Olefin Metathesis in Solution

For the preparation of compound libraries in solution using olefin metathesis, mainly two strategies have been employed. These are the cross-metathesis of mixtures of terminal alkenes, to yield mixtures of internal, disubstituted alkenes, and the oligomerization by ring-opening metathesis of strained, cyclic alkenes (Scheme 20.4). Ring-closing metathesis in solution has been used mainly for the preparation of small arrays of compounds or of single compounds.



Scheme 20.4. Strategies for the preparation of compound mixtures using olefin metathesis.

Scheme 20.4. Strategies for the preparation of compound mixtures using olefin metathesis.

Scope and Limitations of Olefin Metathesis in Solution

Cross-metathesis of two different terminal alkenes in solution only rarely gives high yields of one product (for recent advances in selective cross-metathesis, see

[14, 28, 32-34]). Usually, mixtures of the products of cross-metathesis and of self-metathesis are obtained, each of them as mixtures of E- and Z-isomers. Unfortunately, some alkenes show a high tendency to undergo self-metathesis (to form symmetric ''dimers''; see, for example, [35, 36]), whereas other alkenes (acryloni-trile, styrenes) undergo self-metathesis only slowly or not at all. For this reason, cross-metathesis of mixtures of different olefins will not always yield the statistically expected amounts of internal olefins. This feature can cause problems during the deconvolution of such compound libraries because potent ligands formed only in low quantities are usually difficult to identify by deconvolution.

A further problem of cross-metathesis in solution is that a purification step will usually be required to remove the catalyst. With the recent development of immobilized catalysts (e.g. 4-6) [37-41], however, this problem has been reduced. Unfortunately, all of the immobilized ruthenium carbene complexes described so far (Scheme 20.5) lose activity rather quickly; this fact might be due to the inherent instability of these complexes and to the fact that during catalysis detachment of the metal from the support can readily occur.

Scheme 20.5. Support-bound ruthenium carbene complexes, useful as insoluble metathesis catalysts [24, 38-41]. PS, crosslinked polystyrene; PEG, poly(ethylene glycol).

All known metathesis catalysts, being essentially electrophilic reagents, react with nucleophiles such as amines, nitrogen-containing heterocycles, and thiols. Accordingly, alkenes containing these functional groups (which are often important for the interaction of small molecules with proteins) cannot be used as building blocks for library preparation, unless these functional groups are effectively masked.

Examples of Library Preparation by Cross-metathesis in Solution

One of the first examples of the preparation of compound libraries by cross-metathesis was reported by Boger and coworkers [42-44], who dimerized mixtures of alkenoyl iminodiacetamides by cross-metathesis in solution (Scheme 20.6). The aim of this work was to identify new agonists or antagonists for biochemical signal transduction processes which involve the dimerization or oligomerization of pro-

Scheme 20.6. Preparation of libraries of iminodiacetamides by cross-metathesis.

teins [e.g. tyrosin/serine/threonine kinase receptors, cytokine receptors, tumor necrosis factor (TNF) receptors].

During optimization of the chemistry they found that 3-butenamides (n = 1; Scheme 20.6) did not undergo metathesis at all, and 4-pentenamides (n = 2) only reacted sluggishly under the conditions of cross-metathesis. Longer o-alkenoyl amides, however, cleanly yielded the expected internal alkenes [44]. The libraries were usually purified by column chromatography.

Similarly, Benner and coworkers [45] prepared mixtures of internal alkenes by cross-metathesis of mixtures of terminal olefins. The resulting libraries of alkenes were oxidized to the corresponding diols or epoxides. The mixtures of diols were the starting monomers for ''receptor-assisted combinatorial synthesis'', in which these diols were to be dimerized reversibly to borate esters in the presence of a receptor. Under conditions of dynamic equilibrium, enhanced concentrations of those borate esters with highest affinity to the receptor are to be expected [45].

The authors observed during the optimization of the metathesis reaction that certain alkenes (Scheme 20.7) failed to undergo cross-metathesis and others only reacted sluggishly, depending on the functional groups present in these alkenes. In particular, nitrogen-containing alkenes did not undergo metathesis - this might be due to complexation with the catalyst.

