Formation of Z- using metathesis

Literature Review – 22.3.13 Bryony Elbert Introduction

o In 2005 the Nobel Prize for Chemistry was awarded jointed to Yves Chauvin, Robert H. Grubbs and Richard R. Schrock for “the development of the metathesis method in organic synthesis”

Yves Chauvin Robert H. Grubbs Richard R. Schrock

o Metathesis represents a very powerful C–C bond forming reaction that has been widely used both in academia and industry

o General mechanism:

o A continuing challenge has been the control of the geometry of the forming double bond, and this talk will focus on the preferential formation of Z-geometries 1 Introduction  The Problem of Controlling Geometry

o metathesis is a thermodynamic process that is often reversible o Olefin products can potentially undergo secondary reactions with the catalyst to isomerise to the more thermodynamically stable form

o Therefore, in the majority of cases, the thermodynamic E-isomer results, or mixtures of E and Z geometries result.

o Forming Z-selective alkenes represents a significant challenge :

K. C. Nicolaou in 2005:

“… we still lack the ability to reliably predict (or achieve) product geometry for certain ring-closing metathesis reactions in complex situations. Indeed, this sometimes unpredictable formation of stereoisomeric mixtures represents one of the few significant blots on the landscape of ring-closing metathesis macrocyclization.”

o Only recently has Z-selectivity been achieved in a controllable way o First example reported by Schrock and Hoveyda in early 2009

o Before this, however, there are still numerous examples of Z-olefins forming in metathesis reactions.

2 Nicolaou, K. C. Angew. Chem. Int. Ed. 2005, 44, 4490-4527 Overview

o Introduction

o Substrate Control

o Macrocyclizations o Acrylonitriles and Enynes

o Indirect Control of Alkene Geometry

o Catalyst Control

o Mo/W Catalysts

o Ru Catalysts

o Comparison of Various Methods – Nakadomarin A

o Conclusion Substrate Control  Macrocyclizations o With medium and large rings mixtures of E and Z isomers tend to result o Delicate balance between kinetic and thermodynamic control, affected by: o Solvent, catalyst, temperature… o Substitution pattern of substrate o Steric demand of substrate o Ring size to be formed o Presence of coordinating heteroatoms in substrate o Examples: o Thermodynamic vs. kinetic control (3.5 kcal difference):1

o Remote substituent effects:2

3 1. Fürstner, A.; Radkowski, K.; Wirtz, C.; Goddard, R.; Lehmann, C. W.; Mynott, R. J. Am. Chem. Soc. 2002, 124, 7061-7069; 2. Fürstner, A.; Thiel, O. R.; Blanda, G. Org. Lett. 2000, 2, 3731-3734 Substrate Control  Acrylonitriles and Enynes

o In cross-metatheses where one alkene bears an sp hybridized substituent the Z-olefin is preferentially formed:

o Acrylonitriles:1

o Enynes: 2

o Kinetic product forms, with alkene substituents orientated away from bulky NHC o Acrylonitriles and enynes show low reactivity in metathesis – hence once product forms it is inert to post-metathesis isomerisation to the thermodynamic E-product

4 1. Randl, S.; Gessler, S.; Wakamatsu, H.; Blechert, S. Synlett. 2001, 3, 430-432; 2. Hansen, E. C.; Lee, D. Org. Lett. 2004, 6, 2035-2038 Overview

o Introduction

o Substrate o Indirect Control of Alkene Geometry

o RCAM / Lindlar Hydrogenation o Silicon Tethering o RCM of Vinylsiloxanes

o Catalyst Control

o Mo/W Catalysts

o Ru Catalysts

o Comparison of Various Methods – Nakadomarin A

o Conclusion Indirect Control of Alkene Geometry  RCAM/Lindlar Hydrogenation

o For larger rings (>12 mem) possible to use a ring-closing metathesis, followed by Lindlar hydrogenation:

o of turrianes:

5 Fürstner, A.; Stelzer, F.; Rumbo, A.; Krause, H. Chem. Eur. J. 2002, 8, 1856-1871 Indirect Control of Alkene Geometry  RCAM/Lindlar Hydrogenation

o For larger rings (>12 mem) possible to use a ring-closing alkyne metathesis, followed by Lindlar hydrogenation:

o Total synthesis of turrianes:

o Disadvantages: o Fewer commercially available , syntheses tend to be less concise than for alkenes o Can only access disubstituted alkenes o Can be difficult to completely remove Pd catalyst and Pb poison 6 Fürstner, A.; Stelzer, F.; Rumbo, A.; Krause, H. Chem. Eur. J. 2002, 8, 1856-1871 Indirect Control of Alkene Geometry  Silicon Tethering

o Use of a temporary silicon tether renders metathesis intramolecular, forming small/medium rings where the Z-isomer is the only geometry that can form1 o Reduces enthalpic and entropic cost of metathesis, substituents on Si have a Thorpe- Ingold effect o Applied to acyclic metathesis, ie:2

o Disadvantages: o Low atom ecomony o Complicates a synthesis and adds steps o Principally applied to acyclic systems, not used for macrocycles

7 1. Čusak, A. Chem. Eur. J. 2012, 18, 5800-5824 2. Van de Weghe, P.; Bourg, S.; Eustache, J. Tetrahedron 2003, 59, 7365-7376 Indirect Control of Alkene Geometry  RCM of Vinylsiloxanes o Ring-closing metathesis of vinylsiloxanes gives high E-selectivity: o Protodesilylation – Z-disubstituted alkene:1

o Alternatively, subsequent cross-coupling can provide access to both E- and Z-trisubstituted alkenes:2

8 1. Wang, Y.; Jimenez, M.; Hansen, A. S.; Raiber, E-S.; Schreiber, S. L.; Young, D. W. J. Am. Chem. Soc. 2011, 133, 9196-9199 2. Wang, Y.; Jimenez, M.; Sheehan, P.; Zhong, C.; Hung, A. W.; Tam, C. P.; Young, D. W. Org. Lett. 2013, 15, 1218-1221 Overview

o Introduction

o Substrate Control

o Indirect Control of Alkene Geometry

o Catalyst Control

o Introduction

o Mo/W Catalysts

o Introduction o MAP-Catalysts o Mechanism o Synthesis of Catalysts o Applications o RO/CM and ROMP o RCM o Homocoupling o Cross-metathesis o Case Study in Catalyst Design

o Ru Catalysts o Comparing Mo/W and Ru

o Comparison of Various Methods – Nakadomarin A

o Conclusion Catalyst Control  Introduction

o Currently, there are two types of Z-selective catalyst that have been reported

o and -based complexes

o Ruthenium-based complexes

o There are particular challenges associated with designing such catalytic systems:

o Need to generate a kinetic, thermodynamically unfavourable product

o Catalysts need not to undergo secondary isomerisation reactions to equilibrate the product to the more stable E-geometry (as is seen with most conventional metathesis catalysts)

o Catalysts need to be stable to decomposition

o Needs to survive the duration of the reaction in order to reach high turnover numbers (TONs)

o Decomposition products may promote unwanted side reactions with the products – for example, [Ru]–H species formed by the decomposition of Ru-catalysts can cause olefin migration in both starting materials and products

9 Ibrahem, I., Yu, M., Schrock, R. R., Hoveyda, A. H. J. Am. Chem. Soc. 2009, 131, 3844-3845 Catalyst Control – Mo/W  Introduction

o Z-selective metathesis catalysts first reported by Schrock and Hoveyda in early 2009

o Using a stereogenic-at-Mo monoaryloxide-pyrrolide (MAP) catalyst in a ring- opening/cross metathesis (RO/CM) reaction:

o Since 2009 Mo- and W-MAP complexes have also been used for ring-closing metathesis (RCM), ring-opening metathesis polymerisation (ROMP), homocoupling of olefins and cross-metathesis

10 Ibrahem, I., Yu, M., Schrock, R. R., Hoveyda, A. H. J. Am. Chem. Soc. 2009, 131, 3844-3845 Catalyst Control – Mo/W Imido - Adamantyl or aryl  MAP Catalysts

Imidazole Ligand - With or without Me in 2,5-positions Alkylidene Ligand - Bulky group to prevent bimolecular decomposition (see later)

Aryloxide Ligand - R = CMe3 or CMe2Ph - Very bulky to get good Z- selectivity (see later) - Binol derivatives: Metal Centre - Choice of Mo or W - Mo: - More active - More prone to 2° isomerisation - Achiral aryloxides: - Very air/moisture sensitive - W: - Less active, but more selective - Aryloxy-ligand can freely - Less prone to rotate isomerisation 11 - Air/moisture tolerant Catalyst Control – Mo/W  Mechanism

