Highlights of the Recent U.S. Patent Literature: Focus on Metathesis

Highlights from the Patents pubs.acs.org/OPRD

Highlights of the Recent U.S. Patent Literature: Focus on Metathesis and increased competition from catalyst suppliers that should lead to more favorable terms for the end user. As noted above, 149 patents and patent applications published in 2015, with another 42 during 1Q2016. This review will focus on the subset of patents and applications published within the past year regarding new catalyst structures, cross-metathesis for conversion of seed-based oils to high value products, and catalysts to promote Z-selectivity for cross metathesis. Since patent applications publish 18 months after filing, and the priority date is set at the time of filing, many researchers publish their work in journals shortly after a patent application is filed and well before the patent application is published. Thus, to those active in the field, publication of many patent applications is old news. On the other hand, publication of granted patents is noteworthy since the final patent claims define the scope of the IP for the assignee. The limited scope of the claims in many early metathesis catalyst patents has allowed competitors to make minor changes to patented catalysts, such as changing a single substituent, that fall outside of the original patent claims and allow new IP to be established.

ABSTRACT: Metathesis catalysts and applications of the metathesis reaction have been an area of active patenting over the past 25 years. Industrial use of metathesis is wellestablished in the polymer and commodity chemical industries but only recently have improvements in catalyst activity, robustness, and functional group tolerability allowed expansion to the fine chemical and pharmaceutical industry. This article reviews metathesis patents and patent applications published within the past year focused on newly patented catalyst structures, use of metathesis for conversion of seed oils to high value products, and catalysts that are Z-selective in cross metathesis reactions.

T

he metathesis reaction has generated high intellectual property activity over the past 25 years, likely more so than any other organic reaction. Patent applications and granted patents in the US totaled 149 in 2015, an annual rate that has nearly doubled in the past decade (Figure 1). The

1. BRIEF BACKGROUND Although the metathesis reaction was first reported in 1955,3 Schrock’s group at MIT designed and developed the first truly viable metathesis catalyst 1 for ROMP and ring-closing metathesis (RCM) reactions, published in 1988 and 1990,4 and ushered in the era of modern metathesis chemistry (Figure 2). While highly reactive, the Schrock catalyst had poor functional group tolerance, was thermally unstable, and was highly sensitive to air, water, and impurities. Grubbs’ Ru-based catalysts followed shortly thereafter, with improved functional group tolerance and reduced sensitivity to oxygen and water, making these catalysts useful for organic synthesis and polymerization applications.5 The first generation Grubbs catalyst 2 featured two electron-rich tricyclohexyl phosphine ligands. The second generation Grubbs catalyst 3 introduced an NHC (N-heterocyclic carbene) ligand which increased metathesis activity. This ligand, a strong σ-donor and poor πacceptor, is theorized to stabilize a 14-electron Ru intermediate in the catalytic cycle, leading to increased catalytic activity. Nearly all of the Ru-based catalysts developed subsequently feature an NHC ligand. Hoveyda and his group followed with catalyst 4 having a tethered i-PrO electron-donating group that decreased the initiation period.6

Figure 1. U.S. issued patents and patent applications on the metathesis reaction over the past decade.

active patenting reflects the widespread and diverse industrial use of the reaction, including traditional use in the petroleumbased commodity chemical and polymer industry, and the emerging use in specialty chemicals derived from renewable oils and applications in organic synthesis. A number of commercial polymer products are manufactured using ring-opening metathesis polymerization (ROMP), including those derived from cyclootene (Vestenamer), norbornene (Norsorex), and dicyclopentadiene (Telene, Metton, Prometa, Pentam).1 The uptake of metathesis in the pharmaceutical and fine chemical industry has been slow, as chronicled in a recent review by Fogg,2 due to technical obstacles, such as stability, high dilution, and functional group incompatibility, as well as the complexities of navigating IP issues. The primary use of the metathesis reaction in the process pharmaceutical industry has been to construct macrocycles in the preparation of HCV protease inhibitors. Fogg predicts application of the metathesis reaction will become more widespread in the pharma and fine chemical industries, given the improvements in catalyst design © XXXX American Chemical Society

