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OLEFIN METATHESIS APPLICATION GUIDE WITH BONUS METATHESIS QUICK REFERENCE GUIDE INCLUDED FOREWORD

The metathesis experts at Materia have assembled this guide to help chemists who are interested in applying in their own synthetic routes. It starts by discussing some general reaction parameters and practical considerations for running routine olefin metathesis reactions. It then covers some more challenging metathesis reactions with examples from academic, pharmaceutical, and specialty chemical laboratories that illustrate some of the elegant solutions that have been developed.

DISCLAIMER: This document and the information contained herein, are intended to be used solely as a general guideline and for information purposes only. Actual results may vary. Use of, or reliance on, this document or any product referred to herein shall be at user’s own risk. Materia makes no representations or warranties, express, implied or otherwise, relating to this document or any product referred to herein, including any representation or warranty as to accuracy, completeness, merchantability or fitness for any particular purpose or use. Materia disclaims, and user assumes, any and all liability for any claims, losses, demands or damages of any kind whatsoever arising out of or in connection with the use of, or reliance on, this document or any product referred to herein. Nothing contained herein constitutes an offer for the sale of any product or a license, permission, recommendation or inducement to practice any patented invention without the express written permission of the patent owner.

MATERIA, MATERIA Logo, and are trademarks or registered trademarks of Materia, Inc CONTENTS

About Materia and the Authors 3

Getting Started With Metathesis 4

Synthesis Of Medium-Sized Rings 7

Macrocyclic Ring-Closing Metathesis 8

Sterically Demanding Ring-Closing Metathesis 9

Cross Metathesis of Electron-Deficient Olefins 10

Trisubstituted Linear Olefins 11

® www.materia-inc.com | allthingsmetathesis.com 2 ABOUT MATERIA Adam Johns earned his Ph.D. in 2006 with John Hartwig at Yale and joined Materia in Materia is the provider of high performance 2012 after stints at Dow Chemical and Halcyon catalysts and resins that leading companies Molecular and a visiting professor appointment worldwide use to invent new products, at Claremont McKenna College. enhance , and capitalize on their highest-value opportunities. Dick Pederson earned his Ph.D. with Chi-Huey Wong at Texas A&M in 1989 and joined Materia The history of Materia began in the in 2000 after developing metathesis routes to laboratories of Caltech over twenty years insect pheromones at his own company. ago when Professor Robert H. Grubbs synthesized the world’s first broadly applicable, John Phillips earned his Ph.D. in 2005 with user-friendly olefin metathesis catalyst. The Laura Kiessling followed by post-doctoral technology is one of the most important studies with Brian Stoltz at Caltech and John breakthroughs in modern , enabling Montgomery at University of Michigan, joining significant industrial and commercial Materia in 2010. developments across a broad range of markets. Diana Stoianova earned her Ph.D at the In partnership with Caltech and Dr. Grubbs, University of Zurich in 1995 followed by Materia continues to advance the Grubbs post-doctoral studies with Al Meyers at Colorado Catalyst® technology and the advanced State University and Paul Hanson at the materials based on this technology to solve University of Kansas, joining Materia in 2001. complex global and business challenges, driving major economic and environmental Ba Tran earned his Ph.D. with Daniel Mindiola benefits. Materia’s exclusive Grubbs Catalyst® at Indiana University in 2012, followed by products are the world’s leading olefin post-doctoral studies with John Hartwig at metathesis catalysts. Berkeley, joining Materia in 2014.

Philip Wheeler earned his Ph.D. with Tom Rovis at Colorado State University in 2013, joining ABOUT THE AUTHORS Materia in 2015 after two years at Sigma-Aldrich.

Prof. Bob Grubbs is the Victor and Elizabeth Atkins Professor of Chemistry at the California Institute of Technology and shared the 2005 with Prof. Richard Schrock and Prof. for their contributions towards “the development of the metathesis reaction in organic synthesis.”

