Cross-Metathesis CM Reactions

The main limitation in the broad apphcation of alkene cross-metathesis reactions in the synthesis of unsaturated compounds is the formation of self-coupling byproducts. Moreover, these impurities, frequently difficult to separate, are usually formed alongside the desired compound in an almost statistical ratio. Another issue associated with this kind of reaction is the stereocontrol of fhe newly formed double bond. 

By immobilizing one of the two unsaturated counterparts, homo-couphng involving fhe supported reactant should be, in principle, avoided, and fhe use of excess of fhe second alkene should guarantee high conversion, along wifh ease of separation of impurities. 

Although fhe sohd-phase version of the reaction was obviously slower than the corresponding solution-phase version, high yields and purities of fhe final compounds (118) were obtained, along with almost complete stereocontrol (E/Z 99 1). The reaction was almost insensitive to electronic effects, and fhe intra-site alkene metafhesis products on sohd support [229] were never detected. 

CM has also been applied in the immobilization of biologically active molecules. Thus, [230] Reetz and co-workers supported chiral phosphonate as a potential suicide enzyme inhibitor by reacting alkenyl phosphonates with either allyl-modified SIRAN (a porous glass) or allyl-modified TentaGel in the presence of the Grubbs catalyst in CH2CI2 at reflux. 

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Cross metathesis (CM) reactions can also be used as the key step in a piperidine synthesis (Scheme 40) <2004TL1167> or in sequence with ring-rearrangement metathesis, for example, in the synthesis of (—)-lasubine (Scheme 41) <2004T9629>. 

The development of stable and active well-defined ruthenium carbene complex Cl2(PCy3)2Ru = CHPh and its second-generation successors (la) and (lb) (Figure 9.1) has meant that olefin metathesis reactions have become valuable tools in synthetic organic chemistry.111 Among them the ring-closing (RCM), en-yne and cross-metathesis (CM) reactions have received much attention as they... 

Sequential RRM and cross metathesis (CM) reactions were used in a carefully-designed step in a synthesis of (-)-lasubine 125. The cyclopentenone 126 undergoes RRM to provide the intermediate 127, which reacts with 128 in a CM to provide the intermediate 129 <04T9629>. 

Blechert [24] followed this initial report with a second, where the first example of a supported Grubbs-Hoveyda catalyst (5) was described. Catalyst 12 displayed better recyclability in RCM, although again, no leaching data was presented. The authors additionally noted that the high activity observed in RCM did not translate to the more challenging cross metathesis (CM) reactions of electron-deficient alkenes, where the catalyst displayed reduced activity. 

The terminal cross metathesis (CM) reaction, as depicted in Figure 3.5, is probably the most straightforward synthetic method to introduce complex molecular fragments or functional groups to a ROMP polymer chain end. The propagating ruthenium carbene complex typically reacts with an acyclic olefin in a CM reaction. The newly generated carbene complex is still metathesis-active, and can in principle undergo secondary metathesis reactions or initiate the polymerization of the residual monomer. 

This complex was evaluated in a series of test reactions and compared to 3 and 6. It showed in most cases a higher activity than the above-mentioned complexes with excellent stability. Catalyst 20 was found to be particularly efficient for cross-metathesis (CM) reactions involving acrylonitrile (Scheme 13). 

Recently, our group has reported the feasibility of the Sn2 reaction for the stereoselective synthesis of substituted O-heterocycles (Scheme 3.2) [15]. We applied the intramolecular 8 2 reaction in conjunction with an olefin cross-metathesis (CM) reaction (tandem CM/Sn2 reaction) to the stereoselective synthesis of the 2,3-frani-2,5-fra j-tetrahydrofuran of subglutinol B (3.15). 

A cross metathesis (CM) reaction involving y,(5-unsaturated )S-ketophos-phonate (343) catalysed by a ruthenium catalyst, has been also described by Cossy and co-workers. Depending on the olefinic partners and conditions, a CM/l,4-addition sequence afforded functionalised tetrahydrofurans (344), tetrahydropyrans (345), and pyrrolidines (346) (Scheme 117). ... 

As stated above, olefin metathesis is in principle reversible, because all steps of the catalytic cycle are reversible. In preparatively useful transformations, the equilibrium is shifted to one side. This is most commonly achieved by removal of a volatile alkene, mostly ethene, from the reaction mixture. An obvious and well-established way to classify olefin metathesis reactions is depicted in Scheme 2. Depending on the structure of the olefin, metathesis may occur either inter- or intramolecularly. Intermolecular metathesis of two alkenes is called cross metathesis (CM) (if the two alkenes are identical, as in the case of the Phillips triolefin process, the term self metathesis is sometimes used). The intermolecular metathesis of an a,co-diene leads to polymeric structures and ethene this mode of metathesis is called acyclic diene metathesis (ADMET). Intramolecular metathesis of these substrates gives cycloalkenes and ethene (ring-closing metathesis, RCM) the reverse reaction is the cleavage of a cyclo-... 

