Highly Efficient Olefin-Metathesis Catalysts

Olefin metathesis provides an efficient method for the construction of carbon-carbon double bonds. Significant progress in catalyst development and applications has been made during the past 15 years (1–5). One recent advancement in olefin-metathesis catalysts has been reported by the group of Prof. Warren E. Piers with their synthesis of novel 4-coordinate metathesis catalysts possessing an open coordination site trans to the phosphine or the N -heterocyclic carbene ligand (see Figure 1) (6, 7). These novel, 4-coordinate metathesis catalysts directly mimic the active 14-electron olefin-metathesis catalytic species and negate any prior ligand dissociation step that is necessary with the original 5-coordinate Grubbs- and Hoveyda-type catalysts. Piers' catalysts are active at low temperatures, which makes them particularly useful in inhibiting double-bond migrations (8–12). These new catalysts have contributed to the increasing importance of olefin metathesis as highly functional-group tolerant and as a user-friendly synthetic methodology.

Figure 1 (ALL FIGURES ARE COURTESY OF THE AUTHORS.)

Olefin metathesis in pharmaceutical applications

In recent years, olefin metathesis has been increasingly used by the pharmaceutical industry to synthesize biologically active molecules. Notably, K.C. Nicolaou's group described the syntheses of a variety of complex biologically active molecules using olefin metathesis as the key step (5, 13). Merck reported the synthesis of a NK-1 inflammation drug candidate in which double ring-closing metathesis (RCM) was used to build a key spirocyclic intermediate (see Figure 2) (14). Eisai reported the use of both RCM and cross metathesis (CM) in the synthesis of pladienolide (see Figure 3) (15). Eisai showed that cross-metathesis was successful when the traditional Julia–Kocienski coupling failed to produce the desired product

Figure 2 (ALL FIGURES ARE COURTESY OF THE AUTHORS.)

This article describes the latest progress in olefin-metathesis catalyst technology for applications in both the pharmaceutical and fine-chemical industries and highlights the discovery and use of the new 4-coordinate, 14-electron Piers' olefin-metathesis catalysts.

Figure 3 (ALL FIGURES ARE COURTESY OF THE AUTHORS.)

Olefin-metathesis catalysts

During the past 15 years, major progress has been made in advancing ruthenium olefin-metathesis catalysts. The majority of these new metathesis catalysts were based on ligand modification of well-defined and widely employed Grubbs and Hoveyda ruthenium catalysts (see Catalysts 3, 4, 5, Figure 4) (16–18). Most recently, metathesis catalysts (see Catalysts 6 and 7, Figure 5) were developed to address the need for the highly efficient synthesis of hindered olefins, particularly for RCM reactions forming tetrasubstituted cycloalkenes (see Figure 5) (19, 20).

Figure 4 (ALL FIGURES ARE COURTESY OF THE AUTHORS.)

Two recent, excellent examples of olefin metathesis from the Stoltz group demonstrate the usefulness of Catalyst 6 (see Figure 5) for natural-product synthesis. Catalyst 6 was successfully used for a key RCM step in the synthesis of elatol, a natural product from chamigrene, which has broad antimicrobial activity (21). In another recent example, the Stoltz group reported the synthesis of (–)–Cyanthiwigin F where Catalyst 6 completed both a RCM and CM step in the same reaction flask (22).

Figure 5 (ALL FIGURES ARE COURTESY OF THE AUTHORS.)

The metathesis catalysts shown in Figures 4 and 5 are typical 5-coordinate ruthenium olefin-metathesis catalysts. The first step in the metathesis reaction involving these catalysts is the dissociation of the donor ligand trans to the phosphine or the N -heterocyclic carbene ligand , generating the catalytically active 4-coordinate, 14-electron species. This 14-electron species binds an olefin, forms a metallocyclobutane ring, and productively undergoes a cycloreversion to yield the new olefinic product. Efficient dissociation of the donor ligand and olefin binding are key for fast initiation of these catalysts.

Piers' catalysts are another new addition to the ruthenium olefin-metathesis catalyst family. Piers' catalysts adopt a pseudo-tetrahedral geometry and possess an open coordination site trans to the phosphine (see Catalyst 1, Figure 1) or the N -heterocyclic carbene ligand (see Catalyst 2, Figure 1) (6, 7). This open coordination site eliminates the need for any ligand dissociation prior to olefin coordination. As such, olefin binding and activation is anticipated to be more facile with Piers' catalysts.

