Ring-closing metathesis

Ring-closing metathesis (RCM) is a widely used variation of olefin metathesis in organic chemistry for the synthesis of various unsaturated rings via the intramolecular metathesis of two terminal alkenes, which forms the cycloalkene as the E- or Z- isomers and volatile ethylene.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.Monfette, S.; Fogg, D. E. (2009). "Equilibrium Ring-Closing Metathesis". Chem. Rev. 109 (8): 3783-3816. .

The most commonly synthesized ring sizes are between 5-7 atoms;Deiters, A.; Martin, S. F. (2004). “Synthesis of Oxygen- and Nitrogen-Containing Heterocycles by Ring-Closing Metathesis”. Chem. Rev. 104 (5): 2199-2238. . however, reported syntheses include 45- up to 90- membered macroheterocycles.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. .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. Song, K. H.; Kang, S. O.; Ko, (2007). “Template Synthesis of a Huge Macrocycle by Olefin Metathesis Using Easily Accessible [Pt(PEt3)2] Templates”. Chem. Eur. J. 13 (18): 5129–5134. . These reactions are metal-catalyzed and proceed through a metallacyclobutane intermediate.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. . It was first published by Dider Villemin in 1980 describing the synthesis of an Exaltolide precursor,Villemin, D. (1980). “Synthese de Macrolides par Metathese”. Tetrahedron Lett. 21 (18): 1715-1718. . and later become popularized by Robert H. Grubbs and Richard R. Schrock, who shared the Nobel Prize in Chemistry, along with Yves Chauvin, in 2005 for their combined work in olefin metathesis.Grubbs, R. H. (2006). “Olefin-Metathesis Catalysts for the Preparation of Molecules and Materials (Nobel Lecture)”. Angew. Chem. Int. Ed. 45 (23): 3760–3765. .Schrock, R. R. (2006). “Multiple Metal–Carbon Bonds for Catalytic Metathesis Reactions (Nobel Lecture)”. Angew. Chem. Int. Ed. 45 (23), 3748-3759. . 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.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. . Since the only major by-product is ethylene, these reactions may also be considered atom economic, an increasingly important concern in the development of green chemistry.

There are several reviews published on ring-closing metathesis.Furstner, A. (2000). “Olefin Metathesis and Beyond”. Angew. Chem. Int. Ed. 39 (17): 3012-3043. .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. .

History

The first example of ring-closing metathesis was reported by Dider Villemin in 1980 when he synthesized an Exaltolide precursor using a WCl6/Me4Sn catalyzed metathesis cyclization in 60-65% yield depending on ring size (A). In the following months, Jiro Tsuji reported a similar metathesis reaction describing the preparation of a macrolide catalyzed by WCl6 and dimethyltitanocene (Cp2TiMe2) in a modest 17.9% yield (B).Tsuji, J.; Hashiguchi, S. (1980). “Application of Olefin Metathesis to Organic Synthesis. Syntheses of Civetone and Macrolides”. Tetrahedron Lett. 21 (31): 2955-2958. . 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.

In 1987, Siegfried Warwel and Hans Kaitker published a synthesis of symmetric macrocycles through a cross-metathesis dimerization of starting cycloolefins to afford C14, C18, and C20 dienes in 58-74% yield, as well as C16 in 30% yield, using Re2O7 on Al2O3 and Me4Sn for catalyst activation.Warwel, S.; Katker, H. (1987). “Eine einfache Synthese makrocyclischer Kohlenwasserstoffe durch Metathese von Cyclooflefinen”. Synthesis. 935-937.

After a decade since its initial discovery, Grubbs and 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.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. .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. . The synthetic route allowed access to dihydropyrans in high yield (89-93%) from readily available starting materials. In addition, synthesis of substituted pyrrolines, tetrahydropyridines, and amides were illustrated in modest to high yield (73-89% ). The driving force for the cyclization reaction was attributed to 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 Châtelier's principle.

In 1993, Grubbs and others not only published a report on carbocycle synthesis using a molybdenum catalyst,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. . 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.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. . The ruthenium catalysts, known better as the Grubbs Catalysts, as well as molybdenum catalysts, or 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 unsaturated and highly functionalized cyclic analogues.

Mechanism

General mechanism

The mechanism for transition metal-catalyzed olefin metathesis has been widely researched over the past forty years.Chauvin, Y. (2006). “Olefin Metathesis: The Early Days (Nobel Lecture). Angew. Chem. Int. Ed. 43 (23): 3740-3747”. . RCM undergoes a similar mechanistic pathway as other olefin metathesis reactions, such as cross metathesis (CM), ring-opening metathesis polymerization (ROMP), and acyclic diene metathesis (ADMET).Crabtree, R. H. Applications. The Organometallic Chemistry of the Transition Metals, 6th Ed.; John Wiley & Sons, Inc.: New Jersey, 2014, pp.318-322. 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. In 1971, Chauvin proposed the formation of a metallacyclobutane intermediate through a [2+2] cycloadditionHerisson, J-L.; Chauvin, Y. (1971). “Catalyse de transformation des olefines par les complexes du tungsten”. Makromolekulare Chemie. 141 (1): 161-176. . which then cycloeliminates to either yield the same alkene and catalytic species (a nonproductive pathway), or produce a new catalytic species and an alkylidene (a productive pathway).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. . This mechanism has become widely accepted among chemists and serves as the model for the RCM mechanism.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.

Initiation occurs through substitution of the catalyst’s alkene ligand with substrate. This process occurs via formation of a new 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.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. In an RCM reaction, the alkylidene undergoes an 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 polymerizationLee, C. W.; Grubbs, R. H. (2001). “Formation of Macrocycles via Ring-Closing Olefin Metathesis”. J. Org. Chem. 66 (21):7155-7158. . Cycloelimination of the metallacyclobutane intermediate forms the desired RCM product along with a [M]=CH2, or alkylidene, species which reenters the catalytic cycle. While the loss of volatile ethylene is a driving force for RCM, it is also generated by competing metathesis reactions and therefore cannot be considered the only driving force of the reaction.

Thermodynamics The reaction can be under 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 enthalpic favorability of the cyclic products, as shown by Illuminati and Mandolini on the formation of lactone rings.Illuminati, G.; Mandolini, L. (1981). “Ring Closure Reactions of Bifunctional Chain Molecules”. Acc. Chem. Res. 14 (5): 95-102. . 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. If the RCM product contains a strained olefin, polymerization becomes preferable through ring-opening metathesis polymerization of the newly formed olefin. 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 interactions.Anslyn, E. V.; Dougherty, D. A. Strain and Stability. Modern Physical Organic Chemistry, Murdzek, J., Ed. University Science Books, 2006, pp. 107-111. 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.

Equilibrium