Formation of Z-alkenes 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 Alkene 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 alkyne metathesis, followed by Lindlar hydrogenation: o Total synthesis 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 acetylenes, 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 Molybdenum and tungsten-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 Ligand - 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 ligands? 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.