1. Asymmetric Frontiers in Lanthanide Catalysis
Andrew Lohse
Hsung Group
University of Wisconsin – Madison
December 11, 2008

2. Overview Background/Fundamentals Asymmetric Cycloadditions
Multifunctional Asymmetric Catalysts
C-C Bond Formation
C-P Bond Formation
C-O Bond Formation
Conclusions/Future Directions

3. Location

4. The Lanthanide Contraction
Mikami, K.; Terada, M.; Matsuzawa, H. Angew. Chem., Int. Ed. 2002, 41, 3554.

5. Contracted Nature of the f-Orbitals
Shielded by 5s and 5p
Unavailable for bonding
Lack of orbital restrictions
No ligand field effects
Sterically saturated
Ionic character
“Hard” Lewis acids
Oxophilic
“triple-positively charged closed shell inert gas electron cloud”
Lanthanides: Chemistry and Use in Organic Synthesis; Kobayashi, S., Ed; Springer-Verlag: Berlin, 1999.

6. Well-Known Examples in Synthesis
Luche Reduction
Evans-Tischenko Reduction
Oxidative PMB Deprotection
Luche, J. L. J. Am. Chem. Soc. 1978, 100, Evans, D. A.; Hoveyda, A. H. J. Am. Chem. Soc. 1990, 112, Green, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis; John Wiley & Sons: New York, 1999.

7. Why Use Lanthanides as Catalysts?
Variation of Size/Lewis Acidity Tunability
Nature of f orbitals
ionic character
high coordination #s
NMR Analysis
Diamagnetic: La3+, Ce4+, Yb2+, Lu3+
Paramagnetic: Pr3+, Sm2+/3+, Eu3+
Water/Air stable
Recyclable
Crabtree, R. H. The Organometallic Chemistry of the Transition Metals, 4th ed; Wiley Interscience: New York, 2005.
Lanthanides: Chemistry and Use in Organic Synthesis; Kobayashi, S., Ed; Springer-Verlag: Berlin, 1999.

8. Aqueous Aldol Use of ambient temperature Less rigorous conditions
Recyclable
Mukaiyama, T.; Banno, K.; Narasaka, K. J. Am. Chem. Soc. 1974, 96, 7503.
Kobayashi, S. Chem. Lett. 1991, 2187.

9. Historical Perspective
Parker, D. Chem. Rev. 1991, 91, 1441.
Aspinall, H. C. Chemistry of the f-Block Elements; Gordon and Breach: Amsterdam , 2001.

10. Asymmetric Hetero-Diels-Alder
Bednarski, M.; Maring, C.; Danishefsky, S. Tetrahedron Lett. 1983, 24, 3451.
Mikami, K.; Terada, M.; Matsuzawa, H. Angew. Chem., Int. Ed. 2002, 41, 3554.

11. Aza-Diels-Alder
Kobayashi, S.; Ishitani, H., Araki, M.; Hachiya, I. Tetrahedron Lett. 1994, 35, 6325.
Lanthanides: Chemistry and Use in Organic Synthesis; Kobayashi, S., Ed; Springer-Verlag: Berlin, 1999.

12. Proposed Transition State
First catalytic asymmetric
aza-Diels-Alder
Lewis acid activation of diene
Catalyst not poisoned by
nitrogen functionality
Kobayashi, S.; Ishitani, H., Araki, M.; Hachiya, I. Tetrahedron Lett. 1994, 35, 6325.
Lanthanides: Chemistry and Use in Organic Synthesis; Kobayashi, S., Ed; Springer-Verlag: Berlin, 1999.

13. 1,3-Dipolar Cycloaddition
Sanchez-Blanco, A. I.; Gothelf, K. V.; Jørgensen, K. A. Tetrahedron Lett. 1997, 38, 7923.
Kobayashi, S.; Kawamura, M. J. Am. Chem. Soc. 1999, 120, 5840.

14. Overview Historical Perspective Asymmetric Cycloadditions
Multifunctional Asymmetric Catalysts
C-C Bond Formation
C-P Bond Formation
C-O Bond Formation
Conclusions/Future Directions

15. Concept of Multifunctional Catalysis
Shibasaki, M.; Yoshikawa, N. Chem. Rev. 2002, 102, 2187.
Shibasaki, M.; Kanai, M.; Matsunaga, S. Aldrichim. Acta 2006, 39, 31.

