View source for Ring-closing metathesis

{{Reactionbox
| Name = Ring-closing metathesis
| Type = Ring forming reaction
| Section3 = {{Reactionbox Identifiers
| OrganicChemistryNamed = ring-closing-metathesis
| RSC_ontology_id = 0000245
}}
}}
'''Ring-closing metathesis''' ('''RCM''') is a widely used variation of [[olefin metathesis]] in organic chemistry for the synthesis of various [[Saturated and unsaturated compounds|unsaturated]] rings via the intramolecular [[olefin metathesis|metathesis]] of two [[terminal alkene]]s, which forms the cycloalkene as the  ''E-'' or ''Z-'' [[isomer]]s and [[Volatility (chemistry)|volatile]] [[ethylene]].<ref name=ref1>Carey, F. A.; Sunburg, R. J. Reactions Involving Transition Metals. ''Advanced Organic Chemistry: Reaction and Synthesis'', 5th Ed.; Part B; Springer: New York, '''2010''', pp. 761-767.</ref><ref name=ref2>Monfette, S.; Fogg, D. E. (2009). "Equilibrium Ring-Closing Metathesis". ''Chem. Rev.'' '''109''' (8): 3783-3816. {{doi| 10.1021/cr800541y}}.</ref>
[[File:Ring Closing Metathesis Reaction.png|600px|frameless|center]]
The most commonly synthesized ring sizes are between 5-7 atoms;<ref name=ref3>Deiters, A.; Martin, S. F. (2004). “Synthesis of Oxygen- and Nitrogen-Containing Heterocycles by Ring-Closing Metathesis”. ''Chem. Rev.'' '''104''' (5): 2199-2238. {{doi| 10.1021/cr0200872}}.</ref> however, reported syntheses include 45- up to 90- membered macroheterocycles.<ref name=ref4>Cain, M. F.; Forrest, W. P.; Peryshkov, R. V.; Schrock, R. R. Muller, P. (2013). “Synthesis of a TREN in Which the Aryl Substituents are Part of a 45 Atom Macrocycle”. ''J. Am. Chem. Soc.'' '''135''' (41): 15338-15341. {{doi| 10.1021/ja408964g}}.</ref><ref name=ref5>Dasgupta, S.; Wu, J. (2011). “Template-directed synthesis of kinetically and thermodynamically stable molecular necklace using ring closing metathesis”. ''Org. Biomol. Chem.'' '''9''': 3504-3515. {{doi| 10.1039/c0ob01034k}}</ref><ref name=ref6>Song, K. H.; Kang, S. O.; Ko, (2007). “Template Synthesis of a Huge Macrocycle by Olefin Metathesis Using Easily Accessible [Pt(PEt<sub>3</sub>)<sub>2</sub>] Templates”. ''Chem. Eur. J.'' '''13''' (18): 5129–5134. {{doi| 10.1002/chem.200700213}}.</ref> These reactions are metal-catalyzed and proceed through a [[Metallacycle#Metallacyclobutanes|metallacyclobutane]] intermediate.<ref name=ref7>Schmalz, H.-G. (1995). “Catalytic Ring-Closing Metathesis : A New, Powerful Technique for Carbon- Carbon Coupling in Organic Synthesis”. ''Angew. Chem. Int. Ed. Engl.'' '''34''' (17): 1833-1836. {{doi| 10.1002/anie.199518331}}.</ref> It was first published by Dider Villemin in 1980 describing the synthesis of an Exaltolide precursor,<ref name=ref8>Villemin, D. (1980). “Synthese de Macrolides par Metathese”. ''Tetrahedron Lett.'' '''21''' (18): 1715-1718.  {{doi|10.1016/S0040-4039(00)77818-X}}.</ref> and later become popularized by [[Robert Grubbs|Robert H. Grubbs]] and [[Richard Schrock|Richard R. Schrock]], who shared the [[Nobel Prize in Chemistry]], along with [[Yves Chauvin]], in 2005 for their combined work in [[olefin metathesis]].<ref name=ref9>Grubbs, R. H. (2006). “Olefin-Metathesis Catalysts for the Preparation of Molecules and Materials (Nobel Lecture)”. ''Angew. Chem. Int. Ed.'' '''45''' (23): 3760–3765. {{doi| 10.1002/anie.200600680}}.</ref><ref name=ref10>Schrock, R. R. (2006). “Multiple Metal–Carbon Bonds for Catalytic Metathesis Reactions (Nobel Lecture)”. ''Angew. Chem. Int. Ed.'' '''45''' (23), 3748-3759. {{doi| 10.1002/anie.200600085}}.</ref> RCM is a favorite among organic chemists due to its synthetic utility in the formation of rings, which were previously difficult to access efficiently, and broad substrate scope.<ref name=ref11>Trnka, T. M.; Grubbs, R. H. (2001). “The Development of L2X2Ru=CHR Olefin Metathesis Catalysts: An Organometallic Success Story”. ''Acc. Chem. Res.'' '''34''' (1):18-29. {{doi| 10.1021/ar000114f}}.</ref> Since the only major [[by-product]] is [[ethylene]], these reactions may also be considered [[Atom economy|atom economic]], an increasingly important concern in the development of [[green chemistry]].<ref name=ref7 />
There are several reviews published on ring-closing metathesis.<ref name=ref2 /><ref name=ref3 /><ref name=ref35>Furstner, A. (2000). “Olefin Metathesis and Beyond”. ''Angew. Chem. Int. Ed.'' '''39''' (17): 3012-3043. {{doi| 10.1002/1521-3773(20000901)39:17<3012::AID-ANIE3012>3.0.CO;2-G}}.</ref><ref name=ref53>Gradillas, A.; Perez-Castells, J. (2006). “Macrocyclization by Ring-Closing Metathesis in the Total Synthesis of Natural Products: Reaction Conditions and Limitations”. ''Angew. Chem. Int. Ed.'' '''45''': 6086-6101. {{doi| 10.1002/anie.200600641}}.</ref>
