Ring-closing metathesis

Ring-closing metathesis, or 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. Ring-closing metathesis, or 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. The most commonly synthesized ring sizes are between 5-7 atoms; however, reported syntheses include 45- up to 90- membered macroheterocycles. These reactions are metal-catalyzed and proceed through a metallacyclobutane intermediate. It was first published by Dider Villemin in 1980 describing the synthesis of an Exaltolide precursor, 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. 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. 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. 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 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. 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. 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, 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. 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. The mechanism for transition metal-catalyzed olefin metathesis has been widely researched over the past forty years. 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). 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 cycloaddition which then cycloreverts to either yield the same alkene and catalytic species (a nonproductive pathway), or produce a new catalytic species and an alkylidene (a productive pathway). This mechanism has become widely accepted among chemists and serves as the model for the RCM mechanism. 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 cycloaddition and cycloreversion. Association and dissociation of a phosphine ligand also occurs in the case of Grubbs catalysts. In an RCM reaction, the alkylidene undergoes an intramolecular 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 Cycloreversion of the metallacyclobutane intermediate forms the desired RCM product along with a =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.