Transcript Chiral Phosphine Organocatalysis

Lewis Basic Chiral Phosphine Organocatalysis
John Feltenberger
Hsung Group
University of Wisconsin – Madison
January 29, 2009
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. The binding event may enhance either the
electrophilic or nucleophilic character of the bound species.
Furthermore, the Lewis base should not be consumed or altered
during the course of the reaction.”
n-π* interactions
Denmark, S. E.; Beutner, G. L. Angew. Chem. Int. Ed. 2008, 47, 1560.
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Mode of Activation: n-π*
1,2-addition to carbonyls
Enhances
electrophilic
character
Michael-type additions
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
• Trigonal pyramidal structure
• Non-bonded lone pair of electrons
• Barrier to inversion
Rapid inversion
No inversion at room temp
• Acyclic phosphines retain chirality 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.
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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.
Michael-Type Reactions
• Michael-Type
• Enones
• Morita-Baylis-Hillman
• Aza-MBH
• Ynones and Allenones
• Umpolung γ- 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
• Atmospheric Pressure
• Long reaction time
• Low yield and ee
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
+25.30 ppm
-13.16 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
and Allenones
Allenones
• Umpolung γ- 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
• Reactivity order: ketone > ester > amide
• Catalytic acetic acid and higher temps necessary for esters and amides
• 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 γ-Additions
Trost, B. M.; Li, C.-J. J. Am. Chem. Soc. 1994, 116, 3167.
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Enantioselective γ-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 γ-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 α-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
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