OLEFIN METATHESIS APPLICATION GUIDE - Materia Inc · olefin metathesis application guide with bonus...

OLEFIN METATHESISAPPLICATION GUIDE

WITH BONUS METATHESIS QUICK REFERENCE GUIDE INCLUDED

2® www.materia-inc.com | allthingsmetathesis.com

CONTENTSAbout Materia and the Authors

Getting Started With Metathesis

Synthesis Of Medium-Sized Rings

Macrocyclic Ring-Closing Metathesis

Sterically Demanding Ring-Closing Metathesis

Cross Metathesis of Electron-Deficient Olefins

Trisubstituted Linear Olefins

FOREWORDThe metathesis experts at Materia have assembled this guide to help chemists who are interested in applying olefin metathesis 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 GRUBBS CATALYST are trademarks or registered trademarks of Materia, Inc

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ABOUT MATERIAMateria is the provider of high performance catalysts and resins that leading companies worldwide use to invent new products, enhance industrial processes, and capitalizeon their highest-value opportunities.

The history of Materia began in thelaboratories of Caltech over twenty years ago when Professor Robert H. Grubbs synthesized the world’s first broadly applicable, user-friendly olefin metathesis catalyst. The technology is one of the most important breakthroughs in modern chemistry, enabling significant industrial and commercial developments across a broad range of markets.

In partnership with Caltech and Dr. Grubbs, Materia continues to advance the Grubbs Catalyst® technology and the advanced materials based on this technology to solve complex global and business challenges, driving major economic and environmental benefits. Materia’s exclusive Grubbs Catalyst® products are the world’s leading olefin metathesis catalysts.

ABOUT THE AUTHORS

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

Adam Johns earned his Ph.D. in 2006 with John Hartwig at Yale and joined Materia in 2012 after stints at Dow Chemical and Halcyon Molecular and a visiting professor appointment at Claremont McKenna College.

Dick Pederson earned his Ph.D. with Chi-Huey Wong at Texas A&M in 1989 and joined Materia in 2000 after developing metathesis routes to insect pheromones at his own company.

John Phillips earned his Ph.D. in 2005 with Laura Kiessling followed by post-doctoral studies with Brian Stoltz at Caltech and John Montgomery at University of Michigan, joining Materia in 2010.

Diana Stoianova earned her Ph.D at the University of Zurich in 1995 followed by post-doctoral studies with Al Meyers at Colorado State University and Paul Hanson at the University of Kansas, joining Materia in 2001.

Ba Tran earned his Ph.D. with Daniel Mindiola at Indiana University in 2012, followed bypost-doctoral studies with John Hartwig at Berkeley, joining Materia in 2014.

Philip Wheeler earned his Ph.D. with Tom Rovis at Colorado State University in 2013, joining 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 Nobel Prize in Chemistry with Prof. Richard Schrock and Prof. Yves Chauvin for their contributions towards “the development of the metathesis reaction in organic synthesis.”


GETTING STARTEDWITH METATHESISMETATHESIS REACTION TYPESThere 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).

+

metathesiscatalyst

Figure 1. Ring-closing metathesis (RCM)

+

metathesiscatalyst

Figure 2. Cross metathesis (CM)

GENERAL REACTION SET-UP1. Deoxygenated solvents and reaction mixtures are

recommended for optimal results. If necessary, degas the solvent before use.

2. In a dry, inert reaction vessel with a stir bar, dissolve your substrate(s) in the solvent of choice.

3. Weigh the catalyst (open to the air is fine) and add it to the reaction mixture either as a solid or a solution in the reaction solvent.

4. Heat the reaction to the desired temperature and monitor until complete.

CATALYST SELECTION AND LOADINGIf you are running a metathesis reaction for the first time, consider using Hoveyda-Grubbs Catalyst® 2nd Generation (C627). This catalyst typically displays 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 involving sterically encumbered olefins, it may be necessary to use a more specialized catalyst such as C571 or C711 (see Sterically Demanding Ring Closing Metathesis and Trisubstituted Linear Olefins).

