Ring-closing metathesis
[7] It was first published by Dider Villemin in 1980 describing the synthesis of an Exaltolide precursor,[8] 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.
[9][10] 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.
[11] 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.
[8] 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).
[14] 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.
The loss of the second molecule, ethylene, a highly volatile gas, drives the reaction in the forward direction according to Le Châtelier's principle.
[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.
[25] 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 polymerization[26] Cycloelimination of the metallacyclobutane intermediate forms the desired RCM product along with a [M]=CH2, or alkylidene, species which reenters the catalytic cycle.
Ring strain arises from abnormal bond angles resulting in a higher heat of combustion relative to the linear counterpart.
[11][39][40][41] 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.
[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.
As a general trend, ruthenium 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-isomer.
[47] Additives are also used to overturn conformational preferences, increase reaction concentration, and chelate highly polar groups, such as esters or amides, which can bind to the catalyst.
[48] Another classic example is the use of a bulky Lewis acid to form the E-isomer of an ester over the preferred Z-isomer for cyclolactonization of medium rings.
The aluminum binds with the carbonyl oxygen forcing the bulky diphenylphenoxide groups in close proximity to the ester compound.
In one study [50] it was found that isomerization is suppressed in the RCM reaction of diallyl ether with specific additives capable of removing these hydrides.
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.
[51] 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.
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.
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 isomers in 88% 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.
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.