==History==
The first example of ring-closing metathesis was reported by Dider Villemin in 1980 when he synthesized an [[Exaltolide]] precursor using a WCl<sub>6</sub>/Me<sub>4</sub>Sn catalyzed metathesis cyclization in 60-65% yield depending on ring size '''(A)'''.<ref name=ref8 />  In the following months, Jiro Tsuji reported a similar metathesis reaction describing the preparation of a macrolide catalyzed by WCl<sub>6</sub> and dimethyltitanocene (Cp<sub>2</sub>TiMe<sub>2</sub>) in a modest 17.9% yield '''(B)'''.<ref>Tsuji, J.; Hashiguchi, S. (1980). “Application of Olefin Metathesis to Organic Synthesis. Syntheses of Civetone and Macrolides”. ''Tetrahedron Lett.'' '''21''' (31): 2955-2958. {{doi| 10.1016/0040-4039(80)88007-5}}.</ref>  Tsuji describes the [[olefin metathesis]] reaction as “…potentially useful in organic synthesis” and addresses the need for the development of a more versatile catalyst to tolerate various functional groups.
[[File:Villemin and Tsuji initial macrolide syntheses.png|500px|frameless|center]]
In 1987, Siegfried Warwel and Hans Kaitker published a synthesis of symmetric macrocycles through a [[Olefin metathesis|cross-metathesis]] dimerization of starting cycloolefins to afford C<sub>14</sub>, C<sub>18</sub>, and C<sub>20</sub> dienes in 58-74% yield, as well as C<sub>16</sub> in 30% yield, using [[Rhenium(VII) oxide|Re<sub>2</sub>O<sub>7</sub>]] on [[alumina|Al<sub>2</sub>O<sub>3</sub>]] and [[tetramethyltin|Me<sub>4</sub>Sn]] for catalyst activation.<ref>Warwel, S.; Katker, H. (1987). “Eine einfache Synthese makrocyclischer Kohlenwasserstoffe durch Metathese von Cyclooflefinen”. ''Synthesis.'' 935-937.</ref>
[[File:Warwel and Kaitker cross-metathesis dimerization.png|600px|frameless|center]]
After a decade since its initial discovery, [[Robert Grubbs|Grubbs]] and [[Gregory Fu|Fu]] published two influential reports in 1992 detailing the synthesis of O- and N- heterocycles via RCM utilizing Schrock’s molybdenum alkylidene catalysts, which had proven more robust and functional group tolerant than the tungsten chloride catalysts.<ref name=ref14>Fu, G. C.; Grubbs, R. H. (1992). “The Application of Catalytic Ring-Closing Olefin Metathesis to the Synthesis of Unsaturated Oxygen Heterocycles”. ''J. Am. Chem. Soc.'' '''114''' (13): 5426-5427. {{doi| 10.1021/ja00039a065}}.</ref><ref name=ref15>Fu, G. C.; Grubbs, R. H. (1992).“Synthesis of Nitrogen Heterocycles via Catalytic RingClosing Metathesis of Dienes”. ''J. Am. Chem. Soc.'' '''114''' (18): 7324-7325. {{doi| 10.1021/ja00044a070}}.</ref>  The synthetic route allowed access to [[dihydropyran]]s in high yield (89-93%) from readily available starting materials.<ref name=ref14 /> In addition, synthesis of substituted [[pyrroline]]s, tetrahydropyridines, and [[amides]] were illustrated in modest to high yield (73-89% ).<ref name=ref15 /> The driving force for the cyclization reaction was attributed to [[entropy|entropic]] favorability by forming two molecules per one molecule of starting material. The loss of the second molecule, [[ethylene]], a highly volatile gas, drives the reaction in the forward direction according to [[Le Chatelier's principle|Le Châtelier's principle]].<ref name=ref14 />
[[File:Grubbs initial RCM syntheses.png|700px|frameless|center]]
In 1993, [[Robert Grubbs|Grubbs]] and others not only published a report on carbocycle synthesis using a molybdenum catalyst,<ref>Fu, G. C.; Grubbs, R. H. (1993). “Synthesis of cycloalkenes via alkylidene-mediated olefin metathesis and carbonyl olefination”. ''J. Am. Chem. Soc.'' '''115''' (9): 3800-3801. {{doi| 10.1021/ja00062a066}}.</ref> but also detailed the initial use of a novel ruthenium carbene complex for metathesis reactions, which later became a popular catalyst due to its extraordinary utility. The ruthenium catalysts are not sensitive to air and moisture, unlike the molybdenum catalysts.<ref>Fu, G. C.; Nguyen, S. T.; Grubbs, R. H. (1993). “Catalytic Ring-Closing Metathesis of Functionalized Dienes by a Ruthenium Carbene Complex”. ''J. Am. Chem. Soc.'' '''115''' (21): 9856-9857. {{doi| 10.1021/ja00074a085}}.</ref> The ruthenium catalysts, known better as the [[Grubbs' catalyst|Grubbs Catalysts]], as well as molybdenum catalysts, or [[Olefin metathesis#Schrock catalysts|Schrock’s Catalysts]], are still used today for many metathesis reactions, including RCM. Overall, it was shown that metal-catalyzed RCM reactions were very effective in C-C bond forming reactions, and would prove of great importance in [[organic synthesis]], [[chemical biology]], [[materials science]], and various other fields to access a wide variety of [[Saturated and unsaturated compounds|unsaturated]] and highly functionalized cyclic analogues.<ref name=ref2 /><ref name=ref3 />