Top, left to right: Adam Johns, Philip Wheeler, Diana Stoianova. Bottom, left to right: Dick Pederson, Prof. Bob Grubbs, John Phillips. Not pictured: Ba Tran

® www.materia-inc.com | allthingsmetathesis.com 3 cases, using more catalyst may lead to unwanted side reactions. Even for challenging reactions, loadings GETTING STARTED less than 1 mol% can be effective given the careful choice of other reaction parameters, which will be WITH METATHESIS covered below. METATHESIS REACTION TYPES SOLVENT SELECTION There are three main classes of metathesis reactions, two of which are utilized regularly for small molecule organic synthesis. Ring-closing metathesis is an intramolecular reaction of an acyclic diene to form a ring (Fig. 1), while cross metathesis brings two olefins together in an intermolecular reaction to give an olefin product bearing substituents from each of the starting olefins (Fig. 2).

metathesis catalyst +

Figure 1. Ring-closing metathesis (RCM) The list of preferred solvents for olefin metathesis metathesis reactions includes solvents such as catalyst toluene and heptanes, chlorinated solvents such as + methylene chloride, esters such as ethyl acetate, and Figure 2. Cross metathesis (CM) peroxide-resistant ethers such as TBME.

Ethereal solvents themselves do not cause issues, but the peroxides that can form in ethereal solvents can GENERAL REACTION SET-UP react with the center and cause catalyst 1. Deoxygenated solvents and reaction mixtures are decomposition. When using any peroxide-forming recommended for optimal results. If necessary, solvent, be sure to use solvent that has been stored degas the solvent before use. with BHT as an inhibitor,1 and check for peroxides 2. In a dry, inert reaction vessel with a stir bar, dissolve before use. your substrate(s) in the solvent of choice. 3. Weigh the catalyst (open to the air is fine) and add it While there are many examples of olefin metathesis in to the reaction mixture either as a solid or a solution the presence of protic solvents, a primary can in the reaction solvent. react with the ruthenium complex to form ruthenium 4. Heat the reaction to the desired temperature and hydrides, which are not effective olefin metathesis monitor until complete. catalysts, but are effective olefin isomerization catalysts (see Preventing Olefin Isomerization).

In general, highly coordinating solvents such as DMF or CATALYST SELECTION AND LOADING will interfere with the catalytic activity of the If you are running a metathesis reaction for the first ruthenium complex. At high pH, water (e.g. hydroxide) time, consider using Hoveyda-Grubbs Catalyst® 2nd can also alter the ruthenium complex such that it is no Generation (C627). This catalyst typically displays longer active. similar activity to Grubbs Catalyst® 2nd Generation (C848) but initiates at a lower temperature (<23 °C) and is more stable to storage and handling. In metathesis reactions TEMPERATURE Most Grubbs Catalyst® Products will initiate on an olefin involving sterically encumbered olefins, it may be necessary substrate between 23 and 40 °C, but some reactions to use a more specialized catalyst such as C571 or C711 may require additional heat to achieve suitable rates. (see Sterically Demanding Ring Closing Metathesis and The formation of trisubstituted olefins (see Trisubstituted Trisubstituted Linear Olefins). Linear Olefins), and macrocyclizations (see Macrocyclic Ring-Closing Metathesis) may require temperatures As long as reaction conditions are chosen carefully, as high as 100 °C for conversion to be complete high loadings of catalyst are not necessary. In some within hours.

® www.materia-inc.com | allthingsmetathesis.com 4 the double bonds in either the substrate or the metathesis CONCENTRATION product. This typically occurs because the catalyst has When choosing reaction concentration, keep in mind decomposed to a ruthenium hydride species. The most that intermolecular reactions such as cross common way for this to happen is by reaction metatheses should be run as concentrated as possible, of the ruthenium complex with a primary alcohol, and macrocyclizations should be run as dilute as is present in either the substrate or the solvent.4 Users practical. Ring-closing metathesis reactions forming should be aware of this possibility when running a 5 or 6 membered rings can be run at concentrations metathesis reaction in a primary alcohol solvent. approaching 1 M or greater.