A further example of target-accelerated combinatorial synthesis has been reported by Nicolaou et al. [46]. With the aim of finding new vancomycin dimers with improved antibiotic activity, various alkenylated derivatives of vancomycin were subjected to conditions of olefin metathesis in the presence of derivatives of L-Lys-D-Ala-D-Ala, the peptide to which vancomycin strongly binds and thereby inhibits the cell wall growth of bacteria (Scheme 20.8). Cross-metathesis was performed in aqueous solution at 23 °C in the presence of a phase-transfer catalyst (C12H25NMe3Br) and with (Cy3P)2Cl2Ru=CHPh (0.2 equiv.) (1) as metathesis catalyst. In this instance, it was observed that addition of the target peptide in fact led to increased concentrations of those dimers which were also the more potent antibiotics.



Scheme 20.7. Suitability of alkenes for cross-metathesis [45].

Brandli and Ward [47] prepared mixtures of internal, disubstituted alkenes by equilibration of internal olefins (oleic acid derivatives). Their synthesis was performed either in dichloromethane or without any solvent, and proceeded satisfactorily with as little as 0.1% of (Cy3P)2Cl2Ru=CHPh (1) if no solvent was used. With gas chromatography-mass spectrometry (GC/MS) and 13C-NMR (nuclear magnetic resonance) spectroscopy the authors were able to identify all ten expected products (each as E/ Z mixture) of the equilibration of two different, unsymmet-rical alkenes (Scheme 20.9).


Scheme 20.8. Vancomycin dimers prepared by cross-metathesis (m = 1, 2, 3, 7; R = H, b-Ala, L-Asn, D-LeuNMe, g-Abu, L-Arg, L-Phe [46]).


Scheme 20.8. Vancomycin dimers prepared by cross-metathesis (m = 1, 2, 3, 7; R = H, b-Ala, L-Asn, D-LeuNMe, g-Abu, L-Arg, L-Phe [46]).

+ (Cy3P)2CI2Ru=CHPh

Scheme 20.9. Equilibration of internal alkenes by cross-metathesis [47]. 20.2.3

Examples of Library Preparation by Ring-closing Metathesis in Solution

Ring-closing metathesis is increasingly being used for the preparation of confor-mationally constrained analogs of peptides. Most of the examples reported, however, only describe the synthesis of single compounds or of small arrays of compounds. These syntheses are only rarely based on easily available dienes, and are therefore not always suitable for the preparation of large compound libraries. Moreover, unlike cross-metathesis, ring-closing metathesis is an intramolecular reaction which does not increase the number of products or their diversity. Hence, ring-closing metathesis only allows the conversion of one library into another, without changing the total number of products within this library.

Cyclic peptides are an important tool for the identification of turns within a peptide which are critical for its biological activity. In analogy to the "Ala-scan", in which all the amino acids of a peptide are sequentially replaced by alanine to identify those amino acids which are crucial for biological activity, a ''loop scan'' (Scheme 20.10 [48]) may be used to locate possible turns within a peptide and to identify conformationally constrained analogs (7-10) of the original peptide (11).

Scheme 20.10. Illustrative example of''loop scan''. Four cyclic analogs (7-10) of the original peptide are prepared and their biological activity is compared with the activity of the original peptide (11). X = variable spacer.

Some new strategies for the preparation of cyclic peptides by ring-closing metathesis are presented below to illustrate the scope of these cyclizations.

Liskamp and coworkers have investigated the cyclization of N-alkenylated peptides (12) by ring-closing metathesis (Scheme 20.11) [48-50]. The peptides were prepared by standard solid-phase synthesis, and the N-alkenylation was effected during the assembly of the peptide by N-sulfonylation with 2-nitrobenzenesulfonyl chloride, followed by N-alkenylation under Mitsunobu conditions and sulfonamide cleavage by treatment with mercaptoethanol/1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). Ring-closing metathesis could be performed either in solution or on solid phase, but in solution higher yields were usually obtained [50]. Cyclization experiments showed that the length of the N-alkenyl group was crucial for ring closure. N-Allyl peptides (12) could only be cyclized to yield eight-member rings (13). Larger ring sizes required the use of N-homoallyl or N-(4-penten-1-yl) peptides. The cyclization of tripeptides (to form a 15-member ring, e.g. (14)) was particularly difficult, and only proceeded satisfactorily with N-(4-penten-1-yl) substitution (Scheme 20.11).

