Applications of Metathesis

The industrial applications of metathesis in SHOP, FEAST, and for the synthesis of polymers such as Vestenamer and Norsorex have already been discussed. The exquisite controls over the structures and 

The ease of handling and functional group tolerance of the ruthenium catalysts has made the semicommercial synthesis of a potential hepatitis C drug possible through an RCM reaction. This is shown by reaction 7.3.3.1. 

Complex fragment of several atoms with two stereocenters 

The manufacture of the specialty polymer of dicyclopentadiene by ROMP using the Ru-based catalyst has also been achieved. This is shown by reaction 7.3.3.2. In an older manufacturing process for this polymer, air- and moisture-sensitive multicomponent catalysts in special hardware had to be used. 

A very novel tandem catalytic system that has the potential for large-scale applications in the oil industry has also been reported. By using this catalytic system, it is possible to convert a single low-molecular-weight hydrocarbon to a mixture of hydrocarbons of higher molecular weights. 

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We will focus on the development of ruthenium-based metathesis precatalysts with enhanced activity and applications to the metathesis of alkenes with nonstandard electronic properties. In the class of molybdenum complexes [7a,g,h] recent research was mainly directed to the development of homochi-ral precatalysts for enantioselective olefin metathesis. This aspect has recently been covered by Schrock and Hoveyda in a short review and will not be discussed here [8h]. In addition, several important special topics have recently been addressed by excellent reviews, e.g., the synthesis of medium-sized rings by RCM [8a], applications of olefin metathesis to carbohydrate chemistry [8b], cross metathesis [8c,d],enyne metathesis [8e,f], ring-rearrangement metathesis [8g], enantioselective metathesis [8h], and applications of metathesis in polymer chemistry (ADMET,ROMP) [8i,j]. Application of olefin metathesis to the total synthesis of complex natural products is covered in the contribution by Mulzer et al. in this volume. 

Following the guidelines of typical metathesis reactions outlined in Figs. 1-3, the present review will concentrate - with only a few exceptions - on the most recent applications of metathesis reactions in the total synthesis of natural products. 

With these promising results, application of metathesis reactions for the construction of the substituted fluoroolefins required in peptide isosteres is potentially very useful. 

Since its discovery more than 50 years ago, olefin metathesis has evolved from its origins in binary and ternary mixtures of the Ziegler-Natta type into a research area dominated by well-defined molecular catalysts. Surveys of developments up to 1993 were presented in COMC (1982) and COMC (1995). Major advances in ROMP over the last 10 years include the development of modular, stereoselective group 6 initiators, and easily handled, functional-group tolerant ruthenium initiators. The capacity to tailor polymer functionality, chain length, and microstructure has expanded applications in materials science, to the point where ROMP now constitutes one of the most powerful methods available for the molecular-level design of macromolecular materials. In addition to an excellent and comprehensive text on olefin metathesis, a three-volume handbook s has recently appeared, of which the third volume focuses specifically on applications of metathesis in polymer synthesis. 

By far the largest application of metathesis is a principal step in the Shell higher olefin process (SHOP),24 140 141 with the aim of producing detergent-range olefins... 

Pharmaceutical applications of metathesis are widespread in the patent literature. While CM and ROM are applicable in some syntheses, it is RCM which predominates, as there are few reactions which are as effective for synthesis of highly functionalized medium ring compounds. Such macrolides are key components of a vast range of medicinally active compounds which can combat bacterial and viral infections as well as cancers, bone and neurological... 

The latest industrial application of metathesis was developed by Phillips who started up a plant in late 1985 at Cbannelview, Texas, on the L ondell Petrochemical Complex with a production capacity of 135,000 t/year of propylene from ethylene. This facility carries out the disproportionation of ethylene and 2-butenes, in the vapor phase, around 300 to 350°C, at about 0.5.10 Pa absolute, with a VHSV of 50 to 200 and a once-througb conversion of about 15 per cent 2-butenes are themselves obtained by the dimerization of ethylene in a homogeneous phase, which may be followed by a hydroisomerization step to convert the 1-butene formed (see Sections 13.3.2. A and B). IFP is also developing a liquid phase process in this area. 