==Mechanism==
===General mechanism===
The mechanism for [[transition metal]]-catalyzed [[olefin metathesis]] has been widely researched over the past forty years.<ref>Chauvin, Y. (2006). “Olefin Metathesis: The Early Days (Nobel Lecture). ''Angew. Chem. Int. Ed.'' '''43''' (23): 3740-3747”. {{doi| 10.1002/anie.200601234}}.</ref> RCM undergoes a similar mechanistic pathway as other [[olefin metathesis]] reactions, such as cross metathesis (CM), [[Ring-opening metathesis polymerisation|ring-opening metathesis polymerization (ROMP)]], and [[Acyclic diene metathesis|acyclic diene metathesis (ADMET)]].<ref name=RHC>Crabtree, R. H. Applications. ''The Organometallic Chemistry of the Transition Metals'', 6th Ed.; John Wiley & Sons, Inc.: New Jersey, 2014, pp.318-322.</ref> Since all steps in the catalytic cycle are considered reversible, it is possible for some of these other pathways to intersect with RCM depending on the reaction conditions and substrates.<ref name=ref35 /> In 1971, [[Yves Chauvin|Chauvin]] proposed the formation of a [[Metallacycle#Metallacyclobutanes|metallacyclobutane]] intermediate through a [2+2] [[cycloaddition]]<ref name=RHC /><ref>Herisson, J-L.; Chauvin, Y. (1971). “Catalyse de transformation des olefines par les complexes du tungsten”. ''Makromolekulare Chemie.'' '''141''' (1): 161-176. {{doi| 10.1002/macp.1971.021410112}}.</ref> which then cycloeliminates to either yield the same alkene and catalytic species (a nonproductive pathway), or produce a new catalytic species and an [[Carbene#Carbene ligands in organometallic chemistry|alkylidene]] (a productive pathway).<ref>Stewart, I. C.; Keitz, B. K.; Kuhn, K. M.; Thomas, R. M.; Grubbs, R. H. (2010). “Nonproductive Events in Ring-Closing Metathesis Using Ruthenium Catalysts”. ''J. Am. Chem. Soc.'' '''132''' (25), 8534-8535. {{doi| 10.1021/ja1029045}}.</ref> This mechanism has become widely accepted among chemists and serves as the model for the RCM mechanism.<ref name=RBG>Grossman, R. B. Transition-Metal-Catalyzed & -Mediated Reactions. ''The Art of Writing Reasonable Organic Reaction Mechanisms'', 2nd Ed.; Springer: New York, 2003, pp. 324-325.</ref>
[[File:General mechanism for ring-closing metathesis.png|500px|frameless|center]]
Initiation occurs through substitution of the catalyst’s [[alkene]] ligand with substrate. This process occurs via formation of a new [[Carbene#Carbene ligands in organometallic chemistry|alkylidene]] through one round of [2+2] [[cycloaddition]] and cycloelimination. Association and dissociation of a [[phosphine]] ligand also occurs in the case of Grubbs catalysts.<ref>Ansyln, E. V.; Dougherty, D. A. Organotransition Metal Reaction Mechanisms and Catalysts. ''Modern Physical Organic Chemistry'', Murdzek, J., Ed. University Science Books, 2006, pp. 745-746.</ref>  In an RCM reaction, the [[Carbene#Carbene ligands in organometallic chemistry|alkylidene]] undergoes an [[Intramolecular reaction|intramolecular]] [2+2] [[cycloaddition]] with the second reactive terminal [[alkene]] on the same molecule, rather than an [[intermolecular]] addition of a second molecule of starting material, a common competing side reaction which may lead to polymerization<ref>Lee, C. W.; Grubbs, R. H. (2001). “Formation of Macrocycles via Ring-Closing Olefin Metathesis”. ''J. Org. Chem.'' '''66''' (21):7155-7158. {{doi| 10.1021/jo0158480}}.</ref> Cycloelimination of the [[Metallacycle#Metallacyclobutanes|metallacyclobutane]] intermediate forms the desired RCM product along with a [M]=CH<sub>2</sub>, or [[Carbene#Carbene ligands in organometallic chemistry|alkylidene]], species which reenters the catalytic cycle. While the loss of volatile ethylene is a driving force for RCM,<ref name=RBG /> it is also generated by competing metathesis reactions and therefore cannot be considered the only driving force of the reaction.<ref name=ref2 />
===Thermodynamics===
