Ring-closing metathesis is a variant of the olefin metathesis reaction in which alkylidene moieties are exchanged to form a ring.
The most common catalysts for this reaction are complexes of molybdenum or ruthenium.
However, amides and other protected amines can be used in RCM reactions with Grubbs-type catalysts (Eq. As in the synthesis of carbocycles, some level of conformational bias in the substrate is important in the synthesis of medium and large heterocycles.
For example, bicyclic carbamates containing an eight-membered ring are efficiently synthesized by ring-closing metathesis (Eq. Cyclic boronates are formed in cross-metathesis reactions of allylic alcohols and allylboron reagents.
Ruthenium-based complexes have two general limitations. The first is their tendency to form stable Fischer carbenes in the presence of electron-rich olefins such as enol ethers (Eq. The second is their susceptibility to coordination by Lewis bases, which limits their compatibility with functional groups such as amines and phosphines (however, protection strategies can circumvent this limiation; see below).
When selecting a catalyst for RCM, it is important to consider both the reactivity of the catalyst itself and the structures of the substrate and product.Treatment with hydrogen peroxide and sodium hydroxide yields stereodefined allylic diols (Eq. Unsaturated lactams are a biochemically important class of heterocycles that can be prepared via ring-closing metathesis.Catalyst 1 is effective in the preparation of five- or six-membered lactams, but crotonamides must be used as unsubstituted α,β-unsaturated amides coordinate to molybdenum, preventing reaction (Eq. Unsubstituted α,β-unsaturated esters can likewise coordinate to the metal center and prevent reaction.Olefin metathesis involves the exchange of two alkylidene groups to generate two new olefins from one or more starting alkenes.Cleavage of the carbon-carbon double bond is accompanied by the formation of two new carbon-carbon double bonds.Second-generation Grubbs catalysts 4 - 6 include a strongly donating N-heterocyclic carbene ligand trans to the phosphine ligand, accelerating phosphine dissociation and increasing their activity relative to 2 and 3.In addition, the substrate scope of these catalysts is greater than that of the first-generation Grubbs-type catalysts.In RCM reactions, reactants are typically designed so that the desired cyclic alkene is accompanied by a small gaseous olefin such as ethylene or propene, the loss of which drives the reaction forward.Highly dilute conditions discourage intermolecular metathesis and thereby also promote RCM.For example, chiral molybdenium complex 10 catalyzes the desymmetrization of vinyl ethers to form dihydropyrans with moderate to good enantioselectivity (Eq. Further modification of heterocycles established through desymmetrizing RCM affords chiral and nonracemic acyclic structures containing carbon-carbon double bonds.For example, Schrock-type complex 11 catalyzes the cyclization of an allylborane, which undergoes oxidation to yield a chiral diol with very high stereoselectivity and moderate yield (Eq. The vast majority of olefin metathesis reactions are catalyzed by complexes of either molybdenum (Schrock type) or ruthenium (Grubbs type).