Catalysts 1 and 2 are highly active for the metathesis of terminal olefins. For example, Catalyst 2a reacts with ethylene at –50 °C (8). Kinetic studies on the initiation of metathesis with o –isopropoxystyrene as a test substrate indicated that the initiation rate of Catalyst 2a (see Figure 1) at –10 °C is similar to the initiation rate of the Grubbs catalyst (see Catalysts 3 and 4, Figure 4) at 35 °C (6). Piers' catalysts offer the additional advantage of running metathesis reactions at lower temperatures when the substrates may be temperature sensitive or to suppress double-bond migration.

Use of Piers' olefin-metathesis catalysts

The Piers' group is developing these novel catalysts and, along with Materia, is exploring their use for a range of industrial applications, including ethenolysis, RCM, CM, self-metathesis, and ring-opening metathesis polymerization (ROMP). In general, Catalysts 1 and 2 (see Figure 1) are more active than the Grubbs catalysts (see Catalysts 3 and 4, Figure 4) for the metathesis of terminal olefins. In addition, Piers' catalysts are very active at low temperatures, and thus, are of interest to those applications where low temperatures are desired. Not too surprising, Catalysts 1 and 2 are somewhat slower for metathesis reactions involving only internal olefins such as the CM of internal olefins, which is likely due to the steric bulk of the cationic PCy₃ alkylidene moiety (23).

The high efficiency of Piers' catalysts for metathesis involving ethylene and other terminal olefins is particularly valuable for the industrially significant ethenolysis and RCM reactions described below.

Reaction 1

Ethenolysis

Ethenolysis involves the CM of ethylene and an internal olefin to generate terminal olefins. The ethenolysis of soybean oil to produce 9-decenoic acid is of significant interest to the chemical industry as an antimicrobial agent and as a monomer for polymer-industry applications (24–26). More recently, reports on the synthesis of additional biologically active molecules involving CM reactions of ethylene with internal olefins have been published as well (27). Given the high reactivity of Piers' catalysts with ethylene, we were interested in exploring their use for the ethenolysis of seed oils. This use is important as natural seed oils represent a renewable source of olefinic raw materials that can provide atom-efficient and environmentally friendly products. The affordability of these olefinic sources, coupled with their worldwide availability and inherent functionality, has already contributed to their use in several areas (24). Olefin metathesis offers new and exciting opportunities for the conversion of these unsaturated seed oils into commodity chemicals that can have wide-ranging applications.

Reaction 2

Ethenolysis can be complicated by secondary metathesis reactions (secondary processes generate undesired internal olefins) and by the self-metathesis of internal olefins. For an ethenolysis of methyl oleate model reaction, see Reaction 1, along with a competing self-metathesis process, see Reaction 2.

Reaction 3

Piers' Catalyst 1b (see Figure 1) demonstrated very good selectivity for the desired ethenolysis products, while Piers' Catalyst 2b (see Figure 1) led to the formation of significant amounts of self-metathesis products, and thus, low ethenolysis selectivity.

Reaction 4

The same trend was observed for Grubbs Catalysts 3 and 4 (see Figure 4) (28). The catalytic performance of Piers' Catalyst 1b and Grubbs Catalyst 3 for the ethenolysis of methyl oleate were compared at 20 °C and 40 °C, using toluene as the solvent and 0.02 mol% catalyst under 150 psi ethylene (see Figure 6). Data points were taken at 2 h (29). As shown in Figure 6, Catalysts 1b and 3 showed similar efficiency at 40 °C. At 20 °C, however, Catalyst 1b is much more active than Catalyst 3.

Figure 6 (ALL FIGURES ARE COURTESY OF THE AUTHORS.)

Ring-closing metathesis

RCM is one of the most used metathesis reactions for the synthesis of biologically active molecules. Studies in the Piers' group and at Materia have shown the advantage of Piers' catalysts. The high efficiency of Piers' Catalyst 2a (see Figure 1) for RCM at low temperature (0 °C) was initially reported by Piers and coworkers (6, 7). Using RCM of diethyl diallymalonate as a model reaction (see Reaction 3), they have shown that Catalyst 2a (see Figure 1) outperformed Catalyst 1a (see Figure 1) as well as the other olefin-metathesis catalysts.