The reaction can be under [[chemical kinetics|kinetic]] or [[thermodynamic]] control depending on the exact reaction conditions, catalyst, and substrate. Common rings, 5- through 7-membered cycloalkenes, have a high tendency for formation and are often under greater thermodynamic control due to the [[enthalpy|enthalpic]] favorability of the cyclic products, as shown by ''Illuminati'' and ''Mandolini'' on the formation of [[lactone]] rings.<ref name=ref31>Illuminati, G.; Mandolini, L. (1981). “Ring Closure Reactions of Bifunctional Chain Molecules”. ''Acc. Chem. Res.'' '''14''' (5): 95-102. {{doi| 10.1021/ar00064a001}}.</ref> Smaller rings, between 5 and 8 atoms, are more thermodynamically favored over medium to large rings due to lower [[ring strain]]. [[Ring strain]] arises from abnormal bond angles resulting in a higher [[heat of combustion]] relative to the linear counterpart.<ref name=ref31 /> If the RCM product contains a strained olefin, polymerization becomes preferable through [[Ring-opening metathesis polymerisation|ring-opening metathesis polymerization]] of the newly formed olefin.<ref>{{cite web |url=http://faculty.chemistry.harvard.edu/files/myers/files/31-the_olefin_metathesis_reaction.pdf |last=Myers |first=Andrew |title=The Olefin Metathesis Reaction |access-date=2022-08-09 |website=faculty.chemistry.harvard.edu }}</ref> Medium rings in particular have greater ring strain, in part due to greater transannular interactions from opposing sides of the ring, but also the inability to orient the molecule in such a way to prevent penalizing [[Gauche effect|gauche interactions]].<ref name=ref31 /><ref>Anslyn, E. V.; Dougherty, D. A. Strain and Stability. ''Modern Physical Organic Chemistry'', Murdzek, J., Ed. University Science Books, 2006, pp. 107-111.</ref> RCM may be considered to have a kinetic bias if the products cannot reenter the catalytic cycle or interconvert through an equilibrium. A kinetic product distribution could lead to mostly RCM products or may lead to oligomers and polymers, which are most often disfavored.<ref name=ref2/>
[[File:Ring strain for various cycloalkanes.png|750px|center|frameless]]
===Equilibrium===
With the advent of more reactive catalysts, equilibrium RCM is observed quite often which may lead to a greater product distribution. The mechanism can be expanded to include the various competing equilibrium reactions as well as indicate where various side-products are formed along the reaction pathway, such as oligomers.<ref name=ref23>Conrad, J. C.; Eelman, M. D.; Duarte Silva, J. A.; Monfette, S.; Parnas, H. H.; Snelgrove, J. L.; Fogg, D. E. (2007). “Oligomers as Intermediates in Ring-Closing Metathesis”. ''J. Am. Chem. Soc.'' '''129''' (5): 1024-1025. {{doi| 10.1021/ja067531t}}.</ref>
[[File:Olefin metathesis equilibria.png|450px|center|frameless]]
Although the reaction is still under thermodynamic control, an initial [[Thermodynamic versus kinetic reaction control|kinetic product]], which may be dimerization or oligomerization of the starting material, is formed at the onset of the reaction as a result of higher catalyst reactivity. Increased catalyst activity also allows for the olefin products to reenter the catalytic cycle via non-terminal alkene addition onto the catalyst.<ref name=ref2 /><ref>Hocker, H. (1991). “Metathesis polymerization - stepwise or chain growth reaction?”. ''J. Mol. Catal.'' '''65''' (1-2): 95–99. {{doi| 10.1016/0304-5102(91)85086-H}}.</ref><ref name=ref25>Stewart, I. C.; Ung, T.; Pletnev, A. A.; Berlin, J. B.; Grubbs, R. H.; Schrodi, Y. (2007). “Highly Efficient Ruthenium Catalysts for the Formation of Tetrasubstituted Olefins via Ring-Closing Metathesis”. ''Org. Lett.'' '''9''' (8): 1589-1592. {{doi| 10.1021/ol0705144}}.</ref> Due to additional reactivity in strained olefins, an equilibrium distribution of products is observed; however, this equilibrium can be perturbed through a variety of techniques to overturn the product ratios in favor of the desired RCM product.<ref>Forbes, M. D. E.; Patton, J. T.; Myers, T. L.; Maynard, H. D.; Smith, Jr. D. W.; Schulz, G. R.; Wagener, K. B. (1992). Solvent-Free Cyclization of Linear Dienes Using Olefin Metathesis and the Thorpe lngold Effect".  ''J. Am. Chem. Soc.'' '''114''' (27): 10978-10980. {{doi| 10.1021/ja00053a054}}.</ref><ref>Yamamoto, K.; Biswas, K.; Gaul, C.; Danishefsky, S. J. (2003). “Effects of temperature and concentration in some ring closing metathesis reactions”. ''Tetrahedron Lett.'' '''44''' (16): 3297–3299. {{doi| 10.1016/S0040-4039(03)00618-X}}.</ref>
[[File:Concentration and temperature effect on RCM.png|750px|center|frameless]]
