Ring-closing metathesis
Ring-closing metathesis | |
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Reaction type | Ring forming reaction |
Identifiers | |
Organic Chemistry Portal | ring-closing-metathesis |
RSC ontology ID | RXNO:0000245 |
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.[1][2]
The most commonly synthesized ring sizes are between 5-7 atoms;
There are several reviews published on ring-closing metathesis.[2][3][12][13]
History
The first example of ring-closing metathesis was reported by Dider Villemin in 1980 when he synthesized an
In 1987, Siegfried Warwel and Hans Kaitker published a synthesis of symmetric macrocycles through a
After a decade since its initial discovery,
In 1993,
Mechanism
General mechanism
The mechanism for transition metal-catalyzed olefin metathesis has been widely researched over the past forty years.[20] 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).[21] 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.[12] In 1971, Chauvin proposed the formation of a metallacyclobutane intermediate through a [2+2] cycloaddition[21][22] 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).[23] This mechanism has become widely accepted among chemists and serves as the model for the RCM mechanism.[24]
Initiation occurs through substitution of the catalyst’s
Thermodynamics
The reaction can be under
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.[30]
Although the reaction is still under thermodynamic control, an initial 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.[2][31][32] 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.[33][34]
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)
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.[11][39][40][41]
Reaction scope
Alkene substrate
Ring-closing Metathesis has shown utility in the synthesis of 5-30 membered rings,[42] polycycles, and heterocycles containing atoms such as N, O, S, P, and even Si.[2][3][43][44] Due to the functional group tolerance of modern RCM reactions, the synthesis of structurally complex compounds containing a range of functional groups such as epoxides, ketones, alcohols, ethers, amines, amides, and many others can be achieved more easily than previous methods. Oxygen and nitrogen heterocycles dominate due to their abundance in natural products and pharmaceuticals. Some examples are shown below (the red alkene indicates C-C bond formed through RCM).[3]
In addition to terminal alkenes, tri- and tetrasubstituted alkenes have been used in RCM reactions to afford substituted cyclic olefin products.[32] 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 ring-closing metathesis.[7][45]
E/Z selectivity
In RCM reactions, two possible geometric
Cocatalyst
Additives are also used to overturn conformational preferences, increase reaction concentration, and
Another classic example is the use of a bulky
By orienting the molecule in such a way that the two reactive
Limitations
Many metathesis reactions with ruthenium catalysts are hampered by unwanted
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.[2] Efforts have been made to increase reaction concentration without compromising selectivity.[51]
Synthetic applications
Ring-closing metathesis has been used historically in numerous 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.[2][3][13][42]
Ring-closing metathesis is important in
In 1995,
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.
In 2000, Alois Fürstner reported an eight step synthesis to access (−)-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 (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.[55]
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.[56] 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.[56]
In 2003, Danishefsky and others reported the total synthesis of (+)-migrastatin, a macrolide isolated from Streptomyces which inhibited tumor cell migration.[57] 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.[57]
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
- ^ 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.
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- ^ Warwel, S.; Katker, H. (1987). “Eine einfache Synthese makrocyclischer Kohlenwasserstoffe durch Metathese von Cyclooflefinen”. Synthesis. 935-937.
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- ^ a b c Crabtree, R. H. Applications. The Organometallic Chemistry of the Transition Metals, 6th Ed.; John Wiley & Sons, Inc.: New Jersey, 2014, pp.318-322.
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- ^ a b 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.
- ^ 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.
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- ^ Myers, Andrew. "The Olefin Metathesis Reaction" (PDF). faculty.chemistry.harvard.edu. Retrieved 2022-08-09.
- ^ Anslyn, E. V.; Dougherty, D. A. Strain and Stability. Modern Physical Organic Chemistry, Murdzek, J., Ed. University Science Books, 2006, pp. 107-111.
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- ^ a b "Ring Closing Metathesis".
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- ^ Anslyn, E. V.; Dougherty, D. A. Strain and Stability. Modern Physical Organic Chemistry, Murdzek, J., Ed. University Science Books, 2006, pp. 110-114.
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External links
- Ring-Closing Metathesis at organic-chemistry.org
- Sigma-Aldrich Ring-Closing Metathesis at sigmaaldrich.com
- The Olefin Metathesis Reaction Andrew Myers’ Group Notes