C848 mol (5 %) + O , O O OTHER CONSIDERATIONS CD2Cl2 40 °C Aside from careful selection of the basic reaction no additive: <5% 95% parameters, there are several other precautions that with 10 mol % 1,4-benzoquinone: >95% none none should be taken to ensure maximal reaction efficiency. with 10 mol % AcOH: >95% Figure 4. Preventing olefin isomerization EXCLUSION OF OXYGEN The Grubbs group and others have reported the Although Grubbs Catalyst® Products are air and moisture addition of a mild oxidant such as a 1,4-benzoquinone derivative or a mild acid such as acetic acid to suppress stable as solids, they are less stable to oxygen while in 5 solution. For this reason, it is preferable to degas the double bond isomerization. These additives can be reaction mixture before adding the catalyst. One way to effective even in cases where there is a thermodynamic do this is to sparge the solution with nitrogen or argon driving force toward isomerization, as in the case of for about 20 minutes. It may be advantageous to the ring-closing metathesis of divinyl ether to form continue sparging over the course of the reaction in dihydrofuran (Fig. 4). order to remove any gaseous byproducts from the reaction mixture (see Removal of ). REMOVAL OF ETHYLENE Metathesis reactions that bring together two terminal MASKING FUNCTIONAL GROUPS olefins produce ethylene as a byproduct. Although As mentioned in the Solvent Selection section, strongly ethylene is a gas, it is soluble in organic solvents and coordinating moieties can interfere with the activity of can remain in the reaction mixture. Ensuring that homogeneous ruthenium metathesis catalysts. This is ethylene or any other gaseous byproduct is efficiently also true of strongly coordinating functional groups in removed will drive the reaction equilibrium toward a metathesis substrate. In many cases, it is necessary to completion. protect or at least mask strongly coordinating groups such as amines by adding an acid additive. NHC NHC Cl R ethylene Ru RuCl2 O O + Cl PCy3 H2C PCy3 HN TsOH HN · C627 (1 mol %) alkylidene H O · 2 TsOH NH (1.5 equiv) NH PhMe, 60-80 °C Ph OR Ph OR 85% R Figure 3. RCM in presence of protonated amines NHC Cl NHC NHC In the patented route to rolapitant, an anti-nausea drug Ru CH2 PCy3 Ru CH Ru PCy3 approved by the FDA in 2015, a spirocyclic amine Cl Cl 2 Cl Cl Cl structure is assembled using RCM (Fig. 3).2,3 The tosic PCy3 acid salt of the substrate is first dissolved in toluene, methylidene and an additional 1.5 equivalents of TsOH are added to Figure 5. Catalyst decomposition by ethylene ensure complete protonation before the metathesis reaction is initiated using C627. After recrystallization as Furthermore, removing ethylene can help prevent the hydrochloride salt, the spirocyclic product is isolated catalyst decomposition. When the ruthenium initiates in 85% yield. onto ethylene, it generates a methylidene catalytic intermediate, which is susceptible to attack by a nucleophile ( is shown, but other nucleophiles PREVENTING OLEFIN ISOMERIZATION can result in similar pathways). Once this occurs, the An unwanted side reaction that can occur during the ruthenium complex heads down an irreversible course of a metathesis reaction is the isomerization of decomposition pathway along the lines of the

® www.materia-inc.com | allthingsmetathesis.com 5 mechanism described by the Grubbs group in 2007 (Fig. 5).6 This can cause the reaction to stall, which is sometimes overcome by adding subsequent portions of catalyst.

However, this issue can be circumvented by removal of ethylene over the course of the reaction. The ® simplest way to do this is to bubble an inert gas GRUBBS CATALYST through the reaction mixture over the course of the reaction. On scale, this technique is used frequently to help maximize catalyst lifetime, as exemplified in TECHNOLOGY the Vaniprevir example included in this guide (see Macrocyclic Ring-Closing Metathesis). Mild vacuum can also be used to help pull ethylene out of solution, and can even be combined with a nitrogen sparge to TRUSTED PERFORMANCE FOR maximize ethylene removal. COMMERCIAL DRUG DEVELOPMENT Z-SELECTIVE REACTIONS NOW EASIER THAN EVER TO ACCESS If the desired product is a cis or Z olefin, use Grubbs Catalyst® Z-Selective C633. In both ring-closing and cross metathesis reactions, C633 will give the Z-product selectively.

OH OH

9 C633 + (0.5 mol%) 9 o THF, 40 C 4 70% 88:12 Z:E Figure 6. Z-Selective CM with C633

For example, the Grubbs group used C633 to give a number of Z-olefin intermediates that were taken on NO LICENSE FEES OR ROYALTIES to various insect pheromones used as attractants in the We understand there is enough uncertainty to developing agricultural industry (Fig. 6).7 a new drug, so any licensing costs are reflectedsimply in the price of our catalysts. REFERENCES (1) BHT poses no issue, but other inhibitors can be FREEDOM TO OPERATE problematic. We know protecting your freedom to operate is critical and include rights to patent in the pharmaceutical field (2) Wang, H.; Goodman, S.N.; Dai, Q.; Stockdale, G.W.; with each catalyst sale. Clark, W.M. Jr. Org. Proc. Res. Dev., 2008, 12, 226.

