What’s Hard About Building Carbon-Carbon Bonds? 

Toward Robust Catalysts for Olefin Metathesis

Deryn E. Fogg

Centre for Catalysis Research & Innovation, and Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, Canada K1N 6N5 andDepartment of Chemistry, University of Bergen, Bergen, Norway

Olefin metathesis is the most versatile catalytic methodology now known for the assembly of carbon-carbon bonds. Long embraced by synthetic chemists in academia, it is now seeing uptake in pharmaceutical manufacturing, with the first processes being implemented in 2014 and 2015 (Figure 1a).¹However, while these methodologies have great potential to reduce the environmental footprint associated with drug synthesis, molecular metathesis catalysts suffer from limited productivity and reliability in operational conditions.^1,2This is a major limitation for adoption in process chemistry. 

To date, little research has focused on systematically uncovering the pathways by which the important ruthenium catalysts deactivate or decompose. We believe that such understanding is key to designing better processes and, ultimately, better catalysts. Recent insights into the mechanism of decomposition of key metathesis catalysts (Figure 1b)³will be described, which reveal key challenges and new opportunities⁴relating to catalyst design, synthesis, and deployment. More broadly, these studies highlight opportunities in an as-yet neglected, but critically important, area of catalysis.

Figure 1.(a) HCV Drugs Manufactured via Ring-Closing Metathesis. (b) Key Metathesis Catalysts.

References. (1) Higman, C. S.; Lummiss, J. A. M.; Fogg, D. E. Angew. Chem., Int. Ed. 2016, 55, 3552. (2) van Lierop, B. J.; Lummiss, J. A. M.; Fogg, D. E. Ring-Closing Metathesis. In Olefin Metathesis-Theory and Practice, Grela, K., Ed. Wiley,  2014; pp 85–152. (3) (a) Bailey, G. A.; Foscato, M.; Higman, C. S.; Day, C. S.; Jensen, V. R.; Fogg, D. E. J. Am. Chem. Soc. 2018, 140, 6931–6944; (b) Bailey, G. A.; Lummiss, J. A. M.; Foscato, M.; Occhipinti, G.; McDonald, R.; Jensen, V. R.; Fogg, D. E., J. Am. Chem. Soc. 2017, 139, 16446. (4) Higman, C. S.; Nascimento, D.; Ireland, B. J.; Audorsch, S.; Bailey, G. A.; Fogg, D. E.  J. Am. Chem. Soc. 2018, 140, 1604−1607.