As long as reaction conditions are chosen carefully, high loadings of catalyst are not necessary. In some

cases, using more catalyst may lead to unwanted side reactions. Even for challenging reactions, loadings less than 1 mol% can be effective given the careful choice of other reaction parameters, which will be covered below.

SOLVENT SELECTION

The list of preferred solvents for olefin metathesisreactions includes hydrocarbon solvents such as toluene and heptanes, chlorinated solvents such as methylene chloride, esters such as ethyl acetate, and peroxide-resistant ethers such as TBME.

Ethereal solvents themselves do not cause issues, but the peroxides that can form in ethereal solvents can react with the ruthenium center and cause catalyst decomposition. When using any peroxide-forming solvent, be sure to use solvent that has been stored with BHT as an inhibitor,1 and check for peroxides before use.

While there are many examples of olefin metathesis in the presence of protic solvents, a primary alcohol can react with the ruthenium complex to form ruthenium hydrides, which are not effective olefin metathesis catalysts, but are effective olefin isomerization catalysts (see Preventing Olefin Isomerization).

In general, highly coordinating solvents such as DMF or pyridine will interfere with the catalytic activity of the ruthenium complex. At high pH, water (e.g. hydroxide) can also alter the ruthenium complex such that it is no longer active.

TEMPERATURE Most Grubbs Catalyst® Products will initiate on an olefin substrate between 23 and 40 °C, but some reactions may require additional heat to achieve suitable rates. The formation of trisubstituted olefins (see Trisubstituted Linear Olefins), and macrocyclizations (see Macrocyclic Ring-Closing Metathesis) may require temperatures as high as 100 °C for conversion to be completewithin hours.


CONCENTRATIONWhen choosing reaction concentration, keep in mind that intermolecular reactions such as cross metatheses should be run as concentrated as possible, and macrocyclizations should be run as dilute as is practical. Ring-closing metathesis reactions forming 5 or 6 membered rings can be run at concentrations approaching 1 M or greater.

OTHER CONSIDERATIONSAside from careful selection of the basic reaction parameters, there are several other precautions that should be taken to ensure maximal reaction efficiency.

EXCLUSION OF OXYGENAlthough Grubbs Catalyst® Products are air and moisture stable as solids, they are less stable to oxygen while in solution. For this reason, it is preferable to degas the reaction mixture before adding the catalyst. One way to do this is to sparge the solution with nitrogen or argon for about 20 minutes. It may be advantageous to continue sparging over the course of the reaction in order to remove any gaseous byproducts from the reaction mixture (see Removal of Ethylene).

MASKING FUNCTIONAL GROUPSAs mentioned in the Solvent Selection section, strongly coordinating moieties can interfere with the activity of homogeneous ruthenium metathesis catalysts. This is also true of strongly coordinating functional groups in a metathesis substrate. In many cases, it is necessary to protect or at least mask strongly coordinating groups such as amines by adding an acid additive.

NH

HN

O

Ph OR

C627 (1 mol %)·TsOH·H2O TsOH (1.5 equiv)

PhMe, 60-80 °C NH

HN

O

Ph OR85%

Figure 3. RCM in presence of protonated amines

In the patented route to rolapitant, an anti-nausea drug approved by the FDA in 2015, a spirocyclic amine structure is assembled using RCM (Fig. 3).2,3 The tosic acid salt of the substrate is first dissolved in toluene, and an additional 1.5 equivalents of TsOH are added to ensure complete protonation before the metathesis reaction is initiated using C627. After recrystallization as the hydrochloride salt, the spirocyclic product is isolated in 85% yield.

PREVENTING OLEFIN ISOMERIZATIONAn unwanted side reaction that can occur during the course of a metathesis reaction is the isomerization of

the double bonds in either the substrate or the metathesis product. This typically occurs because the catalyst has decomposed to a ruthenium hydride species. The most common way for this to happen is by reaction of the ruthenium complex with a primary alcohol, present in either the substrate or the solvent.4 Users should be aware of this possibility when running a metathesis reaction in a primary alcohol solvent.