(3) Wu, George G. et al. (Schering-Plough, USA) WO 3RD PARTY PARTNERS ARE WELCOME We realize outsourcing plays an integral role in drug 2010028232, Mar 11, 2010. development and extend the same terms to contract service organizations serving pharmaceutical customers. (4) Trnka et al. J. Am. Chem. Soc. 2003, 125, 2546. For more information, please contact us at (5) Hong, S. H.; Sanders, D. P.; Lee, C. W.; Grubbs, R. H. [email protected] J. Am. Chem. Soc. 2005, 127, 17160.

(6) Hong, S. H.; Wenzel, A. G.; Salguero, T. T.; Day, M. W.; Grubbs, R. H. J. Am. Chem. Soc. 2007, 129, 7961.

(7) Herbert, M. B.; Marx, V. M.; Pederson, R. L.; Grubbs, R. H. Angew. Chem. Int. Ed. 2013, 52, 310.

® www.materia-inc.com | allthingsmetathesis.com 6 CO2Me H CO2Me MeO2C C848 (3 mol%) SYNTHESIS OF H H MeO2C C848, (3 mol%) CH2Cl2 40 °C H CH3 O CH3 CH3 CH95%2Cl2, 40 °C MEDIUM-SIZED RINGS CH3 CH3 O CH3 CH3 95% O CH3 O Figure 8. RCM to form a substituted cyclooctane

[Ru] Although cyclooctanoids are difficult to synthesize due ring strain and conformational issues, Wicha and n - n = 1 8 n co-workers gained access to the 8-membered ring structure of serpendione via the use of Grubbs Catalyst® C848 (Fig. 8).10

O O OVERVIEW O O EtO2C EtO2C EtO2C N C848 (5 mol%)EtO C Perhaps the most common and recognizable application N C848 (5 mol%) 2 N N , o o H H of olefin metathesis in organic synthesis is ring-closing CH2ClCH2 402Cl2C, 40 C metathesis (RCM). This methodology allows for the 92% 92% construction of all-carbon and heteroatom-containing rings that are rich in sp3-centers, a growing theme in FIgure 9. RCM to form an azepane core 8 modern medicinal chemistry. In the synthesis of (–)–stemoamide, a natural product found in root extracts used in Chinese and Japanese folk medicine, Somfai and coworkers used RCM to REACTION-SPECIFIC CONSIDERATIONS construct the azepane core (Fig. 9).11 Using 5 mol% of • The formation of strained rings often requires heating C848, the desired heterocyclic scaffold was obtained in to 40 °C or greater. 92% yield. • Ideal temperature and concentration are influenced by ring size and thermodynamic parameters such as ring strain or sterics. SAMPLE CONDITIONS

Solvent Options: CH2Cl2, PhMe, TBME Concentration (Ring Size): 1.0 M (5), 0.5 M (6), 0.2 M (7), HIGHLIGHTED EXAMPLES 0.1 M (8), 0.05 M or less (9-11) Preferred Catalyst Options: C848, C627, C571 Catalyst Loading: 3-5 mol% H Me H O O Temperature: 40-100 °C Si(t-Bu)2 O O O H H H

C848 (5 mol%) REFERENCES O , o CH2Cl2 40 C (8) Lovering, F.; Bikker, J.;Humblet, C. J. Med. Chem. H Me H 2009, 52, 6752. O O Si(t-Bu)2 O O (9) Clark, J. S.; Romiti, F.; Sieng, B. Paterson, L. C.; O O H H H Stewart, A.; Chaudhury, S.; Thomas, L. H. Org. Lett. 85% 2015, 17, 4694.

Figure 7. RCM to form a 7-membered enone (10) Michalak, K.; Michalak, M.; Wicha, J. Tetrahedron Lett. 2005, 46, 1149. Ring-closing metathesis was used by Clark and coworkers to form the oxepane ring embedded in (11) Torssell, S.; Wanngren, E.; Somfai, P. J. Org. Chem. 9 (-)-gambieric acid (Fig. 7). The desired 7-membered 2007, 72, 4246. enone product was obtained in 85% yield using 5 mol% C848.