Scheme 20.11. Preparation of cyclic peptides by ring-closing metathesis in solution, and lengths of the N-alkenyl substituent required for ring formation [49].

three amide bonds: bis W-(4-penten-1 -yl)

Scheme 20.11. Preparation of cyclic peptides by ring-closing metathesis in solution, and lengths of the N-alkenyl substituent required for ring formation [49].

Other recent examples of the preparation of cyclic peptide analogs by ring-closing metathesis in solution include the cyclic sulfamides 15 [51], cyclic sulfonamides 16 [37], and siloxanes 17 [52] (Scheme 20.12). The last were synthetic intermediates for the preparation of diols such as 18, which were used as building blocks for the solid-phase synthesis of peptide analogs [52]. Further examples of

17 18

Scheme 20.12. Peptidomimetics prepared by ring-closing metathesis in solution.

17 18

Scheme 20.12. Peptidomimetics prepared by ring-closing metathesis in solution.

solution-phase synthesis of peptide mimetics by ring-closing metathesis have been reported [2, 53-56].

Examples of Library Preparation by Ring-opening Metathesis Polymerization in Solution

Functionalized oligomers and polymers are of interest for a variety of applications. These include their use in chromatography as the stationary phase [57] for the separation of metals [58] or soluble receptors, and as carriers for the controlled release of drugs [59]. Oligomers functionalized with biologically relevant molecules such as amino acids or carbohydrates can also be used to mimic various biopolymers (proteins, DNA) or the surface of a cell. Such biopolymer mimetics are useful tools for studying the interaction of cell surfaces with biopolymers.

Ring-opening metathesis polymerization (ROMP), in which a strained, cyclic al-kene is polymerized with the aid of a metathesis catalyst, offers several features which make this reaction particularly attractive for the preparation of functionalized oligomers [58, 60-62]. ROMP can be conducted as a living polymerization because the rate of initiation can be faster than the rate of propagation. This feature enables the preparation of oligomers with well-defined length and narrow molecular weight distribution. Because the oligomers persist as active carbene complexes even when one monomer has been consumed, ROMP also enables the preparation of block copolymers, in which various different monomers are polymerized sequentially.

Kiessling and coworkers have used ROMP for the preparation of carbohydrate-functionalized oligomers, which were used as ligands for various carbohydrate-binding proteins (concanavalin A [63], P-selectin [64], L-selectin [65]). Initially, ROMP was performed with norbornenes that were already covalently linked to a carbohydrate. However, better results were later, obtained by preparing activated oligomers by ROMP, which were then derivatized with the carbohydrate (Scheme 20.13).

Maynard et al. [67] used ROMP of exo-5-norbornene-2-carboxylic acid derivatives for the preparation of oligomers displaying the peptide sequences Gly-Arg-Gly-Asp and Ser-Arg-Asn, which play an important role in the binding of extracellular matrix proteins to cell-surface integrins. Both homopolymers and copolymers were prepared and characterized (Scheme 20.14). Polymers substituted with these peptides are being considered for use in the treatment of cancer [67].


Olefin Metathesis on Solid Phase

In solid-phase synthesis, the metathesis of alkenes has been used both for the chemical transformation of support-bound intermediates as well as for the cleavage of products from the support. Although these techniques have not yet been

Scheme 20.13. Strategies for the preparation of carbohydrate-functionalized oligomers by ROMP [65, 66]. DCE, 1,2-dichloroethane.
Scheme 20.14. Preparation of peptide-functionalized oligomers by ROMP [67].

extensively used for the preparation of large libraries by parallel synthesis, solidphase chemistry is generally well suited for this purpose, and some of the reactions described below can probably be used for the preparation of compound libraries.

Cleavage from the Support by Olefin Metathesis Scope and Limitations

With the discovery of highly efficient and robust soluble catalysts which mediate olefin metathesis under mild reaction conditions even in the presence of water and air, the use of alkenes as linkers for solid-phase synthesis became a realistic option. The use of alkenes as linkers is an attractive alternative to other types of linkers because alkenes are inert toward a broad range of reaction conditions, and because they provide for a reliable fixation of intermediates to the support.

Various strategies for the cleavage of compounds from insoluble supports by olefin metathesis have been described (Scheme 20.15). Support-bound dienes can yield either terminal alkenes or cycloalkenes, depending on how the diene is bound to the resin. Terminal alkenes can also be prepared by cross-metathesis of resin-bound internal alkenes with ethylene [68].