16. Preparation of Catalysts
Shibasaki, M.; Yoshikawa, N. Chem. Rev. 2002, 102, 2187.
Shibasaki, M.; Kanai, M.; Matsunaga, S. Aldrichim. Acta 2006, 39, 31.

17. Asymmetric Nitro-Aldol
Shibasaki, M.; Yoshikawa, N. Chem. Rev. 2002, 102, 2187.
Sasai, H.; Suzuki, T.; Itoh, N.; Arai, S.; Arai, T.; Shibasaki, M. J. Am. Chem. Soc. 1992, 114, 4418.

18. Postulated Catalytic Cycle
Shibasaki, M.; Yoshikawa, N. Chem. Rev. 2002, 102, 2187.
Sasai, H.; Suzuki, T.; Itoh, N.; Arai, S.; Arai, T.; Shibasaki, M. J. Am. Chem. Soc. 1992, 114, 4418.

19. Tunability of Ln3+ Ionic Radius
1st systematic study of its kind
Small changes (0.1 Å) cause
drastic differences
Shibasaki, M.; Yoshikawa, N. Chem. Rev. 2002, 102, 2187.
Sasai, H.; Suzuki, T.; Itoh, N.; Arai, S.; Shibasaki, M. Tetrahedron Lett. 1993, 34, 2657.

20. Concept of Direct Aldol Reaction
Shibasaki, M.; Yoshikawa, N. Chem. Rev. 2002, 102, 2187.
Yoshikawa, N.; Yamada, Y. M. A.; Das, J.; Sasai, H.; Shibasaki, M. J. Am. Chem. Soc. 1999, 121, 4168.

21. Direct Aldol Reaction Long reaction times Excess amounts of ketone
High catalyst loading
Shibasaki, M.; Yoshikawa, N. Chem. Rev. 2002, 102, 2187.
Yoshikawa, N.; Yamada, Y. M. A.; Das, J.; Sasai, H.; Shibasaki, M. J. Am. Chem. Soc. 1999, 121, 4168.

22. A Heteropolymetallic Catalyst
KOH formed in situ
Use of (R)-LPB ineffective
Shibasaki, M.; Yoshikawa, N. Chem. Rev. 2002, 102, 2187.
Yoshikawa, N.; Yamada, Y. M. A.; Das, J.; Sasai, H.; Shibasaki, M. J. Am. Chem. Soc. 1999, 121, 4168.

23. Mechanistic Insights kH/kD ~ 5 with d3-acetophenone
Rate independent of aldehyde
Coordination of aldehyde to La3+
confirmed by NMR studies
Shibasaki, M.; Yoshikawa, N. Chem. Rev. 2002, 102, 2187.
Yoshikawa, N.; Yamada, Y. M. A.; Das, J.; Sasai, H.; Shibasaki, M. J. Am. Chem. Soc. 1999, 121, 4168.

24. Application in Total Synthesis
Yoshikawa, N.; Yamada, Y. M. A.; Das, J.; Sasai, H.; Shibasaki, M. J. Am. Chem. Soc. 1999, 121, 4168.

25. Michael Addition of Malonates
Shibasaki, M.; Yoshikawa, N. Chem. Rev. 2002, 102, 2187.
Sasai, H.; Arai, T.; Satow, Y.; Houk, K. N.; Shibasaki, M. J. Am. Chem. Soc. 1995, 117, 6194.

26. Postulated Catalytic Cycle
Sasai, H.; Arai, T.; Satow, Y.; Houk, K. N.; Shibasaki, M. J. Am. Chem. Soc. 1995, 117, 6194.
Lanthanides: Chemistry and Use in Organic Synthesis; Kobayashi, S., Ed; Springer-Verlag: Berlin, 1999.

27. Enantiofacial Control
pro-(R)
Favored
pro-(S)
Disfavored
+ 4.9 kcal/mol
(UFF)
Sasai, H.; Arai, T.; Satow, Y.; Houk, K. N.; Shibasaki, M. J. Am. Chem. Soc. 1995, 117, 6194.
Rappé, A. K.; Casewit, C. J.; Colwell, K. S.; Goddard III, W. A.; Skiff, W. M. J. Am. Chem. Soc. 1995, 114,

28. NMR Studies Why LSB vs. LLB? No coordination with LLB
LSB activates enone and
controls its direction
Size of coordination sphere
Difference in dihedral angles
of BINOL ligands
Sasai, H.; Arai, T.; Satow, Y.; Houk, K. N.; Shibasaki, M. J. Am. Chem. Soc. 1995, 117, 6194.
Shibasaki, M.; Yoshikawa, N. Chem. Rev. 2002, 102, 2187.

