Highly Efficient Olefin-Metathesis Catalysts - Pharmaceutical Technology

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Highly Efficient Olefin-Metathesis Catalysts
The authors describe the Piers' catalysts and detail latest progress in olefin-metathesis catalyst technology.


Pharmaceutical Technology


When comparing Catalysts 4 and 5 under the same reaction conditions and in the presence of terminal olefins, the authors observed that Catalyst 5 initiates faster and has a faster reaction rate but has a poorer lifetime (Catalyst 5 is often inactivated within 1 h) compared with Catalyst 4. Conversely, Catalyst 4 initiates slower and has a slower reaction rate but has a much better lifetime (Catalyst 4 is active up to 8 h). It is presumed that Catalyst 5 cannot stabilize the methylidene, as a 4-coordinate complex, which leads to catalyst degradation. Catalyst 4 can stabilize the methylidene by having the PCy3 ligand bind to the ruthenium center, thereby forming a stable 5-coordinate complex, which can then dissociate the PCy3 ligand, allowing the methylidene to re-enter a productive metathesis cycle. Research is underway to understand why Catalyst 2b is more efficient at lower temperatures compared with Catalyst 5.

Conclusion

Newly developed Piers' catalysts (see Catalysts 1 and 2, Figure 1) have been shown to be highly efficient for several olefinmetathesis processes, including ethenolysis and RCM. The high proficiency of these catalysts is attributed to the unique 4-coordinate structure, which allows for more facile catalyst initiation compared with the 5-coordinate Grubbs and Hoveyda-type catalysts. The high activity of Piers' catalysts observed even at low temperature makes them ideal candidates for applications where low temperatures are desirable. Investigations into the scope of these catalysts, along with the recently reported catalysts containing a less sterically encumbered phosphonium alkylidene for more diversified substrates and processes is ongoing at Materia (30). It is also anticipated that new catalysts derived from ligand modification of Catalysts 1 and 2 may offer improved efficiency and broader substrate scope in pharmaceutical applications. Particularly, the development of chiral Piers-type catalysts may offer opportunities for improved enantioselectivities in asymmetric olefin-metathesis processes due to the low temperature efficacy of these catalysts.

Acknowledgments

The authors would like to thank Warren E. Piers (University of Calgary, Canada) for allowing us to use results from his publications. The authors would also like to thank Tim Champagne, PhD (Materia), Kevin Kuhn (California Institute of Technology), and Andy Nickel, PhD (Materia) for reviewing this manuscript and for their helpful discussions.

Xiaohong Bei, PhD, is a senior research chemist, Daryl P. Allen, PhD, is a research chemist, and Richard L. Pederson, PhD,* is director of fine chemicals R&D, all at Materia, Inc., 60 N. San Gabriel Blvd., Pasadena, CA 91107, tel. 626.584.8400, fax 626.584.1984,

To whom all correspondence should be addressed.

References

1. Handbook of Metathesis, R.H. Grubbs, Ed., Vol. 1–3 (Wiley-VCH: Weinheim, Germany, 2003).

2. A.H. Hoveyda and A.R. Zhugralin, "The Remarkable Metal-Catalyzed Olefin Metathesis Reaction," Nature 450, 243–251 (2007).

3. Y. Schrodi, and R.L. Pederson, "Evolution and Applications of Second-Generation Ruthenium Olefin Metathesis Catalysts," Aldrichimica Acta 40 (2), 45–52 (2007).

4. R.H. Grubbs, "Olefin Metathesis," Tetrahedron 60 (34), 7117–7140 (2004).

5. K.C. Nicolaou, P.G. Bulger, and D. Sarlah, "Metathesis Reactions in Total Synthesis," Angew. Chem., Int. Ed. 44 (29), 4490–4527 (2005).

6. P.E. Romero, W.E. Piers, and R. McDonald, "Rapidly Initiating Ruthenium Olefin-Metathesis Catalysts" Angew. Chem., Int. Ed. 43 (45), 6161—6165 (2004).


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