Scheme 20.15. Strategies for the cleavage of alkenes from insoluble supports by olefin metathesis.

Occasionally, carbene complex-mediated cleavage reactions give only low yields. When an additional olefin was added to the reaction mixture, however, better yields could be obtained [69]. This effect was attributed to the irreversible fixation of the carbene complex to the support when little or no amounts of terminal alkenes were present in the reaction mixture (Scheme 20.16).

Later studies [71] suggest that the irreversible fixation of the catalyst to the support is not necessarily detrimental to the yield of the cleavage reaction if spacers of sufficient flexibility are used. Thus, diene 19 (Scheme 20.17) could not be cleaved from the support, and even in the presence of 1-octene only traces of the desired product were obtained. The more flexible diene 20, on the other hand, underwent smoothly RCM smoothly in the absence of any additional alkene, to give the expected cyclic product (21) in high yield. The fact that the support was colored after cleavage and catalyzed olefin metathesis suggests that carbene complexes were indeed covalently bound to the support. The flexibility of the spacer enables the metal fragment to migrate from one attachment point to the next, so that catalytic

Scheme 20.16. Mechanism of the cleavage of dienes from supports by RCM [70].
Scheme 20.17. Dependence of cleavage yields on the flexibility of spacers and on the type of alkene used as linker [71].

amounts of the carbene complex are sufficient to achieve complete metathesis of all attachment sites. Another reason for the resistance of 19 toward carbene complex-mediated cleavage may be the fact that 19 is a styrene derivative. Styrenes usually react more slowly with ruthenium carbene complexes than unconjugated, internal cis-alkenes.

One problem which is inherent to olefin metathesis-induced cleavage is the elu-tion of catalyst-derived byproducts together with the final product. The currently known metathesis catalysts (mainly ruthenium carbene complexes) decompose slowly during the metathesis reaction to yield various ruthenium complexes, which do not remain attached to the support. These impurities have to be removed by chromatographic purification of the products. However, large libraries of compounds for direct biological screening cannot always be purified, and cleavage by olefin metathesis will only be of limited use for the preparation of such libraries unless more stable metathesis catalysts or selective scavengers for metal-containing byproducts become available. Examples of Cleavage from the Support by Olefin Metathesis

Knerr and Schmidt [72, 73] have used a metathesis-based cleavage strategy for the solid-phase synthesis of oligosaccharides (Scheme 20.18). Cleavage by treatment with Grubbs' catalyst yielded O-allyl glycosides (22), which represent versatile, protected intermediates for further synthetic manipulations [73].

Scheme 20.18. Synthesis of allyl glycosides by RCM-mediated cleavage from a polymeric support [72, 73].

Scheme 20.18. Synthesis of allyl glycosides by RCM-mediated cleavage from a polymeric support [72, 73].

A similar strategy has been described by Peters and Blechert [74], in which RCM of a support-bound diene was used to release styrenes from a polystyrene-based, insoluble support. Linkers of this type can also be cleaved by cross-metathesis with ethylene [68].

Several groups have investigated the preparation of cyclic compounds by RCM with simultaneous cleavage from the support [71, 75, 76]. One recent example, reported by Piscopio et al. [77], is shown in Scheme 20.19. The substrate (23) for olefin metathesis was prepared in one step by an Ugi reaction. The product (24), a Freidinger lactam, was designed to mimic b-turns, which play a pivotal role in the

Scheme 20.19. Solid-phase synthesis of b-turn mimetics by RCM with simultaneous cleavage from the support [77].

interaction of proteins. Because styrene derivative 25 was chosen as linker, cleavage required prolonged heating for a long time. An unconjugated cis-alkene would probably allow milder cleavage conditions (cf. Schemes 20.17 and 20.18).

Nicolaou et al. [78, 79] have used ring-closing metathesis with simultaneous cleavage from the support in an elegant solid-phase synthesis of epothilone analogs (Scheme 20.20). Epothilones are a group of natural products which promote the polymerization of a- and b-tubulin subunits, and which show higher cytotoxicity than taxol [80]. These interesting biological properties have prompted several research groups to develop syntheses for these compounds and analogs thereof [80, 81].

Scheme 20.20. Solid-phase synthesis of epothilone analogs [78, 79].