Figure 7 (ALL FIGURES ARE COURTESY OF THE AUTHORS.)

Results from Piers' work are shown in Figure 7 (6). Using 1 mol% catalyst and dichloromethane as the solvent, the reaction reached > 90% conversion within 2 h with Catalyst 2a while it took 4 h for the reaction to reach the same conversion with Catalysts 1a as well as with Schrock's catalyst (see Catalyst 8, Figure 8) (8). As shown in Figure 7, Grubbs Catalyst 4 and Grubbs fast-initiation Catalyst 9, which incorporate more labile 3-bromopyridine ligands, offer much lower conversion under otherwise identical conditions. Piers' catalysts possessing other noncoordinating counteranions (i.e., Catalysts 2b, 2c, 2d) display similar efficiencies under the same conditions (6, 7).

Figure 8 (ALL FIGURES ARE COURTESY OF THE AUTHORS.)

The use of Catalyst 2a for RCM of other substrates was further explored at room temperature by the Piers' group (6). Toluene was used as the solvent and the results from their publication are shown in Table I. These results indicate that Catalyst 2a is highly efficient for the RCM of a range of substrates at room temperature. For the formation of di- and trisubstituted 5-membered and 6-membered cycloalkenes (see Entries 1, 3, 4, Table I), the reaction went to completion in less than 10 min using 1 mol% catalyst loading. Disubstituted cyclopentene can be efficiently synthesized at lower catalyst loading (0.1 mol%, see Entry 2, Table I). For the formation of the more hindered trisubstituted cyclohexene (see Entry 5, Table I), the reaction went to completion within 1 h with 1 mol% catalyst loading. A higher catalyst loading (5 mol%) was used to drive the reaction to a high conversion for the formation of challenging 7-membered cycloalkene (see Entry 6, Table I), with the reaction reaching 85% conversion in less than 10 min.

Table I

Building upon Piers' initial results, the authors explored the use of the Piers' Catalyst 2b for the RCM of heteroatom containing substrates. N -Boc-diallyamine was selected as the model substrate, and RCM experiments were conducted at 30 °C and 50 °C with the use of only 0.05 mol% catalyst loading (see Reaction 4). Multiple solvents were screened. Toluene and methyl t -butyl ether (MTBE) were found to be the best for this reaction ( N -Boc-diallyamine concentration was 1M, and reaction time was 8 h). The results for Catalyst 2b are compared with the standard olefin-metathesis catalysts (see Catalysts 4 and 5, Figure 9).

Figure 9 (ALL FIGURES ARE COURTESY OF THE AUTHORS.)

Catalyst 2b gave complete conversion in both toluene and MTBE at 30 °C, while ~90% conversions were produced at 50 °C in both solvents. Catalyst 5 reached complete conversion at 50 °C in toluene, but ~90% conversion under the other reaction conditions. Catalyst 4 performed poorly under these conditions, yielding < 50% conversion under all conditions tested.

Catalyst 2b was efficient at 30 °C due to its fast initiation and stability at this temperature. The lower yields at 50 °C are presumably due to catalyst degradation. Catalyst 5 performed well at 50 °C in toluene but was less efficient in MTBE and in both solvents at 30 °C. The poor performance of Catalyst 4 was attributed to its slow initiation under these conditions.

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, rpederson@materia-inc.com

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).

7. S.R. Dubberley et al., "Synthesis, Characterization and Olefin Metathesis Studies of a Family of Ruthenium Phosphonium Alkylidene Complexes," Inorg. Chim. Acta. 359 (9), 2658–2664 (2006).

8. P.E. Romero and W.E. Piers, "Direct Observation of a 14-Electron Ruthenacyclobutane Relevant to Olefin Metathesis," J. Am. Chem. Soc. 127 (14), 5032–5033 (2005).

9. C. W. Lee et al., "Impurity Reduction in Olefin Metathesis Reactions," US Patent Application US2005/0203324 A1 (Priority Date Aug. 23, 2004, released Sept. 15, 2005).

10. B.P. Paulson and R.L. Pederson, "Impurity Inhibition in Olefin-Metathesis Reactions," US Patent 6,900,347, issued May 31, 2005.

11. R.L. Pederson and B. P. Paulson, "Impurity Inhibition in Olefin-Metathesis Reactions," WO 02094748, A1 Priority Date May 24, 2001.