Since the probability for reactive groups on the same molecule to encounter each other is inversely proportional to the ring size, the necessary intramolecular cycloaddition becomes increasingly difficult as ring size increases. This relationship means that the RCM of large rings is often performed under high dilution (0.05 - 100 mM) '''(A)''' <ref name=ref2/><ref>Arakawa, K.; Eguchi, T.; Kakinuma, K. (1998). “An Olefin Metathesis Approach to 36- and 72-Membered Archaeal Macrocyclic Membrane Lipids”. ''J. Org. Chem.'' '''63''' (14): 4741–4745. {{doi| 10.1021/jo980472k}}.</ref> to reduce [[intermolecular]] reactions; while the RCM of common rings can be performed at greater concentrations, even [[Dry media reaction|neat]] in rare cases.<ref>Kuhn, K. M.; Champagne, T. M.; Hong, S. H.; Wei, W-H.; Nickel, A.; Lee, C. W.; Virgil, S. C.; Grubbs, R. H.; Pederson, R. L. (2010). “Low Catalyst Loadings in Olefin Metathesis: Synthesis of Nitrogen Heterocycles by Ring-Closing Metathesis”. ''Org. Lett.'' '''12''' (5): 984-987. {{doi| 10.1021/ol9029808}}.</ref><ref>Bach, T.; Lemarchand, A. (2002). “Synthesis of Ansa-Bridged Macrocyclic Lactams Related to the Antitumor Antibiotic Geldanamycin by Ring Closing Metathesis”. ''Synlett.''  '''8''': 1302-1304. {{doi| 10.1055/s-2002-32958}}.</ref> The equilibrium reaction can be driven to the desired [[Thermodynamic versus kinetic reaction control|thermodynamic products]] by increasing temperature '''(B)''', to decrease viscosity of the reaction mixture and therefore increase thermal motion, as well as increasing or decreasing reaction time '''(C)'''.<ref name=ref23 /><ref>Crimmins, M. T.; Brown, B. H. (2004). “An Intramolecular Diels-Alder Approach to the Eunicelins: Enantioselective Total Synthesis of Ophirin B”.  ''J. Am. Chem. Soc.'' '''126''' (33): 10264–10266. {{doi| 10.1021/ja046574b}}.</ref>
[[File:Time and catalyst effect on RCM.png|750px|center|frameless]]
Catalyst choice '''(D)''' has also been shown to be critical in controlling product formation. A few of the catalysts commonly used in ring-closing metathesis are shown below.<ref name=ref11 /><ref>Xu, Z.; Johannes, C. W.; Houri, A. F.; La, D. S.; Cogan, D. A.; Hofilena, G. E.; Hoveyda, A. H. (1997). “Applications of Zr-Catalyzed Carbomagnesation and Mo-Catalyzed  Macrocyclic Ring Closing Metathesis in Asymmetric Synthesis. Enantioselective Total Synthesis of Sch 38516 (Fluvirucin B1)”. ''J. Am. Chem. Soc.'' '''119''' (43): 10302–10316. {{doi| 10.1021/ja972191k}}.</ref><ref>Furstner, A.; Thiel, O. R.; Ackermann, L. (2001). “Exploiting the Reversibility of Olefin Metathesis. Syntheses of Macrocyclic Trisubstituted Alkenes and (R,R)-(−)-Pyrenophorin”. ''Org. Lett.'' '''3''' (3): 449–451. {{doi| 10.1021/ol0069554}}.</ref><ref>Furstner, A.; Thiel, O. R.; Kindler, N.; Bartkowska, B. (2000). “Total Syntheses of (S)-(−)-Zearalenone and Lasiodiplodin Reveal Superior Metathesis Activity of Ruthenium Carbene Complexes with Imidazol-2-ylidene Ligands”. ''J. Org. Chem.'' '''65''' (23): 7990–7995. {{doi| 10.1021/jo0009999}}.</ref>
[[File:RCM Catalysts.png|825px|center|frameless]]
==Reaction scope==
===Alkene substrate===
Ring-closing Metathesis has shown utility in the synthesis of 5-30 membered rings,<ref name=ref36>{{Cite web|url=https://www.organic-chemistry.org/namedreactions/ring-closing-metathesis.shtm|title = Ring Closing Metathesis}}</ref> polycycles, and heterocycles containing atoms such as [[Nitrogen|N]], [[Oxygen|O]], [[Sulfur|S]], [[Phosphorus|P]], and even [[Silicon|Si]].<ref name=ref2 /><ref name=ref3 /><ref>Harvey, J. S.; Malcolmson, S. J.; Dunne, K. S.; Meek, S. J.; Thompson, A. L.; Schrock, R. R.; Hoveyda, A. H.; Gouverneur, V. (2008). “Enantioselective Synthesis of P-Stereogenic phosphinates and Phosphine Oxides by Molybdenum-Catalyzed Asymmetric Ring-Closing Metathesis”. ''Angew. Chem. Int. Ed.'' '''48''' (4): 762-766. {{doi| 10.1002/anie.200805066}}.</ref><ref>Kiely, A. F.; Jernelius, J. A.; Schrock, R. R.; Hoveyda, A. H. (2002). “Enantioselective Synthesis of Medium-Ring Heterocycles, Tertiary Ethers, and Tertiary Alcohols by Mo-Catalyzed Ring-Closing Metathesis”. ''J. Am. Chem. Soc.'' '''124''' (12): 2868-2869. {{doi| 10.1021/ja012679s}}.</ref> Due to the functional group tolerance of modern RCM reactions, the synthesis of structurally complex compounds containing a range of functional groups such as [[epoxide]]s, [[ketone]]s, [[Alcohol (chemistry)|alcohol]]s, [[ether]]s, [[amine]]s, [[amide]]s, and many others can be achieved more easily than previous methods. Oxygen and nitrogen heterocycles dominate due to their abundance in [[natural product]]s and pharmaceuticals. Some examples are shown below (the red alkene indicates C-C bond formed through RCM).<ref name=ref3 />
[[File:Exemplary RCM products.png|600px|center|frameless]]
In addition to terminal [[alkene]]s, tri- and tetrasubstituted [[alkene]]s have been used in RCM reactions to afford substituted cyclic olefin products.<ref name=ref25 /> Ring-closing metathesis has also been used to cyclize rings containing an [[alkyne]] to produce a new terminal [[alkene]], or even undergo a second cyclization to form bicycles. This type of reaction is more formally known as [[Enyne metathesis|enyne ring-closing metathesis]].<ref name=ref7 /><ref>Kim, S.-H.; Bowden, N.; Grubbs, R. H. (1994). “Catalytic Ring Closing Metathesis of Dienynes: Construction of Fused Bicyclic Rings”. ''J. Am. Chem. Soc.'' '''116''' (23): 10801-10802. {{doi| 10.1021/ja00102a062}}.</ref>