In Nicolaou's solid-phase synthesis of epothilone analogs, a Merrifield resin (PS-CH2Cl) with low loading (0.3 mmol g_1) was used. After release from the support the products were purified by preparative thin layer chromatography. More than 100 epothilone analogs have been prepared using this methodology, and their biological evaluation gave detailed insight into the structure-activity relationship of this family of natural products [79].

Ring-closing Metathesis on Solid Phase Scope and Limitations

Ring-closing metathesis (RCM), being a reversible process, is best suited to the preparation of unstrained cyclic compounds. In most of the reported examples of RCM on solid phase [2], five- or six-member rings were generated. Other ring sizes are also accessible, but careful optimization of the reaction conditions are often necessary. Macrocyclizations, for instance, usually require the use of supports with low loading to avoid self-metathesis (Scheme 20.21).

Scheme 20.21. Ring-closing metathesis on solid phase, and self-metathesis as a potential side reaction.

Scheme 20.21. Ring-closing metathesis on solid phase, and self-metathesis as a potential side reaction.

20.3 Olefin Metathesis on Solid Phase Examples of Ring-closing Metathesis on Solid Phase

Several examples of the solid-phase synthesis of nitrogen-containing heterocycles have been reported (Scheme 20.22) (for an example performed on soluble polyethylene glycol), see [82]). Heating and substantial amounts of ruthenium car-bene complex are usually required to attain complete conversion of the starting diene (e.g. 25). Eneyne 28 is an interesting example of an intramolecular ene-yne coupling, which gives ready access to highly substituted dienes (29), which in turn are suitable starting materials for Diels-Alder reactions [83].

Scheme 20.22. Examples of the preparation of nitrogen-containing heterocycles by RCM on solid phase [83-85]. PS, crosslinked polystyrene.

Various groups have investigated the preparation of cyclic peptides by RCM on solid phase. In Section 20.2.3, the work of Liskamp and coworkers concerning the cyclization of peptide-derived dienes was presented. These cyclizations generally give higher yields in solution than on solid phase [48-50]. Another example on crosslinked polystyrene is shown in Scheme 20.23.

With the aim of finding efficient routes to structurally complex, polycyclic compounds, Lee et al. [86] recently developed the synthesis shown in Scheme 20.24. With an Ugi reaction followed by an intramolecular Diels-Alder reaction and an


Scheme 20.23. Preparation of cyclic peptides by RCM on solid phase [55]. TG, Tentagel.


Scheme 20.23. Preparation of cyclic peptides by RCM on solid phase [55]. TG, Tentagel.

Scheme 20.24. Synthesis of polycyclic structures using a ring-opening ring-closing metathesis cascade [86].

allylation, strained triene (30) was generated, which upon treatment with a metathesis catalysts underwent a ring-opening/ring-closing cascade to yield highly substituted, tetracyclic compounds (31). A valuable feature of this synthesis is the ready availability of some of the four building blocks. One drawback of this reac tion sequence is the low selectivity of the allylation reaction, which necessitates the protection of all nucleophilic functional groups.

Cross- and Self-metathesis on Solid Phase Scope and Limitations

Cross-metathesis should in principle enable the efficient preparation of unsym-metrical, acyclic alkenes on solid phase. Unfortunately, this reaction does not always proceed as expected, mainly because only few types of terminal alkenes smoothly undergo cross-metathesis (see Scheme 20.7). Alkenes bearing ''interesting'' functional groups (hydrogen bond donors and acceptors) sometimes react only sluggishly or not at all, leading either to complete consumption of the catalyst (formation of unreactive carbene complexes) and/or to formation of large amounts of the products of self-metathesis (e.g. 33) (Scheme 20.25).

Pol 33

Pol 33

Pol 34

35 36

Scheme 20.25. Strategies for performing cross-metathesis on solid phase.

An interesting variant of cross-metathesis is the so-called ring-opening cross-metathesis. Strained, cyclic alkenes (e.g. norbornene (35), cyclobutene) react rapidly and irreversibly with metathesis catalysts to yield a new carbene complex, which can react with a second alkene to yield the product of cross-metathesis (36). This reaction has also been performed successfully on solid phase (Scheme 20.25). Examples of Cross- and Self-metathesis on Solid Phase

Some illustrative preparations of internal alkenes by cross-metathesis on solid phase are shown in Scheme 20.26. Allylsilanes (37) appear to be well suited for this reaction [33, 87], and substituted allylsilanes (38), which are valuable synthetic intermediates, can be easily prepared by cross-metathesis (Scheme 20.26). Nicolaou et al. used cross-metathesis of support-bound, alkenyl-substituted ketophospho-

nates (39) with o-alkenols (40) in a solid-phase synthesis of muscone analogs [88] (Scheme 20.26). Unsaturated a-amino acid derivatives (42) have also been prepared on solid phase by cross-metathesis [35] (Scheme 20.26). The low loading of the starting resin (0.07 mmol g_1) was required to suppress self-metathesis.