12. R.L. Pederson et al., "Applications of Olefin Cross Metathesis to Commercial Products," Adv. Synth. Catal. 344 (6–7), 728–735 (2002).

13. K.C. Nicolaou, A. Ortiz, and R.M. Denton, "Metathesis Reaction in the Synthesis of Complex Molecules," Chem. Today 25 (5), 70–76 (2007).

14. D.J. Wallace et al., "A Double Ring Closing Metathesis Reaction in the Rapid, Enantioselective Synthesis of NK-1 Receptor Antagonists," Org. Lett. 3 (5), 671–674 (2001).

15. R.M. Kanada et al., "Total Synthesis of the Potent Antitumor macrolides Pladienolide B and D," Angew. Chem., Int. Ed. 46 (23), 4350–4355 (2007).

16. P. Schwab, R.H. Grubbs, and J.W. Ziller, "Synthesis and Applications of RuCl₂ (=CHR')(PR₃)₂: The Influence of the Alkylidene Moiety on Metathesis Activity," J. Am. Chem. Soc. 118 (1), 100–110 (1996).

17. M. Scholl, S. Ding, C.W. Lee, and R.H. Grubbs, "Synthesis and Activity of a New Generation of Ruthenium-Based Olefin Metathesis Catalysts Coordinated with 1,3-Dimesityl-4,5-dihydroimidazole-2-ylidene Ligands," Org. Lett. 1 (6), 953–956 (1999).

18. S.B. Garber et al., "Efficient and Recyclable Monomeric and Dendritic Ru-Based Metathesis Catalysts," J. Am. Chem. Soc. 122 (34), 8168–8179 (2000).

19. I.C. Stewart et al., "Highly Efficient Ruthenium Catalysts for the Formation of Tetrasubstituted Olefins via Ring-Closing Metathesis," Org. Lett. 9 (8), 1589–1592 (2007).

20. C.K. Chung and R.H. Grubbs, "Olefin Metathesis Catalyst: Stabilization Effect of Backbone Substitutions of N -Heterocyclic Carbene," Org. Lett. 10 (13), 2693–2692 (2008).

21. D.E. White et al., "The Catalytic Asymmetric Total Synthesis of Elatol," J. Am. Chem. Soc. 130 (3), 810–811 (2008).

22. J.A. Enquist, Jr. and B.M. Stoltz "The Total Synthesis of (-)-Cyanthiwigin F by Means of Double Catalytic Enantioselective Alkylation," Nature 453, 1228–1231 (2008).

23. The Cross-metathesis of 5-decene and 1,10-diacetoxy-5-decene with Catalyst 2b is Slightly Slower than that with the 2nd Generation Grubbs Catalyst 2. Materia (Pasadena, CA), unpublished results.

24. Y. Schrodi et al., "Ruthenium Olefin Metathesis Catalysts for the Ethenolysis of Renewable Feedstocks," Clean—Soil, Air, Water, 36 (8) 619-673 (2008), in press.

25. K.A. Burdett et al., "Renewable Monomer Feedstocks via Olefin Metathesis: Fundamental Mechnistic Studies of Methyl Oleate Ethenolysis with the First-generation Grubbs Catalyst," Organometallics 23 (9), 2027–2047 (2004).

26. Corma, S. Iborra and A. Velty, "Chemical Routes for the Transformation of Biomass into chemicals," Chem. Rev. 107 (6), 2411–2502 (2007).

27. G. Chen et al., "Efficient Synthesis of a-C-galactosyl Ceramide Immunostimulants: Use of Ethylene-Promoted Olefin Cross-Metathesis," Org. Lett. 6 (22), 4077–4080 (2004).

28. D.R. Anderson et al., "Kinetic Selectivity of Olefin Metathesis Catalysts Bearing Cyclic (Alkyl)(Amino) Carbenes," Organometallics 27 (4), 563–566 (2008).

29. Materia, "Results: Yield (GC%) = sum of the percentages of metathesis products as determined by gas chromatography using FID detection (Materia, Pasadena, CA, 2008).

30. E.F. van del Eide, P.E. Romero, and W.E. Piers, "Generation and Spectroscopic Characterization of Ruthenacyclobutane and Ruthenium Olefin Carbene Intermediates Relevant to Ring-Closing Metathesis Catalysis," J. Am. Chem. Soc. 130 (13), 4485–4491 (2008).