OOC848 (5 mol %)

O+CD2Cl2

, 40 °C

no additive:with 10 mol % 1,4-benzoquinone:

with 10 mol % AcOH:

<5%>95%>95%

95%nonenone

Figure 4. Preventing olefin isomerization

The Grubbs group and others have reported the addition of a mild oxidant such as a 1,4-benzoquinone derivative or a mild acid such as acetic acid to suppress double bond isomerization.5 These additives can be effective even in cases where there is a thermodynamic driving force toward isomerization, as in the case of the ring-closing metathesis of divinyl ether to form dihydrofuran (Fig. 4).

REMOVAL OF ETHYLENEMetathesis reactions that bring together two terminal olefins produce ethylene as a byproduct. Although ethylene is a gas, it is soluble in organic solvents and can remain in the reaction mixture. Ensuring that ethylene or any other gaseous byproduct is efficiently removed will drive the reaction equilibrium toward completion.

Ru

NHC

CH2

PCy3

Cl

Cl Ru

NHC

CH2ClCl

PCy3Ru

NHC

ClCl

PCy3

RuCl2

NHC

H2C PCy3

+Ru

NHC

PCy3

Cl

Cl

R

R

ethylene

alkylidene

methylidene

Figure 5. Catalyst decomposition by ethylene

Furthermore, removing ethylene can help prevent catalyst decomposition. When the ruthenium initiates onto ethylene, it generates a methylidene catalytic intermediate, which is susceptible to attack by a nucleophile (phosphine is shown, but other nucleophiles can result in similar pathways). Once this occurs, the ruthenium complex heads down an irreversible decomposition pathway along the lines of the


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 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 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 maximize ethylene removal.

Z-SELECTIVE REACTIONSIf 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.

C633 (0.5 mol%)THF, 40

oC70%

OH

9

OH

9

4

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 to various insect pheromones used as attractants in the agricultural industry (Fig. 6).7

REFERENCES(1) BHT poses no issue, but other inhibitors can be problematic.

(2) Wang, H.; Goodman, S.N.; Dai, Q.; Stockdale, G.W.; Clark, W.M. Jr. Org. Proc. Res. Dev., 2008, 12, 226.

(3) Wu, George G. et al. (Schering-Plough, USA) WO 2010028232, Mar 11, 2010.

(4) Trnka et al. J. Am. Chem. Soc. 2003, 125, 2546.

(5) Hong, S. H.; Sanders, D. P.; Lee, C. W.; Grubbs, R. H. 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.

GRUBBS CATALYST®

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3RD PARTY PARTNERS ARE WELCOMEWe realize outsourcing plays an integral role in drug development and extend the same terms to contract service organizations serving pharmaceutical customers.

For more information, please contact us at [email protected]


SYNTHESIS OFMEDIUM-SIZED RINGS

n

[Ru]

n n = 1 - 8

OVERVIEWPerhaps the most common and recognizable application of olefin metathesis in organic synthesis is ring-closing metathesis (RCM). This methodology allows for the construction of all-carbon and heteroatom-containing rings that are rich in sp3-centers, a growing theme in modern medicinal chemistry.8

REACTION-SPECIFIC CONSIDERATIONS• The formation of strained rings often requires heating

to 40 °C or greater.• Ideal temperature and concentration are influenced

by ring size and thermodynamic parameters such as ring strain or sterics.

HIGHLIGHTED EXAMPLES

C848 (5 mol%)CH2Cl2

, 40 oC

O

OOSi(t-Bu)2

O

O

H

H

O

Me

H H

H

O

OOSi(t-Bu)2

OH

H

Me

H H

H

OO

85% Figure 7. RCM to form a 7-membered enone

Ring-closing metathesis was used by Clark and coworkers to form the oxepane ring embedded in (-)-gambieric acid (Fig. 7).9 The desired 7-membered enone product was obtained in 85% yield using 5 mol% C848.

O CH3CH3

HC848

(3 mol%)

CH3

H

CH3

O

CO2MeMeO2C

CH2Cl2, 40 °C

95%

Figure 8. RCM to form a substituted cyclooctane

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

N

O

H

EtO2CC848 (5 mol%)CH2Cl2

, 40 oC

92%

N

OEtO2C

FIgure 9. RCM to form an azepane core

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 construct the azepane core (Fig. 9).11 Using 5 mol% of C848, the desired heterocyclic scaffold was obtained in 92% yield.