Scheme 20.26. Cross-metathesis on solid phase [35, 87, 89]. PS, crosslinked polystyrene; 1, (Cy3 P)2Cl2 Ru=CHPh.

The combination of ring-opening with cross-metathesis (''ring-opening cross-metathesis'') has been realized on insoluble supports by Cuny and coworkers [9092]. Support-bound norbornene derivative 43 was treated with styrenes 44 (which do not undergo self-metathesis efficiently) and a ruthenium carbene complex, to yield regioisomeric mixtures of highly substituted cyclopentenes 45 (Scheme 20.27). Substituents on styrene which were tolerated included tert-butyl, alkoxy, acyloxy, and hydroxy.

O 43

,co2Me A

O 43

(PS) + regioisomer

Scheme 20.27. Ring-opening cross metathesis on solid phase [92]. (PS), crosslinked polystyrene with spacer; 1, (Cy3P)2Cl2Ru=CHPh.

(PS) + regioisomer

The carbene complex-mediated coupling of alkynes with alkenes to yield 1,3-dienes [13, 16, 93] is one of the most surprising metathesis reactions. Despite a number of potential side reactions (polymerization of the alkyne, self-metathesis of the alkene), high yields of dienes can be obtained. This reaction can also be conducted on insoluble supports, with either the alkene or the alkyne attached to the resin (Scheme 20.28). The resulting dienes can be further transformed by 2 + 4 cycloaddition with suitable dienophiles to yield substituted cyclohexenes [94].

^ps oac if^vps ch2cl OAc jQf 1, ch2ci2,40 °c, 18 h 1.5% tfa L^^

Scheme 20.28. Examples of alkene/alkyne cross-metathesis on solid phase [29, 95]. PS, crosslinked polystyrene; 1, (Cy3P)2Cl2Ru=CHPh.

Self-metathesis of support-bound N-alkenoylated peptides was used by Conde-Friboes et al. [96] for the preparation of symmetric peptidomimetics (Scheme 20.29). Peptides were prepared on crosslinked polystyrene by standard fluorenyl-methoxycarbonyl (Fmoc) chemistry and then acylated with an o-alkenoic acid. In accordance with similar results of Boger and Chai [44] (Section 20.2.2), neither 3-butenamides nor 4-pentenamides underwent self-metathesis efficiently. With longer alkenoic acids, however, the peptide dimers 46 were formed in high yield and purity as mixtures of E/Z isomers.

Scheme 20.29. Self-metathesis of support-bound, N-alkenoyl peptides [96].

606 | 20 Olefin Metathesis and Related Processes for CC Multiple Bond Formation 20.4


With the development of highly efficient and selective catalysts for olefin metathesis in recent years, this reaction has become a valuable tool for organic chemists. Cross-metathesis and ROMP in solution can now be performed with func-tionalized alkenes, and can offer interesting new possibilities for the preparation of compound libraries. In particular, the selective cross-metathesis of different al-kenes, for which the underlying principles are now slowly emerging, has huge potential and could become a process with an impact similar to those of the Wittig or the Diels-Alder reactions if its scope and limitations are clearly understood. Solid-phase synthesis has also greatly benefited from these new catalysts, and new cleavage strategies and other methodologies based on carbene complex-mediated olefin metathesis on solid phase have been developed successfully.

The properties of the currently available catalysts are, however, far from ideal. Because of their limited stability, large amounts of catalyst are often required to drive reactions to completion. This feature can lead to significant amounts of metal-derived impurities in the crude products. Moreover, most carbene complexes suitable for olefin metathesis are also highly sensitive toward amines, azoles, and other nucleophiles, which severely limits the choice of functional groups tolerated in the starting materials. This facet is particularly problematic for the preparation of libraries of biologically active compounds because nucleophilic functional groups are often of crucial importance for biological activity. Future research should aim to overcome these limitations of current catalysts by further enhancing their selectivity and stability.


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