2. ADVANCES IN METATHESIS CATALYSTS Metathesis catalysts that have published recently in the U.S. patent literature are presented in Table 1. Many patents include several structures so only representative structures or the “best” catalyst are included in the table. The series of Apeiron catalysts 10 (Table 1, entry 3) feature a less sterically hindered NHC ligand with bis (o-tolyl) flanking

A

DOI: 10.1021/acs.oprd.6b00167 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

Highlights from the Patents

be carried out in an oxygen atmosphere and that the catalyst was stable up to 150 °C, providing additional flexibility for a range of applications. 2. Catalyst series 14 with ligation via bromine or iodine are described by Umicore (Table 1, entry 7).13 The activity of these catalysts is highly sensitive to temperature. Of the many reactions reported, two of note include the ene-yne metathesis of a hindered substrate that provides a higher conversion than catalysts reported in the literature and a cross metathesis of an ester with a thioester (Scheme 3). 3. Diphenylalkylamino-based catalysts 13 (Table 1, entry 6)12 rapidly initiate and have turnover numbers up to 58 000 and turnover frequencies up to 232 000 h−1. 4. N-Ligation with pyridines, imines, and anilines are reported in a Materia patent with inventors from the Grubbs group.11 The latency of the catalysts can be tuned by the nature of the nitrogen chelating group. The pyridines (cis- and trans12) offer increased latency which is useful for ROMP. 5. Sulfur-ligated catalysts 16 are prepared by an IP-free route.15 These compounds are modest catalysts for RCM, but activity can be improved with BCl3 cocatalysis. The catalysts are primarily useful for depolymerization of rubber.

3. CROSS-METATHESIS. APPLICATIONS WITH BIOBASED OILS Triglycerides of oleic acid and linoleic acid are present in high concentrations in many vegetable oils such as those derived soybean, sunflower, and corn. Triglycerides from soybean oil, for example, contain about 50% oleate and 24% linoleate. The conversion of renewable and low cost seed oils into high value olefins via metathesis has been a long-standing research objective, but only recently has commercial viability been achieved with improved catalyst activity and turnovers.19 The goals of an industrial metathesis of triglycerides include the following: 1. Low catalyst loading; 2. High selectivity for the cross-metathesis vs self-metathesis products; 3. No need to isomerize the internal olefin (Z- to E-isomer) prior to metathesis; 4. Ability to handle unprocessed oils as mixtures of triglycerides. For the cross metathesis of pure methyl oleate with ethylene (termed ethenolysis) to afford methyl 9-decenoate and 1decene (Scheme 4), the first generation Grubbs catalysts 2 are selective for the cross-metathesis product, but high catalyst loadings are required due to catalyst decomposition. The Hoveyda-Grubbs catalyst 4 is active but affords low selectivity for the cross-metathesis products, with about double the amount of self-metathesis products relative to the desired crossmetathesis products using 150 psi ethylene. Three recently published patents and patent applications (Table 2) provide details on improved catalysts for methyl oleate ethenolysis. Metathesis catalysts series 18, featuring novel cyclic alkyl amino carbene (CAAC) ligands designed by the Grubbs’ laboratory (Table 2, entry 1), have exceptional activity, with reactivity at levels down to 3 ppm with turnover numbers >100 000.20 In the best case, selectivity for crossmetathesis of methyl oleate of >90% can be achieved at conversions of 50−60%. The Materia patent (Table 2, entry 2)21 claims a single catalyst structure, the second generation Pier’s catalyst 19,22 for

Figure 2. Representative metathesis catalysts.