SAMPLE CONDITIONSSolvent Options: CH

2Cl

2, PhMe, TBME

Concentration (Ring Size): 1.0 M (5), 0.5 M (6), 0.2 M (7), 0.1 M (8), 0.05 M or less (9-11)Preferred Catalyst Options: C848, C627, C571Catalyst Loading: 3-5 mol%Temperature: 40-100 °C

REFERENCES(8) Lovering, F.; Bikker, J.;Humblet, C. J. Med. Chem. 2009, 52, 6752.

(9) Clark, J. S.; Romiti, F.; Sieng, B. Paterson, L. C.; Stewart, A.; Chaudhury, S.; Thomas, L. H. Org. Lett. 2015, 17, 4694.

(10) Michalak, K.; Michalak, M.; Wicha, J. Tetrahedron Lett. 2005, 46, 1149.

(11) Torssell, S.; Wanngren, E.; Somfai, P. J. Org. Chem. 2007, 72, 4246.

O CH3CH3

HC848 (3 mol%)

CH3

HCH3

O

CO2MeMeO2C

CH2Cl2, 40 °C95%

NO

H

EtO2CC848 (5 mol%)CH2Cl2, 40 oC

92%

NO

EtO2C


MACROCYCLICRING-CLOSING METATHESIS

n

m

n

m[Ru]

OVERVIEWExcellent functional group compatibility in addition to a tolerance of residual moisture and oxygen have facilitated the broad acceptance of ruthenium-catalyzed macrocyclization as a general methodology for the preparation of large rings (≥12 atoms).12

REACTION-SPECIFIC CONSIDERATIONS• To avoid the formation of dimers and oligomers,

macrocyclizations are usually run at lowconcentration (0.01 to 0.1 M).

• When running a macrocyclization reaction, it can be advantageous to slowly add catalyst and substrate to the reaction vessel (see Figure 11).

• Oligomerization is often reversible and a functionof concentration.


0.58mM CH2Cl2, reflux

C848 (15 mol%)

R

O

N

O

PhO

N

O

R

O

PhO

90%

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 the cytotoxic marine natural product (-)-spongidepsin (Fig. 10).13 The desired intermediate was prepared in excellent yield using 15 mol% C848 under high dilution conditions.

N CO2H

OHN

O

O

NO

O

N CO2H

OHN

O

O

NO

O

C627 (0.2 mol%)2,6-dichloro-benzoquinone0.13M toluene100 oC 91%

1

2

simultaneous slow addition of 1 and C627

Figure 11. Key RCM in synthesis of vaniprevir

In an industrial setting, ring-closing metathesis of the diene 1 afforded the 20-membered macrocyclic core of Vaniprevir (HCV protease inhibitor).14 After extensive optimization, a very efficient reaction was achieved by simultaneous slow addition of the catalyst and the substrate. Removal of ethylene by nitrogen sparge and addition of 2,6-dichloroquinone to the reaction mixture minimized catalyst decomposition and isomerization of the allylbenzene-double bond in the starting material. Only 0.2 mol% of C627 was needed to give excellent yield of the desired macrocycle 2 (Fig. 11).


2Cl

2, PhMe, TBME

Concentration: 0.05-0.1 MPreferred Catalyst Options: C627, C848Catalyst Loading: 3-10 mol%Temperature: 40-100 °C

REFERENCES(12). Hanson, P. H.; Maitra, S.; Chegondi, R.; Markley, J. L. General Ring-Closing Metathesis. Synthesis of Macrocycles. In Handbook of Metathesis; Grubbs, R. H.; 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.

n

m

n

m[Ru]

0.58mM CH2Cl2, reflux

C848 (15 mol%)

R

O

N

O

PhO

N

O

R

O

PhO

90%

N CO2H

OHN

O

O

NO

O

N CO2H

OHN

O

O

NO

O

C627 (0.2 mol%)2,6-dichloro-benzoquinone0.13M toluene100 oC 91%

1

2

simultaneous slow addition of 1 and C627


STERICALLY DEMANDING RING-CLOSING METATHESIS

R

n n

R

OVERVIEWFor sterically demanding ring-closing metathesis reactions, catalysts such as C571 (Fig. 12) bearing a less bulky NHC often give superior performance.15 Sterically demanding substrates include 1,1 disubstituted olefins, olefins bearing a bulky group at the allylic position, and olefins that are part of a cage system.

