Cascade metathesis

Figure 5.14. Synthesis of polycyclic structures using a ring-opening, ring-closing metathesis cascade [121].

Fig. 4.13. Examples of enyne metathesis reactions, ring opening-cross metathesis cascades, and other metathesis sequences.

More complex small molecules can also be made by metathesis cascades and tandem reaction sequences involving olehn metathesis components [41], The examples illustrated in Fig. 4.13 include inter- and intramolecular enyne metathesis between an olefin and an alkyne [42], ring-opening cross metathesis to form new substituted acyclic olefins [43], ring-opening ring-closing sequences... 

Metathesis cascades have underpinned the synthesis of diverse small molecule libraries.Metathesis is a superb pairing reaction for the build-couple-pair approach first, it can yield many dilferent ring systems and, second, alkenes (and alkynes) are compatible with the many reactions that may be used to connect building blocks. Metathesis has been used to prepare a library of natural product-like molecules (Scheme 1.7). Initially, unsaturated building blocks were attached iteratively to fluorous-tagged linker to yield metathesis precursors 20. Crucially, alternative attachment reactions were used such that the building blocks were connected through bonds that either did, or... 

Scheme 1.7 Synthesis of natural product-like molecules with unprecedented scaffold diversity. Initially, building blocks were added iteratively to a fluorous-tagged linker, with intermediates purified by fluorous-solid phase extraction. Metathesis cascades were used to reprogramme the scaffolds and to release final products from the fluorous-tagged linker. Reagents and conditions. (1) Grubbs first-generation catalyst, 21a 23% 21b 56% (2) fluorous-tagged Hoveyda-Grubbs second-generation eatalyst, 21c 33%.

In terms of the mechanism of the reaction, the commonly accepted view is that the metathesis reactions occur as postulated by Chauvin in 1971 (Scheme 17.1) [8]. Essentially, the metathesis cascade is promulgated by way of a series of [2+2] cycloadditions and cycloreversions, which center on a number of metallacyclobutane intermediates (Scheme 17.1). It is believed that these [2-h2] processes are thermally allowed at the reaction temperatures due to overlap of the metal d-orbitals with the K systems involved. In addition, the driving force for the reaction to go to completion is often the liberation of gaseous ethylene that will escape from the reaction medium. 

In 1997, Peters and Blechert published an application of what is described as a metathesis cascade to afford substituted benzene-containing compounds from starting materials that had three embedded aUtynes [50]. For example, as shown in Scheme 17.26, the tricyclic compound 135 could be assembled from the triyne precursor 136 upon exposure to 0.5 mol% of the catalyst 1-Ru. 

A mechanism has been proposed by Blechert for this metathesis cascade, which involved the formation of a number of carbon-carbon bonds (in principle, a ruthenium-mediated [2-I-2+2] cycloaddition is also plausible for this transformation [49]). This postulated mechanism, as shown for the conversion of triyne 141 into the substituted aromatic system 142, is depicted in Scheme 17.27 [50]. Initially, complex 1-Ru adds to the less hindered acetylene of 141 to afford the vinyl carbene complex 143, which then undergoes an intramolecular metathesis reaction to afford 144 via 145. The conjugated complex 144 can then undergo a further RCM reaction to yield the product 142. 

SCHEME 17.27 The proposed mechanism for the metathesis cascade leading to substituted benzenes (Adapted with permission from Ref. [10]. Copyright (2009) American Chemical Society). 

SCHEME 17.29 Intermolecular metathesis cascade on triynes leading to substituted benzenes. (Adapted with... 

Alkene metathesis catalysts are also capable of undergoing reaction with aUene and alkyne functionality, which can lead to the synthesis of polyene compounds. For example. Diver has explored the use of alkene/alkyne CM, which leads to 2-substituted 1,3-dienes (Scheme 2.11). Prunet has recently disclosed an elegant metathesis cascade sequence towards the synthesis of Taxol, involving two alkenes and one alkyne functional group (Scheme 2.12) the desired product was accompanied by small quantities of a side product that resulted from metathesis of the two alkenes. 

Scheme 172). " Cross-metathesis of the terminal alkene with 3,4-dime-thoxystyrene, induced in the presence of the Hoveyda—Grubbs catalyst (7), was followed by oxidation of the alcohol to give the unsaturated ketone (—)-1369 in 85% yield. Alternatively, 1367 could be oxidized to the cyclo-pentenone (- -)-1370 initially, after which a one-pot metathesis cascade with... 

Fully intramolecular [2 + 2 + 2] cyclization of triynes affords tricyclic products with complete chemo- and regioselectivity. Despite this advantage, this method is underdeveloped, which is probably due to the diminished accessibility of the triyne substrates. Peters and Blechert reported the first ruthenium-catalyzed fully intramolecular cyclotrimerization using the metathesis cascade strategy with Grubbs catalyst [23]. Later, Yamamoto et al. demonstrated that complex 6 efficiently catalyzes the cyclization of various triynes [14]. Examples of 1,6,11-triyne cyclization are summarized in Table 3.11. As an example, diether 58 (X = = O, R = H) underwent [2 + 2 + 2]... 

In addition to 6, different ruthenium complexes have been investigated as catalysts for alkyne cyclotrimerizations and cyclocotrimerization of alkynes with nitriles. Among them, Grubbs-type carbene complexes are of particular importance since they catalyze inter- and intramolecular metathesis-cascade cyclotrimerizations under mild conditions. In addition, they have good tolerance toward a variety of functional groups. 

Keywords Alkene metathesis Cascade reaction Stereoselective synthesis Total synthesis... 

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