groups.9 These catalysts are effective for the preparation of tetra-substituted olefins by RCM (Scheme 1). While examples of tetra-substituted olefins have been reported,17,18 the Apeiron catalysts are more stable and can be used at lower loadings. Despite increased stability, these catalysts have unexpectedly rapid initiation rates. St. Andrews has been granted a patent for catalysts that use phosphite ligands to replace the phosphine ligands prevalent in the Grubbs-type catalysts, taking advantage of the increased πacidity of the phosphite group (Table 1, entry 8).14 These catalysts tend to be more stable and are equal to, or more active, than the traditional Grubbs catalysts over a wide range of substrates. The trans-isomer 15 is far more active than the cisisomer, with catalysis occurring at room temperature while temperatures of 80 °C are required for the cis-isomer. Tetracoordinate molybdenum alkylidenes 1 developed by Schrock are highly active catalysts but are very sensitive to air and water. Fürstner and co-workers have been awarded a patent for precatalyst series 17A (Table 1, entry 10) in which Schrock alkylidenes are stabilized by coordination with bipyridine or 1,10-phenanthroline, allowing use of the catalysts outside of a glovebox.16 The active catalysts can be generated by decomplexation with zinc chloride (Scheme 2). Several recent metathesis catalysts feature ligation via nitrogen, oxygen, halogen, and sulfur groups appended to the alkylidene moiety. This ligation modifies catalyst properties, such as improving stability and activity, reducing or accentuating latency, and increasing sensitivity to temperature or additives. 1. Catalyst 11 (Table 1, entry 4)10 features bis-ligation via an ester and imine contained within the same molecule. The latency (time to initiate reaction) of this catalyst can be reversibly tuned using either heat or external additives such as HCl and TMS-Cl, providing flexibility depending on need. For ROMP, latency is a beneficial attribute of a catalyst, while in many organic synthetic applications, latency is undesirable. The authors also demonstrated ROMP of dicyclopentadience could B




Table 1. Catalyst Structures Recently Published in the Patent Literature

Scheme 1. Synthesis of Tetra-Substituted Olefins with Apeiron Catalyst 10

Scheme 3. Metathesis Reactions Catalyzed by Umicore Halogen-Chelating Catalysts 14

Scheme 2. Activation of Nitrogen-Ligated Precatalysts with ZnCl2 ethenolysis. With a catalyst level of 100 ppm, selectivity’s of 59−66% can be achieved at conversions of 71−77% with turnover numbers of 4200−5200. Catalyst 20, the sole structure claimed in the Elevance patent (Table 2, entry 3) only affords 34% selectivity for the cross-metathesis product and thus is not an improvement over the Hoveyda-Grubbs catalyst 4.23 While conversion of pure methyl oleate to cross-metathesized products at low catalyst loadings is notable, a greater challenge to support commercial application is the ability to C




Scheme 4. Ethenolysis of Methyl Oleate

Scheme 5. Cross-Metathesis of Soybean Oil with 1-Propene

Table 2. U.S. Patents and Applications for Ethenolysis of Methyl Oleate

The products from soybean oil metathesis can be further cross-metathesized to generate high value products. Elevance patents describe cross-metathesis of mixtures of methyl 9decenoate and methyl 9-dodecanoate to generate a C18 ester that is useful in preparing surfactants (Scheme 6).24 XiMo patent application ‘396 reports homodimerization of methyl 9decenoate to prepare the same C18 diester using catalyst 21 at a loading of 50 ppm.25 Scheme 6. C18 Diester via Cross-Metathesis directly use unprocessed biobased oils. Two Elevance patents describe cross-metathesis of soybean oil with 1-propene to afford mixtures of methyl 9-decenoate and methyl 9undecanoate with low levels of the self-metathesized products (Scheme 5).24 The ruthenium metal is removed by treatment of the reaction mixture with 50 equiv (vs catalyst) of tris(hydroxymethyl)phosphine (THMP) for 20 h at 60 °C. After extraction with water to remove the ruthenium residues, the organic layer is dried and filtered through a bed of silica gel to recover product.24 In a wide ranging patent application from XiMo AG that includes 291 molybdenum and tungsten catalyst structures, 27 catalysts were screened for ethenolysis of purified triglycerides.25 The triglycerides were pretreated with trialkylaluminum to remove catalysts poisons such as water and peroxides, then reacted with ethylene at 10 bar for 18 h at 50 °C. While details on product distribution are not provided, conversions >90% could be achieved with tungsten catalysts 21, 22, and 23 at loadings of 1000 ppm. In January, 2016, Elevance reported they were using XiMo catalysts for ethenolyis of biobased oil at the Soneas manufacturing facility in Budapest.26