29. Tunability of Alkali Metal
Michael Addition
Nitro-Aldol
Sasai, H.; Arai, T.; Satow, Y.; Houk, K. N.; Shibasaki, M. J. Am. Chem. Soc. 1995, 117, 6194.
Shibasaki, M.; Sasai, H.; Arai, T.; Iida, T. Pure & Appl. Chem. 1998, 70, 1027.

30. Improved Catalyst
Kim, Y. S.; Matsunaga, S.; Das, J.; Sekine, A.; Ohshima, T.; Shibasaki, M. J. Am. Chem. Soc. 2000, 122, 6506.

31. Overview Historical Perspective Asymmetric Cycloadditions
Multifunctional Asymmetric Catalysts
C-C Bond Formation
C-P Bond Formation
C-O Bond Formation
Conclusions/Future Directions

32. Hydrophosphonylation of Imines
Sasai, H.; Arai, S.; Tahara, Y.; Shibasaki, M. J. Org. Chem. 1995, 60, 6656.
Shibasaki, M.; Yoshikawa, N. Chem. Rev. 2002, 102, 2187.

33. Hydrophosphonylation of Imines
Gröger, H.; Saida, Y.; Sasai, H.; Yamaguchi, K.; Martens, J.; Shibasaki, M. J. Am. Chem. Soc. 1998, 120, 3089.
Shibasaki, M.; Yoshikawa, N. Chem. Rev. 2002, 102, 2187.

34. Effectiveness of Cyclic Phosphites
Maffei, M.; Buono, G. Tetrahedron 2003, 59, 8821.
Schlemminger, I.; Saida, Y.; Gröger, H.; Maison, W.; Durot, N.; Sasai, H.; Shibasaki, M.; Martens, J. J. Org. Chem. 2000, 65, 4818.

35. Proposed Catalytic Cycle
Gröger, H.; Saida, Y.; Sasai, H.; Yamaguchi, K.; Martens, J.; Shibasaki, M. J. Am. Chem. Soc. 1998, 120, 3089.
Schlemminger, I.; Saida, Y.; Gröger, H.; Maison, W.; Durot, N.; Sasai, H.; Shibasaki, M.; Martens, J. J. Org. Chem. 2000, 65, 4818.

36. Overview Historical Perspective Asymmetric Cycloadditions
Multifunctional Asymmetric Catalysts
C-C Bond Formation
C-P Bond Formation
C-O Bond Formation
Conclusions/Future Directions

37. Epoxidation of Enones
Nemoto, T.; Ohshima, T.; Yamaguchi, K.; Shibasaki, M. J. Am. Chem. Soc. 2001, 123, 2725.

38. Postulated Catalytic Cycle
Nemoto, T.; Ohshima, T.; Yamaguchi, K.; Shibasaki, M. J. Am. Chem. Soc. 2001, 123, 2725.

39. Diversity in Catalysis
Shibasaki, M.; Sasai, H.; Arai, T.; Iida, T. Pure & Appl. Chem. 1998, 70, 1027.
Shibasaki, M.; Yoshikawa, N. Chem. Rev. 2002, 102, 2187.

40. Conclusions Advantages of lanthanide catalysis Limitations
‒ Tunability
‒ Diversity of possible reactions
‒ Water/air stable
‒ Recyclable
Limitations
‒ Long reaction times
‒ High catalyst loading
‒ Aggregation of complexes

41. Future Directions Increase efficiency of catalysts
Application in industry
Broaden the scope of substrates
“These elements perplex us in our researches, baffle us in our speculations, and haunt us in our very dreams. They stretch like an unknown sea before us; mocking, mystifying and murmuring strange revelations and possibilities.”
- Sir William Crookes (1887)
Address to the Royal Society
Aspinall, H. C. Chemistry of the f-Block Elements; Gordon and Breach: Amsterdam , 2001.

42. Acknowledgements Professor Richard Hsung Hsung group members
Practice talk attendees
- John Feltenberger
- Kyle DeKorver
- Brittland DeKorver
- Lauren Carlson
- Jenny Werness
- Aaron Almeida
- Kevin Williamson
- Dr. Yu Zhang
- Dr. Ryuji Hayashi
- Dr. Yu Tang
- Ting Lu
- Gang Li
- Grant Buchanan
- Yonggang Wei
- Hongyan Li
Kat Myhre
Colleen Lohse