12 Wang, C.; Yu, M.; Kyle, A. F.; Jakubec, P.; Dixon, D. J.; Schrock, R. R.; Hoveyda, A. H. Chem. Eur. J. 2013, 19, 2726-2740 Catalyst Control – Mo/W  Aside: Why such bulky ?

o Very large ligands help to keep the metal centres apart and prevent bimolecular decomposition:

o Generates metathesis-inactive bimolecular species o Fastest for methylidene complexes o Running reactions under reduced pressure to remove ethene can help to minimise concentration of highly reactive and unstable methylidene species and promote catalyst stability and improve selectivity

13 Schrock, R. R., Hoveyda, A. H. Angew. Chem. Int. Ed. 2003, 42, 4592-4633 Catalyst Control – Mo/W  Synthesis of Mo- and W-MAP complexes

o 5-step synthesis of catalyst precursors:

14 Schrock, R. R., Hoveyda, A. H. Angew. Chem. Int. Ed. 2003, 42, 4592-4633 Catalyst Control – Mo/W  Synthesis of Mo- and W-MAP complexes

o Active catalyst is then generated in situ by reaction between precursor complex and bulky aryloxide ligand, before being transferred into a solution of metathesis substrate:

o Use chiral, racemic catalysts (metal centre inverts with each forward metathesis step o Typically use 1-2 mol% catalyst

15 Catalyst Control – Mo/W  Applications – ROCM and ROMP

o Ring-opening/cross-metathesis was the first reported use of Mo-MAP catalysts (see slide x) o A recent example demonstrates their use in the enantioselective desymmetrization of cyclic alkenes:

16 Yu, M.; Ibrahem, I.; Hasegawa, M.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2012, 134, 2788-2799 Catalyst Control – Mo/W  Applications – ROCM and ROMP

o Mo-MAP complexes have been most extensive used in ring-opening metathesis polymerisation reactions o They generate highly tactic (regular) polymers with high-cis contents o Controlling polymer structure at the molecular level is key to the synthesis of polymers that have a single structure and therefore uniform and reproducible properties o As stereocentre at the metal inverts with each forward-metathesis step, the polymer is formed from a regular chain of alternating enantiomers

17 Flook, M. M.; Jiang, A. J.; Schrock, R. R.; Müller, P.; Hoveyda, A. H. J. Am. Chem. Soc. 2009, 131, 7962-7963 Catalyst Control – Mo/W  Applications – RCM

o Ring-closing metathesis is commonly used for the synthesis of small, medium and large macrocyclic rings, but with medium/large rings, the control of alkene geometry has been a major problem, which can be circumvented with Mo- or W-MAP complexes o Epothilone C: o Using a conventional catalyst:1

o With a W-MAP catalyst:2

18 1. Nicolaou, K. C.; He, Y.; Vourloumis, D.; Vallberg, H.; Roschangar, F.; Sarabia, F.; Ninkovic, S.; Yang, Z.; Trujillo, J. I. J. Am. Chem. Soc. 1997, 119, 7960-7973; 2. Yu, M.; Wang, C.; Kyle, A. F.; Jakubec, P.; Dixon, D. J.; Schrock, R. R.; Hoveyda, A. H. Nature, 2011, 479, 88-93 Catalyst Control – Mo/W  Applications – RCM

o RCM demonstrates the complementary nature of Mo- and W- based catalysts: o M = Mo o More active catalyst better for more conformationally mobile substrates, but more prone to post-RCM isomerism:

o M = W o Fairly air- and moisture-tolerant catalyst shows better selectivity and can be used for a relatively preorganised substrate:

19 Wang, C.; Yu, M.; Kyle, A. F.; Jakubec, P.; Dixon, D. J.; Schrock, R. R.; Hoveyda, A. H. Chem. Eur. J. 2013, 19, 2726-2740 Catalyst Control – Mo/W  Applications – Homocoupling

o Homocoupling of terminal alkenes has provided a route to symmetrical Z-alkenes:1

o Specific properties of Mo- and W-MAP complexes has allowed very rare homodimerisation of 1,3-dienes to give E,Z,E trienes:2