His proposal involved a metal carbene and a metallocyclobutane intermediate and was the first proposed mechanism consistent with all experimental observations to date. Later, Grubbs and coworkers performed spectroscopic studies on reaction intermediates and confirmed the presence of the proposed metal carbene. These results, along with the isolation of various metal alkyli-dene complexes from reaction mixtures eventually led to the development of well-defined metal carbene-containing catalysts of tungsten and molybdenum [23-25] (Fig. 2). After decades of research on olefin metathesis polymerization, polymer chemists started to use these well-defined catalysts to create novel polymer structures, while the application of metathesis in small molecule chemistry was just beginning. These advances in the understanding of metathesis continued, but low catalyst stability greatly hindered extensive use of the reaction. 

Regarding the possible applications of metathesis-derived LCPs, it was shown that the mesophases of SCLCPs can be aligned in magnetic fields, leading to optically transparent materials with high birefringence (Sect. 2.1). These materials are certainly interesting materials for optical applications. 

Applications of metathesis to the synthesis of more complex organic molecules has been limited by the lack of tolerance of the catalyst systems for functional groups. Many of the new catalyst systems that are being developed appear to be less sensitive to basic functional groups. "46 it is anticipated that there will be numerous advances in this area over the next few years as better and more easily synthesized catalysts become available. 

Another area of ROMP in the early stages of development is the polymerization of highly functionalized monomers in protic and aqueous solutions. These catalysts appear to tolerate most organic functional groups and will polymerize highly functionalized monomers (equation 16). The development of the organometallic chemistry of these catalysts will open a variety of new applications of metathesis in organic synthesis. 

In 2005, Yves Chauvin, Robert Grubbs, and Richard Schrock were awarded the Nobel Prize in Chemistry for their fundamental studies on the mechanism and applications of metathesis. We will encounter much of their work in the following sections. 

Besides the Triolefin Process or OCT, metathesis is a key step in a number of other industrial transformations used to produce small molecules. By far the most important application of metathesis for this task is connected with the Shell... 

Up to this point, our discussion has centered on industrial applications of metathesis in which petrochemical-derived starting materials have been used. 

Olefin metathesis (OM) has proven to be one of the most important advances in catalysis in recent years based on the application of this chemistry to the synthesis of polymers and biologically relevant molecules [1-10]. This unique transformation promotes chain and condensation polymerizations, namely ring opening metathesis polymerization and acyclic diene metathesis polymerization (ADMET). Applications of metathesis polymerization span many aspects of materials synthesis from cell-adhesion materials [11] to the synthesis of linear polyethylene with precisely spaced branches [12]. 

Other modifications of vegetable oils in polymer chemistry include the introduction of alkenyl functions, the study of novel polyesters and polyethers and the synthesis of semi-interpenetrating networks based on castor oil (the triglyceride of ricinoleic acid) [42], and also the production of sebacic acid and 10-undecenoic acid from castor oil [44]. Additionally, the recent application of metathesis reactions to unsaturated fatty acids has opened a novel avenue of exploitation leading to a variety of interesting monomers and polymers, including aliphatic polyesters and polyamides previously derived from petrochemical sources [42, 45]. 

Product stereochemistry is a critical factor determining the applicability of metathesis pheromones to insect control [23]. The steric course of the metathesis reaction normally results in a (thermodynamic) cis/trans mixture, whereas the physiologically active pheromones are either isomerically pure compounds or specific cis/trans mixtures. When it is necessary to obtain a single stereoisomer, the separation step required is tedious and expensive. The synthesis of pure cis isomers via the metathesis reaction, therefore, forms a challenge for catalyst development. 

The application of metathesis catalysis to polyene synthesis may be viewed as following a progressive path from polymerizing acetylene itself, a two-membered ring , to ring-opening a... 

The remarkable success of the application of metathesis processes to a vast array of synthetic procedures [20-23] has also transferred into the use of unsaturated oils and their derivatives as substrates [23-33]. 

This chapter describes the most relevant advances related to application of metathesis... 