Arkema has filed a number of patent applications regarding downstream reactions of methyl 9-decenoate. Cross-metathesis with acrylonitrile affords the nitrile-ester with nearly 100% selectivity versus the self-metathesis product (Scheme 7).27 The optimized process involves initial metathesis with the Umicore catalyst 24 followed by Grubbs-Hoveyda catalyst 4. The process can be run in continuous mode with feed of both reactants and catalyst 24.28 Finally, conversion to the amino acid is accomplished by hydrolysis followed by hydrogenation of the nitrile with ruthenium on silicon carbide using a solvent mixture of 50/50 n-PrOH/20% aq. ammonia, 40 bar hydrogen, 110 °C, and 2 h reaction time. Use of this hydrogenation catalyst and reaction conditions affords the primary amine with D




formation. These catalysts are substantially more active than the previous series. Catalyst 28 promotes homometathesis of terminal olefins at room temperature at 0.2% loading, including 1-octene, 1-decene, allylbenzene, and allylboronic acid pinacolato ester, affording the internal Z-olefin product with yields up to 88% and undetectable E-isomer by NMR analysis. Reaction of methyl 10-undecenoate required 1% catalyst loading to achieve 59% conversion in 24 h, which the authors attributed to coordination of the ester to tungsten. The bulky allyltrimethylsilane substrate was sluggish, with 11% conversion in 24 h with 0.2% catalyst loading, due to increased steric congestion. Running the reactions under vacuum to remove ethylene provided no advantage. Catalyst 27 was reported as far less active than phosphine-ligated catalyst 28. Ring-closing metathesis of large rings to afford predominately the Z-isomer is the focus of patent 801 and application 308.34 A number of the early catalysts developed for Z-selectivity for cross-metathesis provide reasonable selectivity for many macrocyclic ring closures, but the newly developed catalyst 29 is able to catalyze RCM to generate a trisubstituted olefin (Scheme 8), an intermediate in the total synthesis of epothilone D. The screening reactions were carried out on a 4 mg scale in benzene at 22 °C for 24 h with 20 mol % catalyst which was generated in situ from the corresponding bis-pyrrolide. A scale up to 210 mg using 7.5 mol % catalyst afforded 77% conversion and an isolated yield of 73%. XiMo catalysts 22 and 23 afford predominately the Z-isomer in the homometathesis reaction of allylbenzene (Z:E 87:13 to 91:9).25 When allylbenzene is pretreated with activated alumina or trioctylaluminum to remove peroxides and residual water, conversions of >90% can be achieved with catalyst loadings of 50 ppm. Two patent applications originating from the Grubbs’ group for Z-selective ruthenium complexes, represented by catalysts 30 and 31, have recently published.35,36 The highly active catalyst 31 affords Z-selectivity of >95% with TON up to 7400 for the homodimerization of terminal olefins having ester and alcohol functionalities. A key breakthrough in the preparation of catalyst 31 was the finding that sodium pivalate was suitable for C−H activation of the adamantyl moiety for the conversion of the dichloride 32 to the pivalate intermediate 33, which could then be ion-exchanged to the more active nitrato analog (Scheme 9). Silver pivalate, which was used successfully in the preparation of 30, caused decomposition with the bulkier 31, but it turns out silver was not necessary to achieve C−H activation. The Cal Tech patent36a also describes preparation of chiralat-Ru complexes via chromatographic separation of diastereomeric intermediate 35 (>95:5 dr), prepared from reaction of racemic iodide 34 with (S)-α-methoxyphenylacetic acid, followed by conversion to the enantiomerically enriched nitrato analogue 30* (Scheme 10). In the asymmetric ring-opening/cross metathesis (AROCM) reaction of cyclobutene 36 catalyzed by 30*, the Z-isomer 37 was formed in up to 79% yield with a Z:E ratio of 85:15 and 95% ee for the Z-product (Scheme 11). In a patent awarded to Bergen Teknologioverforing AS, use of an arylthiolate ligand coupled with isocyanate or thioisocyanate ligands provided catalyst series 38 that were Zselective in homometathesis reactions of terminal olefins.37 These catalysts are reported to have much greater stability than typical Ru catalysts. Reactions under challenging conditions, including air atmosphere, high water content, presence of acids