20 1. Jiang, A. J.; Zhao, Y.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2009, 131, 16630-16631; 2. 2. Townsend, E. M.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2012, 134, 11334-11337 Catalyst Control – Mo/W  Applications – Cross-Metathesis

o Cross-metathesis is more challenging than homocoupling as there is the potential for several products to form, hence there have been few examples:

o With enol ethers:

o With allylic amides:

21

Meek, S. J.; O’Brien, R. V.; Llaveria, J.; Schrock, R. R.; Hoveyda, A. H. Nature, 2011, 471, 461-466 Catalyst Control – Mo/W  Applications – Cross-Metathesis

o Cross-metathesis is more challenging than homocoupling as there is the potential for several products to form, hence there have been few examples: o Application to stereoselective syntheses: o Anti-oxidant plasmalogen phospholipid C18 (plasm)-16:0

o Immunostimulant KRN7000

22

Meek, S. J.; O’Brien, R. V.; Llaveria, J.; Schrock, R. R.; Hoveyda, A. H. Nature, 2011, 471, 461-466 Catalyst Control – Mo/W  Case Study – How to Train Your Catalyst

o RCM to form a trisubstituted Z-alkene and access epothilones B and D:

o Mo or W? No activity with W

23

Wang, C.; Haeffner, F.; Schrock, R. R.; Hoveyda, A. H. Angew. Chem. Int. Ed., 2013, 52, 1939-1943 Catalyst Control – Mo/W  Case Study – How to Train Your Catalyst

o RCM to form a trisubstituted Z-alkene and access epothilones B and D:

o Mo or W? No activity with W o Catalyst stability

23

Wang, C.; Haeffner, F.; Schrock, R. R.; Hoveyda, A. H. Angew. Chem. Int. Ed., 2013, 52, 1939-1943 Catalyst Control – Mo/W  Case Study – How to Train Your Catalyst

o RCM to form a trisubstituted Z-alkene and access epothilones B and D:

o Mo or W? No activity with W o Catalyst stability – Change imido ligand

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Wang, C.; Haeffner, F.; Schrock, R. R.; Hoveyda, A. H. Angew. Chem. Int. Ed., 2013, 52, 1939-1943 Catalyst Control – Mo/W  Case Study – How to Train Your Catalyst

o RCM to form a trisubstituted Z-alkene and access epothilones B and D:

o Mo or W? No activity with W o Catalyst stability – Change imido ligand o Increase RCM efficiency – more EW ligands

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Wang, C.; Haeffner, F.; Schrock, R. R.; Hoveyda, A. H. Angew. Chem. Int. Ed., 2013, 52, 1939-1943 Catalyst Control – Mo/W  Case Study – How to Train Your Catalyst

o RCM to form a trisubstituted Z-alkene and access epothilones B and D:

o Mo or W? No activity with W o Catalyst stability – Change imido ligand o Increase RCM efficiency – more EW ligands o Small F allows bisaryloxide to form

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Wang, C.; Haeffner, F.; Schrock, R. R.; Hoveyda, A. H. Angew. Chem. Int. Ed., 2013, 52, 1939-1943 Catalyst Control – Mo/W  Case Study – How to Train Your Catalyst

o RCM to form a trisubstituted Z-alkene and access epothilones B and D:

o Mo or W? No activity with W o Catalyst stability – Change imido ligand o Increase RCM efficiency – more EW ligands o Small F allows bisaryloxide to form o Improve Z-selectivity – make aryloxides bigger

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Wang, C.; Haeffner, F.; Schrock, R. R.; Hoveyda, A. H. Angew. Chem. Int. Ed., 2013, 52, 1939-1943 Catalyst Control – Mo/W  Case Study – How to Train Your Catalyst

o RCM to form a trisubstituted Z-alkene and access epothilones B and D:

o Mo or W? No activity with W o Catalyst stability – Change imido ligand o Increase RCM efficiency – more EW ligands o Small F allows bisaryloxide to form o Improve Z-selectivity – make aryloxides bigger o But not too big… Make imido ligand smaller too

Isolated desired macrocyclic Z–alkene in 82% yield as a 91:9 Z:E mixture

23

Wang, C.; Haeffner, F.; Schrock, R. R.; Hoveyda, A. H. Angew. Chem. Int. Ed., 2013, 52, 1939-1943 The Lighter Side of Metathesis…

“Ruthenium–Amido Complexes: Synthesis, Structure, “Highly active catalysts for olefin and Catalytic Activity in ” metathesis in water” Chem. Eur. J. 2012, 18, 6465-6469 Catal. Sci. Technol. 2012, 2, 2424-2427

“Stable ruthenium indenylidene complexes with sterically reduced NHC ligand” “Synthesis of functionalised NHC Chem. Comm. 2013, Adv. Artic. ligands bearing a longer spacer and their use in olefin metathesis” Dalton Trans., 2013, Adv. Artic.

