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

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

Location

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

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” http://int.ch.liv.ac.uk/Lanthanide/Lanthanides.html Lanthanides: Chemistry and Use in Organic Synthesis; Kobayashi, S., Ed; Springer-Verlag: Berlin, 1999.

Well-Known Examples in Synthesis Luche Reduction Evans-Tischenko Reduction Oxidative PMB Deprotection Luche, J. L. J. Am. Chem. Soc. 1978, 100, 2226. Evans, D. A.; Hoveyda, A. H. J. Am. Chem. Soc. 1990, 112, 6447. Green, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis; John Wiley & Sons: New York, 1999.

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.

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.

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

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.

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.

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.

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.

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

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

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

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.

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.

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.

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.

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.

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.

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.

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

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.

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.

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, 10024.

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.

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.

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

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

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.

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.

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.

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.

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

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

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

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.

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

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.

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