Scheme 7. Cross Metathesis with Acrylonitrile and Conversion to 11-Aminoundecanoic Acid

90% Z-isomer using a catalyst loading of 4%. Patent ‘595 claims tungsten oxo alkylidene catalysts 27 and 28, among others, where a small oxo group replaces the bulky N-adamantyl group in the original catalyst 25.33a Patent application 2016/0009746 claims use of these catalysts in metathesis reactions.33c The oxo group is thought to offer a less congested pocket for the developing cis-isomer, while the very large phenol blocks formation of the trans-isomer, leading to improved Z-selectivity. In addition, use of tungsten instead of molybdenum minimizes Z- to E-isomerization after product E




Table 3. Catalyst Structures for Z-Selective Cross Metathesis Reactions from Recent U.S. Patent Literature

Scheme 8. Z-Selective Ring-Closing Metathesis of a Macrocycle

Scheme 9. Preparation of Z-Selective Nitrato Catalyst 31

F




closing metathesis; HCV, hepatitis C virus; Ad, adamantyl; TON, turnover number; AROCM, asymmetric ring-opening/ cross metathesis

Scheme 10. Preparation of Homochiral 30*

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(1) (a) Mol, J. C. J. Mol. Catal. A: Chem. 2004, 213, 39−45. (b) http:// allthingsm etathe sis.com/ring-opening-metathesispolymerization/. (2) Higman, C. S.; Lummiss, J. A. M.; Fogg, D. E. Angew. Chem., Int. Ed. 2016, 55, 3552−3565. (3) Anderson, A. W.; Merckling, M. G. Chem. Abstr. 1955, 50, 3008i. (4) (a) Schrock, R. R.; DePue, R. T.; Feldman, J.; Schaverien, C. J.; Dewan, J. C.; Liu, A. H. J. Am. Chem. Soc. 1988, 110, 1423. (b) Schrock, R. R.; Murdzek, J. S.; Bazan, G. C.; Robbins, J.; DiMare, M.; O’Regan, M. J. Am. Chem. Soc. 1990, 112, 3875. (c) Schrock, R. R. Chem. Rev. 2002, 102, 145. (5) For an excellent review of Grubbs metathesis catalyst development to 2007, see: Schrodi, Y.; Pederson, R. L. Aldrichimica Acta 2007, 40, 45−51. (6) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2000, 122, 8168−8179. (7) (a) Nolan, S. P.; Huang, J. Catalyst Complex with Carbene Ligand, U.S. Patent 9,233,365 B2, January 12, 2016. (b) Huang, J.; Stevens, E. D.; Nolan, S. P.; Petersen, J. L. J. Am. Chem. Soc. 1999, 121, 2674−2678. (c) Huang, J.; Schanz, H.-J.; Stevens, E. D.; Nolan, S. P. Organometallics 1999, 18, 5375−5380. (8) (a) Verpoort, F. W. C.; Yu, B. Catalyst Complexes with Carbene Ligand and Method for Making Same and Use in Metathesis Reaction. U.S. Patent Application 2015/0367338 A1, December 24, 2015. (b) Yu, B.; Luo, Z.; Hamad, F. B.; Leus, K.; van Hecke, K.; Verpoort, F. Catal. Sci. Technol. 2016, 6, 2092−2100. (c) Yu, B.; Xie, Y.; Hamad, F. B.; Leus, K.; Lyapkov, A. A.; van Hecke, K.; Verpoort, F. New J. Chem. 2015, 39, 1858−1867. (9) (a) Grela, K.; Torborg, C.; Szczepaniak, G.; Zieliński, A. Metal Complexes, Especially the Ruthenium Complexes, and Use Thereof. U.S. Patent 9,221,042 B2, December 29, 2015. (b) Torborg, C.; Szczepaniak, G.; Zieliński, A.; Malińska, M.; Woźniak, K.; Grela, K. Chem. Commun. 