Figure 12. Grubbs Catalyst® C571

REACTION-SPECIFIC CONSIDERATIONS• Sterically demanding reactions often require heating.• If you are seeing intermolecular cross coupling at the less hindered olefin center, try diluting the reaction.


N

Ph

N

Ph

C571 (10 mol%)

PhMe, 80 oCN

Ph

NPh

OEt

O

EtO O

82 %

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).

C571 (6 mol %)

89 %

N

O

N

O

ethylene (1 atm)PhMe, 100 °C

Figure 14. Metathesis rearrangement

Vanderwal and co-workers reported the use of C571 to generate complex polycyclic scaffolds from Himbert cycloadducts.17 An N-allylpyrrolidinone fused 2,2,2-bicycle is opened under ethylene atmosphere to give the rearranged polycyclic product in 89% yield (Fig. 14).


2Cl

2, PhMe, TBME

Concentration (Ring Size): 1.0 M (5), 0.5 M (6), 0.2 M (7), 0.1M (8), 0.05M or less (9-11)Preferred Catalyst Options: C571Catalyst 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. Chem. 2013, 21, 5707.

(17). Lam, J. K.; Schmidt, Y.; Vanderwal, C. D. Org. Lett. 2012, 14, 5566.

R

n n

R

N

Ph

N

Ph

C571 (10 mol%)

PhMe, 80 oCN

Ph

NPh

OEt

O

EtO O

82 %

C571 (6 mol %)

89 %

N

O

N

O

ethylene (1 atm)PhMe, 100 °C


CROSS METATHESIS OF ELECTRON-DEFICIENTOLEFINS

R + EWG[Ru] R

EWG

OVERVIEWElectron deficient olefins are intrinsically less reactive than electron rich olefins in metathesis reactions. However, this feature makes selective cross-metathesis between an electron rich and an electron deficient olefin possible given the slower rate of the reverse reaction. In general, 2nd Generation catalysts such as C949 (Fig. 15) or C848 are preferred in this application which has been used on large scale to generate value-added chemicals from biorenewable sources and to generate biologically active analogues of medicinally relevant substructures.


REACTION-SPECIFIC CONSIDERATIONS• An excess of the electron-deficient cross metathesis

partner may produce better yields.• Cross metatheses typically work best at high

concentration of the substrates.


PhMe, 60°C

CO2Me

RCO2Me

acrylate

(R = H)crotonate (R = Me)

C949 (29 ppm)

Conversion58%96%

Productive TON6,000

31,110

6

6

CO2Me

6

MeO2Cdesired

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

for cross metathesis over self metathesis is necessary. Furthermore, minimization of catalyst loading is crucial in these cost-sensitive applications. Gauvin and coworkers improved the catalytic turnover in the synthesis of bis-esters from methyl oleate when methyl acrylate was replaced with methyl crotonate as the 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 Catalyst Decomposition by Ethylene). High conversion to the desired cross metathesis product was observed using only 29 ppm of C949.

CH2Cl2, 40°C

C848

(CH2)12CH3

O

O

Ph

(CH2)12CH3

Ph

O

O68%

Figure 17. CM of a ẞ-lactone Michael acceptor

A cross metathesis approach to synthesize serine hydrolase inhibitors was reported by Howell andCravatt.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).


2Cl

2, PhMe, neat (no solvent)

Concentration: 1 M or greaterPreferred Catalyst Options: C627, C848, C949Catalyst Loading: 1-5 mol%Temperature: 40-60 °C

REFERENCES(18). Vignon, P.; Vancompernolle, T.; Couturier, J.-L.; Dubois, J.-L.; Mortreaux, A.; Gauvin, R. M. ChemSusChem 2014, 8, 1143.