® www.materia-inc.com | allthingsmetathesis.com 7 O N O N O MACROCYCLIC O

N CO2H RING-CLOSING METATHESIS H N CO2H O NH O N O O O O 1 1 C627 (0.2 mol%) C627 (0.2 mol%) m [Ru] m 2,6-dichloro-benzoquinone [Ru] simultaneous slow addition 2,6-dichloro-benzoquinone simultaneous slow addition 0.13M toluene m m of 1 and C627 0.13M toluene of 1 and C627 o 100 oC n n 100 C 91% n n 91% OO NN OO

OVERVIEW CO2H N CO2H Excellent compatibility in addition to HH OO NN a tolerance of residual moisture and oxygen have O facilitated the broad acceptance of ruthenium- OO catalyzed macrocyclization as a general methodology 12 for the preparation of large rings (≥12 atoms). 22 Figure 11. Key RCM in synthesis of vaniprevir

REACTION-SPECIFIC CONSIDERATIONS In an industrial setting, ring-closing metathesis of the • To avoid the formation of dimers and oligomers, diene 1 afforded the 20-membered macrocyclic core macrocyclizations are usually run at low of Vaniprevir (HCV protease inhibitor).14 After extensive concentration (0.01 to 0.1 M). optimization, a very efficient reaction was achieved • When running a macrocyclization reaction, it can be by simultaneous slow addition of the catalyst and the advantageous to slowly add catalyst and substrate to substrate. Removal of ethylene by nitrogen sparge and the reaction vessel (see Figure 11). addition of 2,6-dichloroquinone to the reaction mixture • Oligomerization is often reversible and a function minimized catalyst decomposition and isomerization of of concentration. the allylbenzene-double bond in the starting material. Only 0.2 mol% of C627 was needed to give excellent HIGHLIGHTED EXAMPLES yield of the desired macrocycle 2 (Fig. 11).

O O O O Ph Ph PhPh SAMPLE CONDITIONS Solvent Options: CH Cl , PhMe, TBME N N N N 2 2 C848C848 (15 (15 mol% mol%)) Concentration: 0.05-0.1 M O O , O O Preferred Catalyst Options: C627, C848 O O 0.58mM0.58mM CH CH2Cl2Cl, reflux2 refluxO O 90% Catalyst Loading: 3-10 mol% R 90% R R R Temperature: 40-100 °C Figure 10. Key RCM in synthesis of spongidepsin

Burgess and coworkers used ring-closing metathesis to a 13-membered lactam as a key step to prepare REFERENCES the cytotoxic marine natural product (-)-spongidepsin (12). Hanson, P. H.; Maitra, S.; Chegondi, R.; Markley, (Fig. 10).13 The desired intermediate was prepared in J. L. General Ring-Closing Metathesis. Synthesis of excellent yield using 15 mol% C848 under high dilution Macrocycles. In Handbook of Metathesis; Grubbs, R. H.; conditions. O’Leary, D. J., Eds.; Wiley-VCH: Weinheim, Germany, 2015; Vol. 2, pp 105–126.

(13). Zhu, Y.; Loudet, A., Burgess, K. Org. Lett. 2010, 12, 4392.

(14). Kong, J.; Chen, C.; Balsells-Padros, J.; Cao, Y.; Dunn, R. F.; Dolman, S. J.; Janey, J.; Li, H.; and Zacuto, M. J. J. Org. Chem. 2012, 77, 3820.

® www.materia-inc.com | allthingsmetathesis.com 8 STERICALLY DEMANDING C571 (6 mol %)

C571 mol N (6 %) N N ethylene (1 atmN ) RING-CLOSING METATHESIS ethylene (1PhMe, atm) 100 °C PhMe, 100 °C O O O O 89 % 89 % R Figure 14. Metathesis rearrangement R R R Vanderwal and co-workers reported the use of C571 to generate complex polycyclic scaffolds from Himbert cycloadducts.17 An N-allylpyrrolidinone fused 2,2, n n n n 2-bicycle is opened under ethylene atmosphere to give the rearranged polycyclic product in 89% yield (Fig. 14). OVERVIEW For sterically demanding ring-closing metathesis SAMPLE CONDITIONS Solvent Options: CH Cl , PhMe, TBME reactions, catalysts such as C571 (Fig. 12) bearing a less 2 2 bulky NHC often give superior performance.15 Sterically Concentration (Ring Size): 1.0 M (5), 0.5 M (6), 0.2 M (7), demanding substrates include 1,1 disubstituted olefins, 0.1M (8), 0.05M or less (9-11) olefins bearing a bulky group at the allylic position, and Preferred Catalyst Options: C571 olefins that are part of a cage system. Catalyst Loading: 3-10 mol% Temperature: 40-100 °C REFERENCES (15). Stewart, I. C.; Benitez, D.; O’Leary, D. O.; Tkatchouk, E.; Day, M. W.; Goddard, W. A. III; Grubbs, R. H. J. Am. Chem. Soc. 2009, 131, 1931.