2013, 49, 3188−3190. (10) Grela, K.; Czarnecki, S. Novel Ruthenium Complexes, Methods of Their Production and Their Usage. U.S. Patent Application 2015/ 0329576, November 19, 2015. (11) (a) Ung, T.; Schrodi, Y.; Trimmer, M. S.; Hejl, A.; Sanders, D.; Grubbs, R. H. Latent, High-Activity Olefin Metathesis Catalysts Containing an N-Heterocyclic Ligand. U.S. Patent 9,238,709 B2, January 19, 2016. (b) Ung, T.; Hejl, A.; Grubbs, R. H.; Schrodi, Y. Organometallics 2004, 23, 5399−5401. (12) (a) Plenio, H.; Peeck, L. Ruthenium-Based Metathesis Catalysts and Precursors for Preparation. U.S. Patent 9,108,996 B2, August 18, 2015. (b) Peeck, L. H.; Savka, R. D.; Plenio, H. Chem. - Eur. J. 2012, 18, 12845−12853. (13) (a) Grela, K.; Barbasiewicz, M.; Michalak, M. Complexes of Ruthenium, Methods for Their Preparation, and Their Application in Olefin Metathesis Reactions. U.S. Patent 9,074,028 B2, July 7, 2015. (b) Barbasiewicz, M.; Michalak, M.; Grela, K. Chem. - Eur. J. 2012, 18, 14237−14241. (14) (a) Cazin, C. Ruthenium Complexes for Use in Olefin Metathesis. U.S. Patent 9,223,994 B2, January 12, 2016. (b) Bantreil, X.; Cazin, C. S. J. Monatsh. Chem. 2015, 146, 1043−1052. (15) (a) Stepan, D. W.; Lund, C.; Sgro, M.; Dahcheh, F.; Ong, C. Ruthenium-Based Complexes, Their Preparation and Use as Catalysts, U.S. Patent Application 2016/0090396 A1. March 31, 2016. (b) Dahcheh, F.; Stephan, D. W. Dalton Trans. 2015, 44, 1724−1733. (16) (a) Heppenkausen, J.; Furstner, A. Molybdenum and Tungsten Metal Complexes and Use Thereof as Precatalysts for Olefin Metathesis. U.S. Patent 9,233,362 B2, January 12, 2016. (b) Heppekausen, J.; Furstner, A. Angew. Chem., Int. Ed. 2011, 50, 7829−7832. (17) Stewart, I. C.; Ung, T.; Pletnev, A. A.; Berlin, J. M.; Grubbs, R. H. Org. Lett. 2007, 9, 1589−1592.

Scheme 11. AROCM Reaction Using 30*

and bases, in ethereal solvents, and at high concentrations, afforded measurable amounts of products although yields were generally quite low under the harsh conditions.

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SUMMARY While the era of modern metathesis chemistry began some 25 years ago, the field is far from reaching maturity as evidenced by the steady growth in the number of granted patents and filed patent applications. Continued advancements in metathesis catalyst design and development are leading to increasing scope for the metathesis reaction, offering expanded commercial opportunities. Metathesis of renewable biobased oils afford unique olefin products that are in turn being converted to products for use in detergents, polymers, lubricants, and other specialty applications. While most of the commercially available metathesis catalysts are covered by active patents, the large number of catalysts that are available from an increasing number of suppliers, is making the terms of use of these catalysts more favorable and will no doubt lead to even wider use of metathesis chemistry within the fine chemical and pharmaceutical industries. David L. Hughes* Cidara Therapeutics, Inc., 6310 Nancy Ridge Drive, Suite 101, San Diego, California 92121, United States

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REFERENCES

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected].