[[File:Enyne RCM to access bicylic rings.png|550px|center|frameless]]
===''E''/''Z'' selectivity===
In RCM reactions, two possible geometric [[isomer]]s, either [[E-Z notation|''E-'' or ''Z-''isomer]], may be formed. Stereoselectivity is dependent on the catalyst, ring strain, and starting diene. In smaller rings, [[E-Z notation|''Z-''isomers]] predominate as the more stable product reflecting ring-strain minimization.<ref>Anslyn, E. V.; Dougherty, D. A. Strain and Stability. ''Modern Physical Organic Chemistry'', Murdzek, J., Ed. University Science Books, 2006, pp. 110-114.</ref> In macrocycles, the [[E-Z notation|''E-''isomer]] is often obtained as a result of the thermodynamic bias in RCM reactions as [[E-Z notation|''E-''isomers]] are more stable compared to [[E-Z notation|''Z-''isomers]]. As a general trend, ruthenium [[persistent carbene|NHC (N-heterocyclic carbene)]] catalysts favor ''E'' selectivity to form the trans isomer. This in part due to the steric clash between the substituents, which  adopt a trans configuration as the most stable conformation in the metallacyclobutane intermediate, to form the [[E-Z notation|''E-''isomer]].<ref name=RHC /> The synthesis of stereopure [[E-Z notation|''Z-'' isomers]] were previously achieved via [[Enyne metathesis|ring-closing alkyne metathesis]]. However, in 2013 [[Robert Grubbs|Grubbs]] reported the use of a chelating ruthenium catalyst to afford ''Z'' macrocycles in high selectivity. The selectivity is attributed to the increased steric clash between the catalyst ligands and the metallacyclobutane intermediate that is formed. The increased steric interactions in the transition state lead to the ''Z'' olefin rather than the ''E'' olefin, because the transition state required to form the ''E-'' isomer is highly disfavored.<ref>Marx, V. M.; Keitz, B. K.; Grubbs, R. H. (2013). “Stereoselective Access to Z and E Macrocycles by Ruthenium-Catalyzed Z‑Selective Ring-Closing Metathesis and Ethenolysis”. ''J. Am. Chem. Soc.'' '''135''' (1): 94-97. {{doi| 10.1021/ja311241q}}.</ref>
[[File:Stereoselective Z- RCM.png|600px|center|frameless]]
===Cocatalyst===
Additives are also used to overturn conformational preferences, increase reaction concentration, and [[chelate]] highly polar groups, such as [[ester]]s or [[amide]]s, which can bind to the catalyst.<ref name=ref2 /> [[Titanium isopropoxide|Titanium isopropoxide (Ti(O<sup>''i''</sup>Pr)<sub>4</sub>)]] is commonly used to [[chelate]] polar groups to prevent [[catalyst poisoning]] and in the case of an ester, the titanium Lewis acid binds the carbonyl oxygen. Once the oxygen is chelated with the titanium it can no longer bind to the ruthenium metal of the catalyst, which would result in catalyst deactivation.  This also allows the reaction to be run at a higher effective concentration without dimerization of starting material.<ref>Mitchell, L.; Parkinson, J. A.; Percy, J. M.; Singh, K. (2008). “Selected Substituent Effects on the Rate and Efficiency of Formation of an Eight-Membered Ring by RCM”. ''J. Org. Chem.'' '''73''' (6): 2389–2395. {{doi| 10.1021/jo702726b}}.</ref>
[[File:Addition of Titanium cocatalyst.png|600px|center|frameless]]
Another classic example is the use of a bulky [[Lewis acid]] to form the [[E-Z notation|''E-''isomer]] of an [[ester]] over the preferred [[E-Z notation|''Z''-isomer]] for cyclolactonization of medium rings. In one study, the addition of aluminum tris(2,6-diphenylphenoxide) (ATPH) was added to form a 7-membered lactone. The aluminum binds with the carbonyl oxygen forcing the bulky diphenylphenoxide groups in close proximity to the ester compound. As a result, the ester adopts the [[E-Z notation|''E-''isomer]] to minimize penalizing steric interactions. Without the [[Lewis acid]], only the 14-membered dimer ring was observed.<ref>Pentzer, E. B.; Gadzikwa, T.; Nguyen, S. T. (2008). “Substrate Encapsulation: An Efficient Strategy for the RCM Synthesis of Unsaturated ϵ-Lactones”. ''Org. Lett.'' '''10''' (24): 5613-5615. {{doi| 10.1021/ol8022227}}.</ref>
[[File:Addition of bulky Lewis acid.png|600px|center|frameless]]
By orienting the molecule in such a way that the two reactive [[alkene]]s are in close proximity, the risk of [[intermolecular]] [[olefin metathesis|cross-metathesis]] is minimized.