(16). Allen, C. E.; Chow, C. L.; Caldwell, J. J.; Westwood, I. M.; M. van Montfort, R. L.; Collins, I. Bioorg. Med. Figure 12. Grubbs Catalyst® C571 Chem. 2013, 21, 5707. REACTION-SPECIFIC CONSIDERATIONS (17). Lam, J. K.; Schmidt, Y.; Vanderwal, C. D. Org. Lett. • Sterically demanding reactions often require heating. 2012, 14, 5566. • If you are seeing intermolecular cross coupling at the less hindered olefin center, try diluting the reaction.

HIGHLIGHTED EXAMPLES

OEt EtO O OEt EtO O

O O PhPh

NN Ph NN C571C571 (10 (10 mol%mol%)) oo PhMe,PhMe, 80 80 CC NN NN 8282 %% PhPh PhPh Figure 13. Hindered RCM spirocyclization

In a report by Collins and co-workers exploring various spirocyclic compounds for activity against protein kinases,16 ring-closing metathesis to form a trisubstituted olefin was attempted using C823 and C627. Neither of these catalysts was effective in the transformation, but the less bulky Grubbs Catalyst® C571 gave excellent yield of a key diazaspirocyclic scaffold used for SAR exploration (Fig. 13).

® www.materia-inc.com | allthingsmetathesis.com 9 for cross metathesis over self metathesis is necessary. Furthermore, minimization of catalyst loading is crucial CROSS METATHESIS OF in these cost-sensitive applications. Gauvin and coworkers improved the catalytic turnover in the ELECTRON-DEFICIENT synthesis of bis-esters from methyl oleate when methyl acrylate was replaced with methyl crotonate as the OLEFINS cross metathesis partner (Fig. 16).18 The authors postulated that the catalyst decomposition was minimized by avoiding the presence of a terminal olefin, preventing the formation of any Ru-methylidene species (see [Ru] R + [Ru] R Catalyst Decomposition by Ethylene). High conversion R EWG R EWG + EWG EWG to the desired cross metathesis product was observed using only 29 ppm of C949. OVERVIEW Electron deficient olefins are intrinsically less reactive Ph Ph than electron rich olefins in metathesis reactions. However, this feature makes selective cross-metathesis between an electron rich and an electron deficient olefin Ph O Ph possible given the slower rate of the reverse reaction. O C848 nd O C848, O In general, 2 Generation catalysts such as C949 CH2Cl2 40°C O 2 12CH O (CH ) 3 CH2Cl2, 40°C (Fig. 15) or C848 are preferred in this application which (CH2)12CH3 68% O has been used on large scale to generate value-added 68% O(CH2)12CH3 chemicals from biorenewable sources and to generate (CH2)12CH3 biologically active analogues of medicinally relevant substructures. Figure 17. CM of a ẞ-lactone Michael acceptor

A cross metathesis approach to synthesize serine hydrolase inhibitors was reported by Howell and Cravatt.19 Using C848 as the catalyst and an exo-methylene ẞ-lactone as the cross metathesis partner, the authors generated a library of novel ẞ-lactone structures bearing a variety of alkyl chains at the 3-position (Fig. 17). Figure 15. Grubbs Catalyst® C949 SAMPLE CONDITIONS REACTION-SPECIFIC CONSIDERATIONS Solvent Options: CH2Cl2, PhMe, neat (no solvent) • An excess of the electron-deficient cross metathesis Concentration: 1 M or greater partner may produce better yields. Preferred Catalyst Options: C627, C848, C949 • Cross metatheses typically work best at high Catalyst Loading: 1-5 mol% concentration of the substrates. Temperature: 40-60 °C HIGHLIGHTED EXAMPLES REFERENCES COCO2Me2Me (18). Vignon, P.; Vancompernolle, T.; Couturier, J.-L.; COCOMe Me COCO22MeMe 2 2 Dubois, J.-L.; Mortreaux, A.; Gauvin, R. M. ChemSusChem 6 6 RR 6 2014, 8, 1143. C949C949 (29 ppm)ppm) 6 MeO C 6 PhMe, 60°C Me2O2C 6 PhMe, 60°C desired desired (19). Camara, K.; Kamat, S. S.; Lasota, C. C.; Cravatt, B. methyl oleate Conversion Productive TON F.; Howell, A. R. Bioorg. Med. Chem. Lett. 2015, 25, 317. Conversion Productive TON acrylate (R = H) 58% 6,000 acrylatecrotonate (R(R == Me) H) 96%58% 31,1106,000 crotonate (R = Me) 96% 31,110