Scheme 2 Different modes of the olefin metathesis reaction cross metathesis (CM), ringclosing metathesis (RCM), ring-opening metathesis (ROM), acyclic diene metathesis polymerization (ADMET), and ring-opening metathesis polymerization (ROMP)...

Fig. la—d Typical alkene metathesis reactions ring-closing (RCM) and ring-opening (ROM) metathesis (a), diene cross metathesis (CM, b), ROM-RCM (c), and ROM-double RCM (d) sequences (ring-rearrangement reactions, RRM)... 

Since the alkene formed in this reaction can further react with other alkenes, many products should be formed in the cross-metathesis (CM). Therefore, in the early days, only ring-closing metathesis (RCM) of diene was investigated. It is known that the reaction is catalyzed by a transition metal. Pioneering work on olefin metathesis was undertaken by Villemin and Tsuji, who reported the synthesis of lactones using alkene metathesis ... 

The appreciable levels of asymmetric induction observed in the catalytic ARCM reactions mentioned above suggest a high degree of enantiodifferentiation in the association of olefinic substrates and chiral complexes. This stereochemical induction may also be exploited in asymmetric ring-opening metathesis (AROM). Catalytic ROM transformations [20] offer unique and powerful methods for the preparation of complex molecules [2d, 2g]. The chiral Mo-alkyli-denes that are products of AROM reactions can be trapped either intramolecu-larly (RCM) or intermolecularly (cross metathesis, CM) to afford a range of optically enriched adducts. 

Many reviews deal with the main mechanistic aspects of the metathesis reaction [10]. There are three basic metathesis reactions (apart from polymerization reactions) the ring-closing metathesis (RCM), the cross-metathesis (CM) and the ringopening metathesis (ROM) [11]. Among the fundamental aspects that govern the reaction course, the thermodynamic versus kinetic issue is particularly important when considering the application of RCM to the construction of macrocydes. 

Metathesis is a versatile reaction applicable to almost any olefinic substrate internal, terminal or cyclic alkenes, as well as dienes or polyenes. (Alkyne metathesis is a growing area, but will not be dealt with here.) The reaction is also known as olefin disproportionation or olefin transmutation, and involves the exchange of fragments between two double bonds. Cross metathesis (CM, Figure 1) is defined as the reaction of two discrete alkene molecules to form two new alkenes. Where the two starting alkene molecules are the same it is called self-metathesis. Ethenolysis is a specific type of cross metathesis where ethylene... 

Substituted vinylphosphonates (195) and allylphosphonates (196) with E-olefin stereochemistry have been prepared for the first time via intermolecular olefin cross-metathesis (CM) using ruthenium alkylidene complex (197) in good yield. A variety of terminal olefins, styrenes and geminally substituted olefins has been successfully employed in these reactions (Scheme 49). ... 

Summary Two catalytic reactions, i.e. silylative coupling (mms-silylation) (SC) catalyzed by complexes containing or generating Ru-H and/or Ru-Si bonds (I, II, V, VI) and cross-metathesis (CM) catalyzed by mthenium-carbene (i.e. 1st and 2nd generation mthenium Grubbs catalyst (ID, IV)) of vinyl and allyl-substituted hetero(N,S,B)organic compounds with conunercially available vinyltrisubstituted silanes, siloxanes, and silsesquioxane have been overviewed. They provide a universal route toward the synthesis of well-defined molecular compounds with vinylsilicon functionality. 

In the last 15 years we have developed two new catalytic reactions between the same parent substances, i.e. silylative coupling (SC) (also called tmns-silylation or silyl groiq> transfer) and cross-metathesis (CM) of alkenes, which have provided an universal route for the synthesis of well-defined molecular compounds with vinylsilicon functionality. While the cross-metathesis is catalyzed by well-defined Ru and Mo carbenes, the silylative coupling is catalyzed by complexes initialing or generating M-H or M-Si bonds (where M = Ru, Rh, Ir). For recent reviews see Refs. [4-6],... 

Olefin metathesis is a unique carbon skeleton redistribution in which unsaturated carbon-carbon bonds are rearranged in the presence of metal carbene complexes. With the advent of efficient catalysts, this reaction has emerged as a powerful tool for the formation of C-C bonds in chemistry [1]. Olefin metathesis can be utilized in five types of reactions ring-closing metathesis (RCM), ring-opening metathesis (ROM), respective ringopening metathesis polymerization (ROMP), cross-metathesis (CM), and acyclic diene metathesis polymerization (ADMET). 

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