===Limitations===
Many metathesis reactions with ruthenium catalysts are hampered by unwanted [[isomerization]] of the newly formed double bond, and it is believed that ruthenium [[hydride]]s that form as a side reaction are responsible. In one study <ref>Hong, S. H.; Sanders, D. P.; Lee, C. W.; Grubbs, R. H. (2005). "Prevention of Undesirable Isomerization during Olefin Metathesis". ''J. Am. Chem. Soc.'' '''127''' (49): 17160–17161. {{doi|10.1021/ja052939w}}. {{PMID| 16332044}}.</ref> it was found that [[isomerization]] is suppressed in the RCM reaction of diallyl ether with specific additives capable of removing these [[hydride]]s. Without an additive, the reaction product is [[2,3-Dihydrofuran|2,3-dihydrofuran]] (2,3-DHF) and not the expected [[2,5-Dihydrofuran|2,5-dihydrofuran]] (2,5-DHF) together with the formation of [[ethylene]] gas. [[Radical (chemistry)|Radical]] scavengers, such as [[TEMPO]] or [[phenol]], do not suppress [[isomerization]]; however, additives such as [[1,4-benzoquinone]] or [[acetic acid]] successfully prevent unwanted [[isomerization]]. Both additives are able to oxidize the ruthenium [[hydride]]s which may explain their behavior.
[[File:Metathesis-additives.png|center|frameless|449x449px|Effects of additives on the ratio of 2,3- and 2,5-DHF obtained by ring closing metathesis reaction of dially ether.]]
Another common problem associated with RCM is the risk of catalyst degradation due to the high dilution required for some cyclizations. High dilution is also a limiting factor in industrial applications due to the large amount of waste generated from large-scale reactions at a low concentration.<ref name=ref2 /> Efforts have been made to increase reaction concentration without compromising selectivity.<ref>Raymond, M.; Holtz-Mulholland, M.; Collins, S. K. (2014). “Macrocyclic Olefin Metathesis at High Concentrations by Using a Phase-Separation Strategy”. ''Chem. Eur. J.'' '''20''' (4): 12763-12767. {{doi| 10.1002/chem.201404202}}.</ref>
==Synthetic applications==
Ring-closing metathesis has been used historically in numerous [[Organic synthesis|organic syntheses]] and continues to be used today in the synthesis of a variety of compounds. The following examples are only representative of the broad utility of RCM, as there are numerous possibilities. For additional examples see the many review articles.<ref name=ref2 /><ref name=ref3 /><ref name=ref53 /><ref name=ref36 />
Ring-closing metathesis is important in [[total synthesis]]. One example is its use in the formation of the 12-membered ring  in the synthesis of the naturally occurring [[cyclophane]] floresolide. Floresolide B was isolated from an [[Ascidiacea|ascidian]] of the genus Apidium and showed [[cytotoxicity]] against KB tumor cells. In 2005, [[K. C. Nicolaou]] and others completed a synthesis of both isomers through late-stage ring-closing metathesis using the 2nd Generation Grubbs catalyst to afford a mixture of ''E-'' and ''Z-'' isomers (1:3 ''E/Z'') in 89% yield. Although one [[Prochirality|prochiral]] center is present the product is [[Racemic mixture|racemic]]. Floresolide is an [[atropisomer]] as the new ring forms (due to steric constraints in the transition state) passing through the front of the [[carbonyl]] group in and not the back. The carbonyl group then locks the ring permanently in place. The [[E-Z notation|''E/Z'' isomers]] were then separated and then the phenol nitrobenzoate protective group was removed in the final step by potassium carbonate to yield the final product and the unnatural ''Z''-isomer.<ref>Nicolaou, K. C.; Xu, H. (2006). “Total synthesis of floresolide B and 6,7-Z-floresolide B”. ''Chem. Commun.'' '''6''': 600-602. {{doi| 10.1039/B517385J}}.</ref>
[[File:Synthesis of Floreside.png|700px|center|frameless]]
In 1995, [[Robert Grubbs]] and others highlighted the stereoselectivity possible with RCM. The group synthesized a diene with an internal hydrogen bond forming a β-turn. The [[hydrogen bond]] stabilized the macrocycle precursor placing both dienes in close proximity, primed for metathesis. After subjecting a mixture of [[diastereomer]]s to the reaction conditions, only one [[diastereomer]] of the olefin β-turn was obtained. The experiment was then repeated with (''S,S,S'') and (''R,S,R'') [[peptide]]s. Only the (''S,S,S'') [[diastereomer]] was reactive illustrating the configuration needed for ring-closing to be possible. The olefin product’s absolute configuration mimics that of Balaram’s disulfide peptide.<ref>Miller, S. J.; Grubbs, R. H. (1995). “Synthesis of Conformationally Restricted Amino Acids and Peptides Employing Olefin Metathesis”.  ''J. Am. Chem. Soc.'' '''117''' (21), 5855-5856. {{doi| 10.1021/ja00126a027}}.</ref>
[[File:Synthesis of B-turn mimic.png|725px|center|frameless]]