As a tool for monomer synthesis, the metathesis reaction is applied in fatty-acid modifications. That is, exploitation of the reactions shown in Scheme 5.1 CM, SM, RCM and ROM. However, due to the inherent long, acyclic, aliphatic structure of vegetable oils and their derivatives, and in view of further applications in polymerisation (or any other modification reactions), most studies on application of metathesis systems to unsaturated fatty acids have been based on SM and CM mechanisms (Scheme 5.1a and b) to synthesise the desired ensuing molecules (usually monomers). 

However, these studies were not made on the recent carbene catalysts (if one excepts the studies on the Basset carbene W(OAr)(OAr)(=CHC(CH3)3)(Cl)(OEt2) made some years ago [6, 7]) while most applications of metathesis in ROMP or organic synthesis now use these systems. We therefore undertook a study of the stereoselectivity of various carbene catalysts usually used in metathesis and compared the results to those of the... 

The design of versatile, highly active, and well-defined catalysts remains one of the main objectives of the research in olefin metathesis [1-3]. This is especially true for the application of metathesis to acyclic or cyclic olefins bearing functional groups which probably constitutes one of the most promising uses of this reaction. In fact, metathesis offers many interesting possibilities for the synthesis of valuable organic products or polymers that are often difficult to obtain by other methods [4-6]. 

It is still unclear how the initiation step in alkene metathesis occurs and how the initial carbene forms. Commercial applications of metathesis include the triolefin process, in which propylene is converted to ethylene and butene, the neohexene process, in which the dimer of isobutylene, Me3CCH=CMe2, is metathesized with ethylene to give Me3CCH=CH2, an intermediate in the manufacture of synthetic musk, and a 1,5-hexadiene synthesis from 1,5-cy-clooctadiene and ethylene. Two other applications, SHOP and ROMP (Shell higher olefins process and ring-opening metathesis polymerization), are discussed in the next section. 

RCM was the first application of metathesis in synthesis. The reaction is driven to completion not only by loss of ethene from the reaction mixture, but also by entropy as one molecule is converted into two. The mechanism follows that outlined by Chauvin (Scheme 8.61 compare Scheme 8.52). The Grubbs catalyst must first dissociate one of the two phosphine ligands to generate a 14-electron monophosphine carbene. The mechanism then follows the steps laid down by Chauvin through metallacyclobutanes 8.217 and 8.219 and the carbene 8.218. It should be noted that the Grubbs catalyst is the benzylidene complex (R = Ph). This is purely for stability as the methylene complexes are unstable. In the catalytic cycle, R = Ph can only work for the first round, thereafter, it is the methylene species with R = H. 

The catalyst systems mentioned above are widely used in the commercial applications of metathesis polymerization due to their low costs and simplicity of preparation (see Section VII). However, the harsh reaction conditions and strong Lewis acids often required limit the utility of such catalysts [81]. These may cause side-reactions and make them incompatible with most functional groups [82]. The propagating species are poorly defined and often neither quantitatively formed nor uniform. Hence, there is often a lack of reaction control using these systems. Moreover, for the polymerization of functionalized monomers it is often necessary to use tin organyls instead of aluminium alkyls. These are more expensive and may cause severe injuries of health [25,83]. 

Recent developments and applications of metathesis reactions have been reviewed and also discussed at a symposium. ... 

Metathesis can be catalyzed homogeneously and heterogeneously. The biggest applications of metathesis such as the SHOP process [4] and Phillips Triolefin process use heterogeneous catalysts. Norbornene (Norsorex by CdF Chimie), cyclooctene (Vestenamer by Hiils AG), and dicyclopenta-diene (Hercules) practice homogeneous catalysis. 

The Shell Higher-Olefins Process (SHOP), which inclndes a commercial application of metathesis, was developed to convert ethylene into a range (Cio-Cig)... 

Broadly speaking, metathesis covers a class of reactions where an interchange of carbon atoms between pairs of double bonds takes place. We have already seen application of metathesis (see Section 6.8.1) in Shell higher olefin process (SHOP). It is also used for the manufacture of the specialty polymer Vestenamer from cyclooctene (see reaction 7.2.3). As shown by reactions 7.3.1 and 7.3.2, in both these cases the highlighted carbon atoms are exchanged between the pair of double bonds. 

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