ABBREVIATIONS IP, intellectual property; NHC, N-heterocyclic carbene; ROMP, ring-opening metathesis polymerization; RCM, ringG




(18) Sashuk, V.; Peeck, L. H.; Plenio, F. Chem. - Eur. J. 2010, 16, 3983−3993. (19) (a) Review: Nickel, A.; Pederson, R. L. Commercial Potential of Olefin Metathesis of Renewable Feedstocks. In Olefin Metathesis: Theory and Practice; Grela, K., Ed.; John Wiley & Sons, Inc.: Hoboken, NJ, 2014; Chapter 11. (b) Elevance Renewable Sciences, a joint venture between Materia and Cargill, was formed to commercialize the metathesis chemistry of seed oil-based feedstocks. In partnership with Wilmar International, a 440 million pound per year bio-refinery was commissioned in Gresik, Indonesia, in 2013. (20) (a) Marx, V. M.; Virgil, S. C.; Grubbs, R. H. Reactions in the Presence of Ruthenium Complexes. U.S. Patent Application 2015/ 0284313 A1, Oct 8, 2015. (b) Marx, V. M.; Sullivan, A. H.; Melaimi, M.; Virgil, S. C.; Keitz, B. K.; Weinberger, D. S.; Bertrand, G.; Grubbs, R. H. Angew. Chem., Int. Ed. 2015, 54, 1919−1923. (21) Schrodi, Y. Synthesis of Terminal Alkenes from Internal Alkenes and Ethylene via Olefin Metathesis. U.S. Patent 9,255,117, February 9, 2016. (22) Romero, P. E.; Piers, W. E.; McDonald, R. Angew. Chem., Int. Ed. 2004, 43, 6161−6165. (23) (a) Schrodi, Y. Synthesis of Terminal Alkenes from Internal Alkenes and Ethylene via Olefin Metathesis. U.S. Patent 9,139,605, September 22, 2015. (b) The structure of catalyst 20 is incorrectly depicted in patent claim 6. The alkylidene “Py” group should be “Ph” as shown in Table 2 (Y. Schrodi, private communication).. (24) (a) Snead, T. E.; Cohen, S. A.; Gildon, D. L. Methods of Refining and Producing Dibasic Esters and Acids from Natural Oil Feedstocks. U.S. Patent 9,284,512 B2, March 15, 2016. (b) Snead, T. E.; Cohen, S. A.; Gildon, D. L. Methods of Refining and Producing Dibasic Esters and Acids from Natural Oil Feedstocks. U.S. Patent 9,000,246 B2, April 7, 2015. (25) (a) Ondi, L.; Varga, J.; Bucsai, A.; Toth, F.; Lorincz, K.; Hegedus, C.; Robe, E.; Frater, G. E. Metathesis Catalysts and Reactions Using the Catalysts. U.S. Patent Application 2016/0030936 A1, February 4, 2016. (b) Ondi, L.; Varga, J.; Bucsai, A.; Toth, F.; Lorincz, K.; Hegedus, C.; Robe, E.; Frater, G. E. Metathesis Catalysts and Reactions Using the Catalysts. U.S. Patent Application 2014/ 0309466 A1, October 16, 2014. (26) Elevance press release January 19, 2016: http://elevance.com/ index.php/news/pressreleases/item/291-elevance-ethenolysis-run; accessed May 9, 2016. (27) Dubois, J.-L.; Courturier, J.-L. Cross Metathesis Process, U.S. Patent Application 2015/0353479 A1. December 10, 2015. (28) Dubois, J.-L.; Couturier, J.-L. Cross Metathesis Process, U.S. Patent Application 2015/0344416 A1. December 3, 2015. (29) Dubois, J.-L.; Couturier, J.-L. Method of Synthesizing Amino Acid by Metathesis, Hydrolysis, then Hydrogenation. U.S. Patent Application 2016/0002147 A1, January 7, 2016. (30) (a) Ibrahem, I.; Yu, M.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2009, 131, 3844−3845. (b) Jiang, A. J.; Zhao, Y.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2009, 131, 16630−16631. (c) Flook, M. M.; Jiang, A. J.; Schrock, R. R.; Muller, P. M.; Hoveyda, A. H. J. Am. Chem. Soc. 2009, 131, 7962−7963. (31) Reviews: (a) Hoveyda, A. H.; Khan, R. K. M.; Torker, S.; Malcolmson, S. J. Catalyst-Controlled Stereoselective Olefin Metathesis, in Handbook of Metathesis; Grubbs, R. H., Wenzel, A. G., O’Leary, D. J., Khosravi, E., Eds.; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, Germany, 2015. (b) Shahane, S.; Bruneau, C.; Fischmeister, C. ChemCatChem 2013, 5, 3436−3459. (32) (a) Schrock, R. R.; King, A. J.; Zhao, Y.; Flook, M. M.; Hoveyda, A. H. Highly Z.-Selective Olefins Metathesis. U.S. Patent 9,079,173, July 14, 2015. (b) Schrock, R. R.; King, A. J.; Zhao, Y.; Flook, M. M.; Hoveyda, A. H. Highly Z-Selective Olefins Metathesis. U.S. Patent Application 2016/0008802 A1, January 14, 2016. (33) (a) Schrock, R. R.; Peryshkov, D. V.; Hoveyda, A. H. Tungsten Oxo Alkylidene Complexes for Z-Selective Olefin Metathesis. U.S. Patent 9,085,595 B2, July 21, 2015. (c) Peryshkov, D. V.; Schrock, R. R.; Takase, M. K.; Müller, P.; Hoveyda, A. H. J. Am. Chem. Soc. 2011, 133, 20754−20757. (c) Schrock, R. R.; Peryshkov, D. V.; Hoveyda, A.

