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Lewis Basic Chiral Phosphine Organocatalysis. John Feltenberger Hsung Group University of Wisconsin – Madison January 29, 2009. Lewis Basic Organocatalysis.

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lewis basic chiral phosphine organocatalysis

Lewis Basic Chiral Phosphine Organocatalysis

John Feltenberger

Hsung Group

University of Wisconsin – Madison

January 29, 2009

slide2

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-π* interactions

Denmark, S. E.; Beutner, G. L. Angew. Chem. Int. Ed. 2008, 47, 1560.

slide3

Mode of Activation: n-π*

  • Michael-type additions

1,2-addition to carbonyls

Enhances electrophilic character

Enhances nucleophilic character

Masks electrophilic character

Denmark, S. E.; Beutner, G. L. Angew. Chem. Int. Ed. 2008, 47, 1560.

slide4

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

slide5

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. Acta1991, 82, 271.

slide6

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.

slide7

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.

slide8

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.

slide9

Michael-Type Reactions

  • Michael-Type
    • Enones
      • Morita-Baylis-Hillman
      • Aza-MBH
    • Ynones and Allenones
      • Umpolung γ- addition
      • [3 + 2] Cycloaddition
      • [4 + 2] Annulation
  • Michael-Type
    • Enones
      • Morita-Baylis-Hillman
      • Aza-MBH
    • Ynones and Allenones
      • Umpolung γ- addition
      • [3 + 2] Cycloaddition
      • [4 + 2] Annulation
slide10

Morita-Baylis-Hillman Reaction

Discovery by Morita, 1968

Proposed Mechanism

Morita, K.; Suzuki, Z.; Hirose, H. Bull. Chem. Soc. Jpn.1968, 41, 2815.

slide11

First ChiralPhosphine MBH Reaction

  • Low yield and ee
  • Long reaction time
  • Atmospheric Pressure

Hayase, T.; Shibata, T.; Soai, K.; Wakatsuki, Y. Chem. Commun. 1998, 1271.

slide12

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.

slide13

BifunctionalPhosphine Activated Aza-MBH

with MS 4Å

Shi, M.; Chen, L.-H.; Li, C.-Q. J. Am. Chem. Soc.2005, 127, 3790.

slide14

Modification of BifunctionalPhosphine

(R)-2,2’ disubstituted 1,1’ binapthyl

Shi, M.; Chen, L.-H.; Li, C.-Q. J. Am. Chem. Soc.2005, 127, 3790.

slide15

Proposed Mechanism for the Aza-MBH

Shi, M.; Chen, L.-H.; Li, C.-Q. J. Am. Chem. Soc.2005, 127, 3790.

slide16

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.

slide17

Michael-Type Reactions

  • Michael-Type
    • Enones
      • Morita-Baylis-Hillman
      • Aza-MBH
    • Ynones and Allenones
      • Umpolung γ- Addition
      • [3 + 2] Cycloaddition
      • [4 + 2] Annulation
  • Michael-Type
    • Enones
      • Morita-Baylis-Hillman
      • Aza-MBH
    • Ynones and Allenones
      • Umpolung γ- Addition
      • [3 + 2] Cycloaddition
      • [4 + 2] Annulation
slide18

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.

slide19

Isomerization Reactivity

  • Catalytic acetic acid and higher temps necessary for esters and amides
  • Reactivity order: ketone > ester > 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.

slide20

Phosphine-Catalyzed Umpolungγ-Additions

Trost, B. M.; Li, C.-J. J. Am. Chem. Soc.1994, 116, 3167.

slide21

Enantioselectiveγ-Addition to Ynoate

Chen, Z.; Zhu, G.; Jiang, Q.; Xiao, D.; Cao, P.; Zhang, X. J. Org. Chem. 1998, 63, 5631.

slide22

Enantioselective γ-Addition to Allenoate

Chen, Z.; Zhu, G.; Jiang, Q.; Xiao, D.; Cao, P.; Zhang, X. J. Org. Chem. 1998, 63, 5631.

slide23

Phosphine-Catalyzed [3 + 2] Cycloaddition

No reaction with Et3N

Zhang, C.; Lu, X. J. Org. Chem. 1995, 60, 2906.

slide24

Amine Catalyzed Pathway

Evans, C. A.; Miller, S. J. J. Am. Chem. Soc.2003, 125, 12394.

slide25

Asymmetric [3 + 2] Cycloaddition

Zhu, G.; Chen, Z.; Jiang, Q.; Xiao, D.; Cao, P.; Zhang, X. J. Am. Chem. Soc.1997, 119, 3836.

slide26

Another Asymmetric [3 + 2] Cycloaddition

Wilson, J. E.; Fu, G. C. Angew. Chem. Int. Ed. 2006, 45, 1426.

slide27

Asymmetric Spirocyclization

Wilson, J. E.; Fu, G. C. Angew. Chem. Int. Ed. 2006, 45, 1426.

slide28

Phosphine-Containing α-Amino Acid

Cowen, B. J.; Miller, S. J. J. Am. Chem. Soc.2007, 129, 10988.

slide29

Deracemization of (±) Allenic Ester

Cowen, B. J.; Miller, S. J. J. Am. Chem. Soc.2007, 129, 10988.

slide30

Phosphine Catalyzed [4 + 2] Annulation

Zhu, X-F.; Lan, J.; Kwon, O. J. Am. Chem. Soc.2003, 125, 4716.

slide31

[4 + 2] Annulation Pathway

Zhu, X-F.; Lan, J.; Kwon, O. J. Am. Chem. Soc.2003, 125, 4716.

slide32

Asymmetric [4 + 2] Annulation

Wurz, R. P.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 12234.

slide33

Asymmetric [4 + 2] Annulation - Applications

Wurz, R. P.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 12234.

slide34

Conclusions

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