“Easily removable olefin metathesis catalysts” 24 Green. Chem. 2012, 14, 3264-3268 Overview

o Introduction

o Substrate Control

o Indirect Control of Alkene Geometry

o Catalyst Control

o Introduction

o Mo/W Catalysts

o Ru Catalysts o Introduction o Chen – Modified 1st Generation Grubbs-Hoveyda o Grubbs – Chelating NHC Catalysts o Synthesis of Catalysts o Mechanism o Applications o Homodimerization o Cross-metathesis o RCM o Hoveyda – Bridging Aryloxy Ligand o Jensen – 1 Step Modification of Grubbs-Hoveyda 2nd Generation o Comparing Mo/W and Ru

o Comparison of Various Methods – Nakadomarin A

o Conclusion Catalyst Control – Ru  Introduction

o Pioneering work by Schrock and Hoveyda on Mo and W catalysts opened the door for the development of complementary ruthenium-based systems, and their use in Z-selective olefin metathesis was first reported by Chen et al (see later) in 2010.

o Tend to be more tolerant of functionality than Mo/W variants.

o Ru-complexes have less well-defined structure-property relationships than Mo- and W-MAP complexes, making them more challenging to design.

o However, their ease of synthesis has led to a greater diversity of examples in the literature, with several mecanistically distinct ‘classes’ being reported:

o Chen et al – modified ‘first generation’ Ru complexes with bulky sulfonates o Grubbs et al – chelated NHC catalysts o Hoveyda et al – catalysts with a bidentate NHC with aryloxide bridging ligand o Jensen et al – Grubbs-Hoveyda 2nd gen. catalysts modified with thiolate ligand

25 Catalyst Control – Ru  Chen – Modified 1st Gen Grubbs-Hoveyda

o The first example of Ru-based Z-selective catalyst, applied to ring-opening metathesis polymerisation:

o Catalyst features a bulky sulfonate ligand in the plane of the Ru-carbene:

26 Torker, S.; Müller, A.; Chen, P. Angew. Chem. Int. Ed. 2010, 49, 3762-3766 Catalyst Control – Ru  Grubbs – Chelating NHC Catalysts

o Grubbs et al first reported a Z-selective Ru catalyst in 2011 o Stable to water and protic solvents o Formed in 2 steps from commercially available precursors by intramolecular C–H activation of the NHC ligand:

27 Endo, K.; Grubbs, R. H. J. Am. Chem. Soc. 2011, 133, 8525-8527 Catalyst Control – Ru  Grubbs – Mechanism of Z-selectivity

28 Dang, Y.; Wang, Z-X.; Wang, X. Organometallics 2012, 31, 7222-7234 Catalyst Control – Ru  Grubbs – Use in Homodimerization

o Initially, published a series of homocouplings with a pivalate ligand which gave inferior results.1 o Found that switching to the nitrato ligand gave increased yields and selectivities, allowing catalyst loading as low as 0.1 mol%.2

29 1. Keitz, B. K.; Endo, K.; Herbert, M. B.; Grubbs, R. H. J. Am. Chem. Soc. 2011, 133, 9686-9688; 2. Keitz, B. K.; Endo, K.; Patel, P. R.; Herbert, M. B.; Grubbs, R. H. J. Am. Chem. Soc. 2012, 134, 693-699 Catalyst Control – Ru  Grubbs – Cross-Metathesis

o Used to synthesise a series of insect phermones as potential pest-control agents from renewable plant oils. o Avoids the difficulty of completely removing the Pd catalyst and Pb poison used in Lindlar reductions. o One partner used in great excess (as co-solvent)

In the example above, industrial synthesis involves expensive formation of disubstituted

acetylenes, which requires large amounts of liquid NH3. There are also issues with incomplete reduction and migration and isomerisation of double bonds.