H. Tungsten Oxo Alkylidene Complexes for Z-Selective Olefin Metathesis. U.S. Patent Application 2016/0009746, January 14, 2016. (34) (a) Hoveyda, A. H.; Yu, M.; Wang, C.; Schrock, R. R. ZSelective Ring Closing Metathesis Reactions. U.S. Patent 9,073,801 B2, July 7, 2015. (b) Hoveyda, A. H.; Yu, M.; Wang, C.; Schrock, R. R. Z-Selective Ring Closing Metathesis Reactions. U.S. Patent Application 2015/0246348 A1, September 3, 2015. (c) Wang, C.; Haeffner, F.; Schrock, R. R.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2013, 52, 1939−1943. (35) (a) Rosebrugh, L. E.; Herbert, M. B.; Marx, V. M.; Keitz, B. K.; Grubbs, R. H. Z-Selective Metathesis Catalysts. U.S. Patent Application 2015/0299236 A1, October 22, 2015. (b) Herbert, M. B.; Marx, V. M.; Pederson, R. L.; Grubbs, R. H. Angew. Chem., Int. Ed. 2013, 52, 310−314. (c) Herbert, M. B.; Grubbs, R. H. Angew. Chem., Int. Ed. 2015, 54, 5018−5024. (d) Rosebrugh, L. E.; Marx, V. M.; Keitz, B. K.; Grubbs, R. H. J. Am. Chem. Soc. 2013, 135, 10032−10035. (e) Marx, V. M.; Herbert, M. B.; Keitz, B. K.; Grubbs, R. H. J. Am. Chem. Soc. 2013, 135, 94−97. (f) Rosebrugh, L. E.; Herbert, M. B.; Marx, V. M.; Keitz, B. K.; Grubbs, R. H. J. Am. Chem. Soc. 2013, 135, 1276−1279. (36) (a) Hartung, J.; Grubbs, R. H. Highly Z-Selective and Enantioselective Ring Opening/Cross Metathesis Catalyzed by a Resolved-at-Ru Complex. U.S. Patent Application 2016/0101414 A1, April 14, 2016. (b) Hartung, J.; Grubbs, R. H. J. Am. Chem. Soc. 2013, 135, 10183−10185. (37) Jensen, V. R.; Occhipinti, G. Organometallic Catalysts. U.S. Patent 9,303,100 B2, April 5, 2016.

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Highlights of the Recent U.S. Patent Literature: Focus on Metathesis

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