The ring strain in 8-11 atom rings has proven to be challenging for RCM; however, there are many cases where these cyclic systems have been synthesized.<ref name=ref3 /> In 1997, Fürstner reported a facile synthesis to access jasmine ketolactone (''E/Z'') through a final RCM step. At the time, no previous 10-membered ring had been formed through RCM, and previous syntheses were often lengthy, involving a macrolactonization to form the decanolide. By adding the diene and catalyst over a 12-hour period to refluxing toluene, Fürstner was able to avoid oligomerization and obtain both [[E-Z notation|''E/Z'' isomers]] in 88% yield. CH<sub>2</sub>Cl<sub>2</sub> favored the formation of the ''Z-''isomer in 1:2.5 (''E/Z'') ratio, whereas, toluene only afforded a 1:1.4 (''E/Z'') mixture.<ref>Furstner, A.; Muller, T. (1997). “The First Synthesis of a 10-Membered Ring by Olefin Metathesis: Jasmine Ketolactone”. ''Syn. Lett.'' '''8''': 1010-1012. {{doi| 10.1055/s-1997-930}}.</ref>
[[File:Synthesis of 10 membered rings.png|500px|center|frameless]]
In 2000, Alois Fürstner reported an eight step synthesis to access [[balanol|(−)-balanol]] using RCM to form a 7-member heterocycle intermediate. [[Balanol]] is a metabolite isolated from ''erticiullium balanoides'' and shows inhibitory action towards [[Protein kinase C|protein kinase C (PKC)]]. In the ring closing metathesis step, a ruthenium indenylidene complex was used as the precatalyst to afford the desired 7-member ring in 87% yield.<ref>Furstner, A.; Thiel, O. R. (2000). “Formal Total Synthesis of (−)-Balanol: Concise Approach to the Hexahydroazepine Segment Based on RCM” . ''J. Org. Chem.'' '''65''' (6): 1738-1742. {{doi| 10.1021/jo991611g}}.</ref>
[[File:Synthesis of Balanol.png|650px|center|frameless]]
In 2002, [[Stephen F. Martin]] and others reported the 24-step synthesis of manzamine A with two ring-closing metathesis steps to access the polycyclic [[alkaloid]].<ref name=ref51>Humphrey, J. H.; Liao, Y.; Ali, A.; Rein, T.; Wong, Y.-L.; Chen, H.-J.; Courtney, A. K.; Martin, S. F. (2002). “Enantioselective Total Syntheses of Manzamine A and Related Alkaloids”. ''J. Am. Chem. Soc.'' '''124''' (29): 8584-8592. {{doi| 10.1021/ja0202964}}.</ref> The natural product was isolated from marine sponges off the coast of Okinawa. Manzamine is a good target due to its potential as an antitumor compound. The first RCM step was to form the 13-member D ring as solely the ''Z''-isomer in 67% yield, a unique contrast to the usual favored ''E''-isomer of metathesis. After further transformations, the second RCM was used to form the 8-member E ring in 26% yield using stoichiometric 1st Generation Grubbs catalyst. The synthesis highlights the ability for functional group tolerance metathesis reactions as well as the ability to access complex molecules of varying ring sizes.<ref name=ref51 />
[[File:Synthesis of Manzamine A.png|725px|center|frameless]]
In 2003, [[Samuel J. Danishefsky|Danishefsky]] and others reported the total synthesis of [[Migrastatin|(+)-migrastatin]], a [[macrolide]] isolated from ''Streptomyces'' which inhibited tumor cell migration.<ref name=ref49>Gaul, C.; Njardarson, J. T.; Danishefsky, S. J. (2003). “The Total Synthesis of (+)-Migrastatin”. ''J. Am. Chem. Soc.'' '''125''' (20): 6042-6043. {{doi| 10.1021/ja0349103}}.</ref> The [[macrolide]] contains a 14-member heterocycle that was formed through RCM. The metathesis reaction yielded the protected [[migrastatin]] in 70% yield as only the (''E,E,Z'') isomer. It is reported that this selectivity arises from the preference for the ruthenium catalyst to add to the less hindered olefin first then cyclize to the most accessible olefin. The final deprotection of the silyl ether yielded [[Migrastatin|(+)-migrastatin]].<ref name=ref49 />
[[File:Synthesis of Migrastatin.png|825px|center|frameless]]
Overall, ring-closing metathesis is a highly useful reaction to readily obtain cyclic compounds of varying size and chemical makeup; however, it does have some limitations such as high dilution, selectivity, and unwanted isomerization.
==See also==
* [[Olefin Metathesis]]
* [[Ring-opening metathesis polymerization]]
* [[Alkane metathesis]]
* [[Alkyne metathesis]]
* [[Enyne metathesis]]
==References==
{{Reflist|35em}}
==External links==
* [https://www.organic-chemistry.org/namedreactions/ring-closing-metathesis.shtm Ring-Closing Metathesis] at organic-chemistry.org
* [http://www.sigmaaldrich.com/technical-documents/articles/chemfiles/ring-closing-metathesis.html Sigma-Aldrich Ring-Closing Metathesis] at sigmaaldrich.com
* [http://faculty.chemistry.harvard.edu/files/myers/files/31-the_olefin_metathesis_reaction.pdf The Olefin Metathesis Reaction] Andrew Myers’ Group Notes
{{DEFAULTSORT:Ring-Closing Metathesis}}
[[Category:Rearrangement reactions]]
[[Category:Organometallic chemistry]]
[[Category:Carbon-carbon bond forming reactions]]
[[Category:Homogeneous catalysis]]