Alkene metathesis ring-closing

Recent studies by Grubbs on the effect of stereochemistry on synthesis of macrocyclic peptides (disubstituted alkenes) by ring closing metathesis were not disclosed at the time of our planning. See (a) Ref. 6a. (b) Miller SJ, Blackwell H, Grubbs RH (1996) J Am Chem Soc 118 9606... 

With the discovery by Grubbs of ruthenium carbene complexes such as Cl2(PCy3)2Ru=CHR, which mediate olefin metathesis under mild reaction conditions and which are compatible with a broad range of functional groups [111], the application of olefin metathesis to solid-phase synthesis became a realistic approach for the preparation of alkenes. Both ring-closing metathesis and cross-metathesis of alkenes and alkynes bound to insoluble supports have been realized (Figure 5.12). 

Ruthenium-catalyzed olefin cross-metathesis (ring-closing metathesis, RGM) between terminal alkenes and vinyl-boronic acid or esters has recently been developed for the synthesis of ( )-l-alkenylboron compounds from alkenes.459,460 The efficiency of protocol was proved in the synthesis of a key intermediate of epothilone 490 292 461 (Equation (84)). The vinyl boronate was given almost exclusively the trans-adduct. 

A methodology to access trisubstituted macrocyclic ( )- and (Z)-alkenes from ring-closing metathesis (RCM) has been described. The strategy employs a substrate controlled RCM reaction of linear vinylsiloxanes to generate macrocyclic ( )-alkenyl siloxanes selectively. Conditions were developed to convert the alkenyl siloxane products into alkenyl halides with retention or inversion of configuration of the alkene geometry. 

The construction of trisubstituted alkenes by ring-closing metathesis can be difficult, and medium rings with their transannular strain are notoriously challenging to form. Nevertheless, Karl-Heinz Altmann of the ETH Zurich was able (Angew. Chem. Int. Ed. 2008, 47, 10081), using the H2 catalyst, to cyclize 12 to cyclononene 13, the precursor to the Xenia lactone (+)-Blumiolide C 14. 

When a mixture of alkenes 1 and 2 or an unsymmetrically substituted alkene 3 is treated with an appropriate transition-metal catalyst, a mixture of products (including fi/Z-isomers) from apparent interchange of alkylidene moieties is obtained by a process called alkene metathesis. With the development of new catalysts in recent years, alkene metathesis has become a useful synthetic method. Special synthetic applications are, for example, ring-closing metathesis (RCM) and ring-opening metathesis polymerization (ROM) (see below). 

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-... 

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)... 

With a-monosubstituted ylides the oxidation results in the formation of alkenes (by subsequent Wittig reaction on the intermediate aldehyde). A recent example of such synthesis is found in the preparation of all-(Z)-cyclododecate-traene by oxidation of the appropriate bis-ylide [33]. It must be pointed out that an approach of the same macrocycle based on ring closing metathesis was found ineffective. 

Catalytic ring-closing metathesis makes available a wide range of cyclic alkenes, thus rendering a number of stereoselective olefin functionalizations practical. The availability of effective metathesis catalysts has also spawned the development of a variety of methods that prepare specially-outfitted diene substrates that can undergo catalytic ring closure. The new metathesis catalysts have already played a pivotal role in a number of enantioselective total syntheses. 

From a mechanistic point of view, the titanocene(II)-promoted intramolecular cyclopro-panation of gem-dihalides possessing a terminal double bond is interesting. Although the products of ring-closing metathesis, i. e. cycloalkenes, are produced in certain cases, the treatment of 6,6- and 7,7-dihalo-l-alkenes (e. g. 39 and 40) with titanocene(II) species affords bicyclo[3.1. OJhexane and bicyclo[4.1.0]heptane derivatives 41 and 42, respectively (Scheme 14.19) [34],... 

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 ... 

Ring-Opening Metathesis (ROM)-Ring-Closing Metathesis (RCM) of Alkene... 

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