Figure 16. Crotonate vs acrylate as CM partner

Biscarboxylic acids are precursors for polymers, coatings, plasticizers, and detergents. To generate these desired products using metathesis, selectivity

® www.materia-inc.com | allthingsmetathesis.com 10 are preferred for 1,1-disubstituted olefins,C627 or C848 (bearing the sIMes NHC) may outperform C711 TRISUBSTITUTED in making 1,2-disubstituted olefins bearing large allylic LINEAR OLEFINS substituents. OAc OAc

R22 2 R R2 2 1 [Ru] R 4 C848 (5 mol%) R1 + 3 [Ru] + 1 R 4 R R + R 3 R +R 1 R O neat, 80 2 h R R R3 R ºC, O R 1 = 4 3 33 mbar R1 H, alkyl R4 R R = H, alkyl R 2 83% 67:33 E:Z OVERVIEW Figure 19. Grubbs Catalyst® C711 Although the preparation of highly substituted olefins Netscher and coworkers utilized the cross-metathesis by cross-metathesis is challenging, it can be achieved of trisubstituted and 1,1-disubstituted olefins to access using 2nd Generation catalysts. Both 1,1-disubstituted vitamin E intermediates in good yields using C848 (Fig. 20). and trisubstituted olefins have been used successfully Conducting the reaction in vacuo (33 mbar) to remove as cross metathesis partners.20 improved the yield of this transformation from 67% to 83%.22 REACTION-SPECIFIC CONSIDERATIONS • Sterically demanding reactions often require heating OAc to 40 °C or greater. OAc • Cross metatheses typically work best at high 2 concentration of the substrates. C848 (5 mol%) • An excess of the sterically hindered substrate may O neat, 80 ºC, 2 h O be required. 33 mbar 2 83% 67:33 E:Z HIGHLIGHTED EXAMPLES Figure 20. Tocopherol derivatives by CM

LL ClCl Ru SAMPLE CONDITIONS Ru Cl Solvent Options: CH Cl , PhMe, neat (no solvent) Cl 2 2 O Concentration: 1 M or greater iPrO i Pr Preferred Catalyst Options: C627, C848, C711 L = sIMes (C627) L = sIMes (C627) sIPr (C711) Catalyst Loading: 1-5 mol% sIPr (C711) s(o-Tol) (C571) Temperature: 40-100 °C s(o-Tol) (C571)

OAc OAc Catalyst (5 mol%) OAc + OAc Catalyst, (5 mol%)° + CH2Cl2 40 C REFERENCES CH2Cl2, 40 °C (20). Chatterjee, A. K.; Grubbs, R. H. Org. Lett. 1999, 1, Catalyst Yield CatalystC571 Yiel60%d 1751-1753. Chatterjee, A. K.; Sanders, D. P.; Grubbs, R. C571C627 60%78% H. Org. Lett. 2002, 4, 1939-1942. C627C711 78%98% C711 98% (21). Stewart, I. C.; Douglas, C. D.; Grubbs, R. H. Org. Figure 18. CM of methylenecyclohexane Lett. 2008, 10, 441. C711 is often the optimal catalyst for the cross metathesis (22). Netscher, T. J. Organomet. Chem. 2006, 691, of 1,1-disubstituted olefins. This is counter to the trend 5155-5162. Malaisé, G.; Bonrath, W.; Breuninger, M.; in ring-closing metathesis of sterically-hindered Netscher, T. Helv. Chim. Acta 2006, 89, 797-812. substrates, where C571 bearing minimal steric bulk is often preferred. In a comparison study, C711 (Fig. 19) outperformed both C627 and C571 in the cross metathesis of methylene cyclohexane with 4-penten-1-yl acetate (Fig. 18).21 While bulky NHC

® www.materia-inc.com | allthingsmetathesis.com 11 * For Z-selective Macrocyclization

Pyridine, Et3N