30 Herbert, M. B.; Marx, V. M.; Pederson, R. L.; Grubbs, R. H. Angew. Chem. Int. Ed. 2013, 52, 310-314 Catalyst Control – Ru  Grubbs – RCM

o The first report of ring-closing metathesis with catalysts of this type was published only 3 months ago:

31 Marx, V. M.; Herbert, M. B.; Keitz, B. K.; Grubbs, R. H. J. Am. Chem. Soc. 2013, 135, 94-97 Catalyst Control – Ru  Grubbs – A New Catalyst

o Very recently, Grubbs et al reported that milder C–H activation conditions had allowed them to access a new catalyst o Replace Mes group on NHC with a bulkier DIPP group:

o Has significantly improved Z-selectivity and efficiency o Now possible to use loadings as low as 0.01 mol% of A:

o Also effective for RCM and cross-metathesis

32 Rosebrugh, L. E.; Herbert, M. B.; Marx, V. M.; Keitz, B. K.; Grubbs, R. H. J. Am. Chem. Soc. 2013, 135, 1276-1279 Catalyst Control – Ru  Hoveyda – Bridging Aryloxy Ligand

o Last year, Hoveyda et al reported a new highly enantioselective and Z-selective catalyst for ring-opening/cross-metathesis of enol ethers

o Complex used was enantiomerically pure, and stereogenic at Ru

o No explanation given for Z-selectivity, which they weren’t expecting

33 Khan, R. K. M.; O’Brien, R. V.; Torker, S.; Li, B.; Hoveyda, A. H. J. Am. Chem. Soc. 2012, 134, 12774-12779 Catalyst Control – Ru  Jensen – 1 Step Modification of G-H 2nd Gen

o Modified the commercially available Grubbs-Hoveyda 2nd generation catalyst with a one-step substitution of a single chloride ligand:

o Employed in homocoupling of various terminal olefins

o Terrible yields – reactions run to low conversion to minimise post-metathesis isomerism o Propose that selectivity arises from substituents pointing away from stereochemical ‘wall’ of triphenylbenzene moiety o Catalyst displays similar stability to parent complex – tolerates water, and to some extent oxygen

34 Occhipinti, G.; Hansen, F. R.; Törnroos, Jensen, V. R. J. Am. Chem. Soc. 2013, 135, 3331-3334 Catalyst Control  Comparing Mo-/W- and Ru- Based Catalysts

Molybdenum/Tungsten Ruthenium 5-step synthesis of catalyst 1-3 step synthesis of catalyst

Lots of structural variation – generally Little variation within each catalyst ‘class’, make lots of changes to the catalyst tend to be more ‘one-size-fits-all’

Catalyst can undergo secondary Catalyst can decompose to [Ru]–H reactions with product to isomerise it species that cause olefin migration

Much broader reaction profile, more Still limited to fairly simple examples – but developed field is the field growing faster?

Mo – very air and water sensitive Catalysts tend to be less sensitive W – can be water and air tolerant

Need higher catalyst loadings (0.1 – 10 Generally use lower catalyst loadings mol%) (0.01-5 mol%)

More ‘designable’, can make logical Less well-defined structure-property modifications relationships

35 So Which Method Do You Choose?  Case Study – Nakadomarin A

o A potent anti-microbial and anti-cancer agent isolated in minute quantities o Olefin metathesis - Grubb’s I1 vs. W-MAP complex:2

o RCAM/Lindlar strategy3

36 1. Jakubec, P.; Cockfield, D. M.; Dixon, D. J. J. Am. Chem. Soc. 2009, 131, 16632-16633 2. Yu, M; Wang, C.; Kyle, A. F.; Jakubec, P.; Dixon, D. J.; Schrock, R. R.; Hoveyda, A. H. Nature, 2011, 479, 88-93 3. Jakubec, P.; Kyle, A. F.; Calleja, J.; Dixon, D. J. Tet. Lett. 2011, 52, 6094-6097 Conclusion

o Z-selective olefin metathesis represents a significant challenge, that has only recently begun to be addressed directly

o Various options are available for forming Z-alkenes using metathesis, from more ‘traditional’ indirect methods to powerful new catalytic systems

o Currently, the catalyst-controlled methodology is limited by the difficulty in accessing catalysts and the general lack of examples

o However, this is likely to change over the next few years as this is an exciting, rapidly expanding area!

Any questions?

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