Å
Shi, M. Chen, L.-H. Li, C.-Q. J. Am. Chem. Soc.
2005, 127, 3790.
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Modification of Bifunctional Phosphine
(R)-2,2 disubstituted 1,1 binapthyl
Shi, M. Chen, L.-H. Li, C.-Q. J. Am. Chem. Soc.
2005, 127, 3790.
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Proposed Mechanism for the Aza-MBH
Shi, M. Chen, L.-H. Li, C.-Q. J. Am. Chem. Soc.
2005, 127, 3790.
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31P NMR Analysis
-13.16 ppm
LB1
-13.16 ppm
25.30 ppm
LB1 with MVK
Phosphonium salt A
26.07 ppm
Shi, M. Chen, L.-H. Li, C.-Q. J. Am. Chem. Soc.
2005, 127, 3790.
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Michael-Type Reactions

• Michael-Type
• Enones
• Morita-Baylis-Hillman
• Aza-MBH
• Ynones and Allenones
• Umpolung ?- Addition
• 3 2 Cycloaddition
• 4 2 Annulation

• Michael-Type
• Enones
• Morita-Baylis-Hillman
• Aza-MBH
• Ynones and Allenones
• Umpolung ?- Addition
• 3 2 Cycloaddition
• 4 2 Annulation

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Alkyne to 1,3-Diene Isomerization
Trost, B. M. Kazmaier, U. J. Am. Chem. Soc.
1992, 114, 7933. Guo, C. Lu, X. J. Chem. Soc.,
Perkin Trans. 1 1993, 1921.
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Isomerization Reactivity

• Catalytic acetic acid and higher temps necessary
  for esters and amides

• Reactivity order ketone gt ester gt amide

• PBu3 was faster, but considerable oligomerization

• No reaction was observed with tertiary amines

Trost, B. M. Kazmaier, U. J. Am. Chem. Soc.
1992, 114, 7933.
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Phosphine-Catalyzed Umpolung ?-Additions
Trost, B. M. Li, C.-J. J. Am. Chem. Soc. 1994,
116, 3167.
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Enantioselective ?-Addition to Ynoate
Chen, Z. Zhu, G. Jiang, Q. Xiao, D. Cao, P.
Zhang, X. J. Org. Chem. 1998, 63, 5631.
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Enantioselective ?-Addition to Allenoate
Chen, Z. Zhu, G. Jiang, Q. Xiao, D. Cao, P.
Zhang, X. J. Org. Chem. 1998, 63, 5631.
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Phosphine-Catalyzed 3 2 Cycloaddition
No reaction with Et3N
Zhang, C. Lu, X. J. Org. Chem. 1995, 60, 2906.
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Amine Catalyzed Pathway
Evans, C. A. Miller, S. J. J. Am. Chem.
Soc.2003, 125, 12394.
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Asymmetric 3 2 Cycloaddition
Zhu, G. Chen, Z. Jiang, Q. Xiao, D. Cao, P.
Zhang, X. J. Am. Chem. Soc. 1997, 119, 3836.
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Another Asymmetric 3 2 Cycloaddition
Wilson, J. E. Fu, G. C. Angew. Chem. Int. Ed.
2006, 45, 1426.
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Asymmetric Spirocyclization
Wilson, J. E. Fu, G. C. Angew. Chem. Int. Ed.
2006, 45, 1426.
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Phosphine-Containing a-Amino Acid
Cowen, B. J. Miller, S. J. J. Am. Chem.
Soc.2007, 129, 10988.
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Deracemization of () Allenic Ester
Cowen, B. J. Miller, S. J. J. Am. Chem.
Soc.2007, 129, 10988.
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Phosphine Catalyzed 4 2 Annulation
Zhu, X-F. Lan, J. Kwon, O. J. Am. Chem. Soc.
2003, 125, 4716.
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4 2 Annulation Pathway
Zhu, X-F. Lan, J. Kwon, O. J. Am. Chem. Soc.
2003, 125, 4716.
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Asymmetric 4 2 Annulation
Wurz, R. P. Fu, G. C. J. Am. Chem. Soc. 2005,
127, 12234.
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Asymmetric 4 2 Annulation - Applications
Wurz, R. P. Fu, G. C. J. Am. Chem. Soc. 2005,
127, 12234.
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Conclusions

• Advantages of Phosphine Catalysts
• Tunability
• Diversity of possible reactions
• Source of chirality
• Limitations
• Air sensitive
• Long reaction times
• High catalyst loadings

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Acknowledgements

• Professor Richard Hsung
• Hsung group members
• Practice talk attendees
• -Andrew Lohse
• - Grant Buchanan
• - Jin Haek Yang
• - Lauren Carlson
• - Aaron Almeida
• - Mike Giuliano
• - Jay Steinkruger
• - Christle Guevarra
• - Dr. Ryuji Hayashi

• Kat Myhre
• Ashley Feltenberger