Metathesis catalyst

A significant problem is the dehydrocoupling reaction, which proceeds only at low yields per pass and is accompanied by rapid deactivation of the catalyst. The metathesis step, although chemically feasible, requires that polar contaminants resulting from partial oxidation be removed so that they will not deactivate the metathesis catalyst. In addition, apparendy both cis- and /ra/ j -stilbenes are obtained consequendy, a means of converting the unreactive i j -stilbene to the more reactive trans isomer must also be provided, thus complicating the process. 

More detailed and theoretical explanations of the role of the catalyst, based on this scheme, have appeared (72, 74, 77-82). In order to obtain experimental evidence for this scheme, some investigators did experiments in which 1,2-dimethylcyclobutane or cyclobutane were brought into contact with an active metathesis catalyst. However, 1,2-dimethylcyclobutane was stable under conditions where propene gave a high conversion to ethene and 2-butene (63). The experiments with cyclobutane led to the same conclusion (83). From this, and from the fact that cyclobutanes are not reaction products, although this can be expected thermodynamically, it follows that cyclobutanes are not free intermediates. This prompted Lewandos and Pettit (83) to propose a tetramethylene complex as the key intermediate ... 

Grubbs and Brunck (86) have recently reported experimental evidence supporting this mechanism. They have made an attempt to synthesize the proposed metallocyclic intermediate for the metathesis of ethene. Starting from the assumption that a mixture of WC1 and two equivalents of (C4H9)Li forms an active metathesis catalyst (49), they treated WC1 with 1,4-dilithio-2,3-dideuterobutane. One may expect that the following reaction would take place ... 

The above studies are consistent with the hypothesis that the metathesis reaction itself brings about cis-trans isomerization (46). This hypothesis is further supported by the results of a kinetic study of the reactions of the three linear butenes on the metathesis catalyst Mo(CO)6-A1203 by Davie et al. (107), who concluded that cis-trans isomerization for their system is a bimolecular reaction. 

AT-heterocyclic carbenes show a pure donor nature. Comparing them to other monodentate ligands such as phosphines and amines on several metal-carbonyl complexes showed the significantly increased donor capacity relative to phosphines, even to trialkylphosphines, while the 7r-acceptor capability of the NHCs is in the order of those of nitriles and pyridine [29]. This was used to synthesize the metathesis catalysts discussed in the next section. Experimental evidence comes from the fact that it has been shown for several metals that an exchange of phosphines versus NHCs proceeds rapidly and without the need of an excess quantity of the NHC. X-ray structures of the NHC complexes show exceptionally long metal-carbon bonds indicating a different type of bond compared to the Schrock-type carbene double bond. As a result, the reactivity of these NHC complexes is also unique. They are relatively resistant towards an attack by nucleophiles and electrophiles at the divalent carbon atom. 

Origins of Enhanced Reactivity of Second-Generation Metathesis Catalysts 244... 

Synthetic routes to active ruthenium metathesis catalysts are classified according to the ruthenium precursor used. 

Ruthenium hydride complexes, e.g., the dimer 34, have been used by Hofmann et al. for the preparation of ruthenium carbene complexes [19]. Reaction of 34 with two equivalents of propargyl chloride 35 gives carbene complex 36 with a chelating diphosphane ligand (Eq. 3). Complex 36 is a remarkable example because its phosphine ligands are, in contrast to the other ruthenium carbene complexes described so far, arranged in a fixed cis stereochemistry. Although 36 was found to be less active than conventional metathesis catalysts, it catalyzes the ROMP of norbornene or cyclopentene. 

Table 4 Comparative investigations efficiency of some metathesis catalysts...

In summary, the order of reactivity for the most commonly used ruthenium-based metathesis catalysts was found to be 56d>56c>9=7. This order of reactivity is based on IR thermography [39], determination of relative rate constants for the test reaction 58—>59 (Eq. 8) [40], and determination of turnover numbers for the self metathesis of methyl-10-undecenoate [43]. 

The search for even more active and recyclable ruthenium-based metathesis catalysts has recently led to the development of phosphine-free complexes by combining the concept of ligation with N-heterocyclic carbenes and benzyli-denes bearing a coordinating isopropoxy ligand. The latter was exemplified for Hoveyda s monophosphine complex 13 in Scheme 5 [12]. Pioneering studies in this field have been conducted by the groups of Hoveyda [49a] and Blechert [49b], who described the phosphine-free precatalyst 71a. Compound 71a is prepared either from 56d [49a] or from 13 [49b], as illustrated in Scheme 16. 

Several approaches toward immobilization of phosphine-free ruthenium-based metathesis catalysts bearing a coordinating ether group have been made over the past 3 years [61]. This aspect has been covered in a recently published review by Blechert and Connon [8d] and will therefore not be discussed here. 

The metathesis of ene-ynamides has been investigated by Mori et al. and Hsung et al. [80]. Second-generation ruthenium catalysts and elevated temperatures were required to obtain preparatively useful yields. Witulski et al. published a highly regioselective cyclotrimerization of 1,6-diynes such as 98 and terminal alkynes using the first-generation ruthenium metathesis catalyst 9... 

It has been demonstrated that group 6 Fischer-type metal carbene complexes can in principle undergo carbene transfer reactions in the presence of suitable transition metals [122]. It was therefore interesting to test the compatibility of ruthenium-based metathesis catalysts and electrophilic metal carbene functionalities. A series of examples of the formation of oxacyclic carbene complexes by metathesis (e.g., 128, 129, Scheme 26) was published by Dotz et al. [123]. These include substrates where double bonds conjugated to the pentacarbonyl metal moiety participate in the metathesis reaction. Evidence is... 

The reversible nature of cross metathesis is of synthetic importance because, by the use of a sufficiently active metathesis catalyst, it generally ensures the preferential formation of the most thermodynamically stable product. This results in the transformation of terminal olefins into internal ones, and we have seen that undesired self-metathesis products can be recycled by exposing them to a second CM process. 

An obvious drawback in RCM-based synthesis of unsaturated macrocyclic natural compounds is the lack of control over the newly formed double bond. The products formed are usually obtained as mixture of ( /Z)-isomers with the (E)-isomer dominating in most cases. The best solution for this problem might be a sequence of RCAM followed by (E)- or (Z)-selective partial reduction. Until now, alkyne metathesis has remained in the shadow of alkene-based metathesis reactions. One of the reasons maybe the lack of commercially available catalysts for this type of reaction. When alkyne metathesis as a new synthetic tool was reviewed in early 1999 [184], there existed only a single report disclosed by Fiirstner s laboratory [185] on the RCAM-based conversion of functionalized diynes to triple-bonded 12- to 28-membered macrocycles with the concomitant expulsion of 2-butyne (cf Fig. 3a). These reactions were catalyzed by Schrock s tungsten-carbyne complex G. Since then, Furstner and coworkers have achieved a series of natural product syntheses, which seem to establish RCAM followed by partial reduction to (Z)- or (E)-cycloalkenes as a useful macrocyclization alternative to RCM. As work up to early 2000, including the development of alternative alkyne metathesis catalysts, is competently covered in Fiirstner s excellent review [2a], we will concentrate here only on the most recent natural product syntheses, which were all achieved by Fiirstner s team. 

Ongoing research efforts will lead to the arrival of even more efficient and selective metathesis catalysts with specifically tailored properties [196]. Due to the synergistic relationship between catalyst design and subsequent application in advanced synthesis [197], this progress will further expand the scope of metathesis and its popularity amongst the synthetic community. 

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