(19). Camara, K.; Kamat, S. S.; Lasota, C. C.; Cravatt, B.

F.; Howell, A. R. Bioorg. Med. Chem. Lett. 2015, 25, 317.

R + EWG[Ru] R

EWG

PhMe, 60°C

CO2Me

RCO2Me

acrylate (R = H)crotonate (R = Me)

C949 (29 ppm)

Conversion58%96%

Productive TON6,00031,110

6

6

CO2Me

6

MeO2Cdesired

CH2Cl2, 40°CC848

(CH2)12CH3

O

O

Ph

(CH2)12CH3

Ph

O

O68%

methyl oleate


TRISUBSTITUTEDLINEAR OLEFINS

RR1

R3

R2

+ R1R3

R2

R +

R1 = H, alkyl R4

R4[Ru]

OVERVIEWAlthough the preparation of highly substituted olefins by cross-metathesis is challenging, it can be achieved using 2nd Generation catalysts. Both 1,1-disubstituted and trisubstituted olefins have been used successfully as cross metathesis partners.20

REACTION-SPECIFIC CONSIDERATIONS• Sterically demanding reactions often require heating

to 40 °C or greater.• Cross metatheses typically work best at high

concentration of the substrates.• An excess of the sterically hindered substrate may

be required.


Catalyst (5 mol%)CH2Cl2

, 40 °C

OAcOAc

+

CatalystC571C627C711

Yield60%78%98%

Ru

OiPr

Cl

ClL

L = sIMes (C627) sIPr (C711) s(o-Tol) (C571)

Figure 18. CM of methylenecyclohexane

C711 is often the optimal catalyst for the cross metathesis of 1,1-disubstituted olefins. This is counter to the trend in ring-closing metathesis of sterically-hindered 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

ligands are preferred for 1,1-disubstituted olefins, C627 or C848 (bearing the sIMes NHC) may outperform C711 in making 1,2-disubstituted olefins bearing large allylic substituents.

OAc

O

83%

OAc

OC848

(5 mol%)

neat, 80 ºC, 2 h33 mbar

2

2

67:33 E:Z


Netscher and coworkers utilized the cross-metathesis of trisubstituted and 1,1-disubstituted olefins to access vitamin E intermediates in good yields using C848 (Fig. 20). Conducting the reaction in vacuo (33 mbar) to remove isobutylene improved the yield of this transformation from 67% to 83%.22

Figure 20. Tocopherol derivatives by CM


2Cl

2, PhMe, neat (no solvent)

Concentration: 1 M or greaterPreferred Catalyst Options: C627, C848, C711Catalyst Loading: 1-5 mol%Temperature: 40-100 °C

REFERENCES(20). Chatterjee, A. K.; Grubbs, R. H. Org. Lett. 1999, 1, 1751-1753. Chatterjee, A. K.; Sanders, D. P.; Grubbs, R. H. Org. Lett. 2002, 4, 1939-1942.

(21). Stewart, I. C.; Douglas, C. D.; Grubbs, R. H. Org. Lett. 2008, 10, 441.

(22). Netscher, T. J. Organomet. Chem. 2006, 691, 5155-5162. Malaisé, G.; Bonrath, W.; Breuninger, M.; Netscher, T. Helv. Chim. Acta 2006, 89, 797-812.

RR1

R3

R2

+ R1R3

R2

R +

R1 = H, alkyl R4

R4[Ru]

Catalyst (5 mol%)CH2Cl2, 40 °C

OAcOAc

+

CatalystC571C627C711

Yield60%78%98%

Ru

OPr

Cl

ClL

L = sIMes (C627) sIPr (C711) s(o-Tol) (C571)

OAc

O

83%

OAc

OC848 (5 mol%)neat, 80 ºC, 2 h

33 mbar

2

2

67:33 E:Z

i

* For Z-selective M

acrocyclizatio

n

Pyrid

ine

, Et3 N

OLEFIN METATHESIS APPLICATION GUIDE - Materia Inc · olefin metathesis application guide with bonus...

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