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

2. Furthermore, the Lewis base should not be consumed or altered during the course of the reaction.” “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. Lewis Basic Organocatalysis Denmark, S. E.; Beutner, G. L. Angew. Chem. Int. Ed. 2008, 47, 1560. 2 n- π * interactions

3. 1,2-addition to carbonyls Michael-type additions Mode of Activation: n- π * Enhances nucleophilic character Masks electrophilic character Denmark, S. E.; Beutner, G. L. Angew. Chem. Int. Ed. 2008, 47, 1560. 3 Enhances electrophilic character

4. Source of Chirality Within groups attached to P P-Chirality Why Use Phosphines as Organocatalysts? Highly Tunable Electronics Sterics Phosphorus Ligands in Asymmetric Catalysis; Börner, A., Ed.; Wiley-VCH: Weinheim,2008 4

5. Barrier to inversion Acyclic phosphines retain chirality at room temp Trigonal pyramidal structure Structure: Amines and Phosphines Kölmel, C.; Ochsenfeld, C.; Ahlrichs, R. Theor. Chim. Acta 1991, 82, 271. Rapid inversion No inversion at room temp Non-bonded lone pair of electrons 5

6. Nucleophilicity vs. Basicity Methot, J. L.; Roush, W. R. Adv. Synth. Catal. 2004, 346, 1035. Pearson, R. G.; Songstad, J. J. Am. Chem. Soc. 1967, 89, 1827. n MeI = log(k Y /k MeOH ) where k Y is the rate of reaction of Y with MeI in methanol at 25 °C 6

7. 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 7 Methot, J. L.; Roush, W. R. Adv. Synth. Catal. 2004, 346, 1035. Pearson, R. G.; Songstad, J. J. Am. Chem. Soc. 1967, 89, 1827.

8. Typical Uses of Phosphines 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. Nucleophile – Wittig Olefination Reducing Agent – Mitsunobu Reaction Ligand – Asymmetric Hydrogenation High yields, ee 8

9. 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 Michael-Type Reactions 9

10. Morita-Baylis-Hillman Reaction Discovery by Morita, 1968 Morita, K.; Suzuki, Z.; Hirose, H. Bull. Chem. Soc. Jpn. 1968, 41, 2815. Proposed Mechanism 10

11. Low yield and ee Long reaction time First Chiral Phosphine MBH Reaction Atmospheric Pressure Hayase, T.; Shibata, T.; Soai, K.; Wakatsuki, Y. Chem. Commun. 1998, 1271. 11

12. Chiral Amine Catalyzed MBH 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. 12 Bifunctional catalyst – improved enantioselectivity High pressures necessary for higher enantioselectivity

13. Bifunctional Phosphine Activated Aza-MBH Shi, M.; Chen, L.-H.; Li, C.-Q. J. Am. Chem. Soc. 2005, 127, 3790. 13 with MS 4Å

14. Modification of Bifunctional Phosphine Shi, M.; Chen, L.-H.; Li, C.-Q. J. Am. Chem. Soc. 2005, 127, 3790. 14 (R)-2,2’ disubstituted 1,1’ binapthyl

15. Proposed Mechanism for the Aza-MBH Shi, M.; Chen, L.-H.; Li, C.-Q. J. Am. Chem. Soc. 2005, 127, 3790. 15

16. 31 P NMR Analysis Shi, M.; Chen, L.-H.; Li, C.-Q. J. Am. Chem. Soc. 2005, 127, 3790. LB1 LB1 with MVK Phosphonium salt A -13.16 ppm +25.30 ppm +26.07 ppm 16

17. 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 Michael-Type Reactions 17

18. 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. 18

19. Catalytic acetic acid and higher temps necessary for esters and amides Isomerization Reactivity Reactivity order: ketone > ester > amide PBu 3 was faster, but considerable oligomerization No reaction was observed with tertiary amines Trost, B. M.; Kazmaier, U. J. Am. Chem. Soc. 1992, 114, 7933. 19

20. Trost, B. M.; Li, C.-J. J. Am. Chem. Soc. 1994, 116, 3167. Phosphine-Catalyzed Umpolung γ -Additions 20

21. Enantioselective γ -Addition to Ynoate Chen, Z.; Zhu, G.; Jiang, Q.; Xiao, D.; Cao, P.; Zhang, X. J. Org. Chem. 1998, 63, 5631. 21

22. Enantioselective γ -Addition to Allenoate Chen, Z.; Zhu, G.; Jiang, Q.; Xiao, D.; Cao, P.; Zhang, X. J. Org. Chem. 1998, 63, 5631. 22

23. Phosphine-Catalyzed [3 + 2] Cycloaddition Zhang, C.; Lu, X. J. Org. Chem. 1995, 60, 2906. 23 No reaction with Et 3 N

24. Amine Catalyzed Pathway Evans, C. A.; Miller, S. J. J. Am. Chem. Soc.2003, 125, 12394. 24

25. Asymmetric [3 + 2] Cycloaddition Zhu, G.; Chen, Z.; Jiang, Q.; Xiao, D.; Cao, P.; Zhang, X. J. Am. Chem. Soc. 1997, 119, 3836. 25

26. Another Asymmetric [3 + 2] Cycloaddition Wilson, J. E.; Fu, G. C. Angew. Chem. Int. Ed. 2006, 45, 1426. 26

27. Asymmetric Spirocyclization Wilson, J. E.; Fu, G. C. Angew. Chem. Int. Ed. 2006, 45, 1426. 27

28. Phosphine-Containing α-Amino Acid Cowen, B. J.; Miller, S. J. J. Am. Chem. Soc.2007, 129, 10988. 28

29. Deracemization of (±) Allenic Ester Cowen, B. J.; Miller, S. J. J. Am. Chem. Soc.2007, 129, 10988. 29

30. Phosphine Catalyzed [4 + 2] Annulation Zhu, X-F.; Lan, J.; Kwon, O. J. Am. Chem. Soc. 2003, 125, 4716. 30

31. [4 + 2] Annulation Pathway Zhu, X-F.; Lan, J.; Kwon, O. J. Am. Chem. Soc. 2003, 125, 4716. 31

32. Asymmetric [4 + 2] Annulation Wurz, R. P.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 12234. 32

33. Asymmetric [4 + 2] Annulation - Applications Wurz, R. P.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 12234. 33

34. Advantages of Phosphine Catalysts – Tunability – Diversity of possible reactions – Source of chirality Limitations – Air sensitive – Long reaction times – High catalyst loadings Conclusions 34

35. Acknowledgements 35 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