Cascade enyne metathesis

Norbornene derivatives bearing two alkynes undergo cascade enyne metathesis reactions when treated with a first generation ruthenium carbene and ethylene, giving heterocyclic dienes [28]. The ROM of the norbornene moiety initiates the cascade enyne RCM reactions (Scheme 14). When ethylene is replaced by a monosubstituted alkene, a single enyne RCM takes place, after the initial ROM of norbornene. 

In 2009, Lee and coworkers reported the concise total syntheses of epoxyquinoid namral products (+)-asperpentyn (103), (-)-harveynone (104), and (—)-tricholo-menyn A (105) via cascade enyne metathesis and metallotropic [l,3]-shift (Fig. 29) [78]. In order to initiate the cascade effectively, arelay metathesis strategy was also adopted. By treatment of the polyenyne precursor (106) with Grubbs II catalyst, a mixture of epimers (107) and (108) was isolated in 62% yield. This cascade process selectively commenced from the terminal alkene of the allyl ether (106) to form the relay intermediate (109), which then underwent sequential relay metathesis and enyne metathesis to form alkynyl Ru-alkylidene (111). Subsequent facile metallotropic [1,3]-shift took place to provide the conjugated alkyhdene product (112), which would ultimately deliver the final products (107) and (108) through termination at the less hindered carbon. 

In turn, the propensity of 1 to respond to steric hindrance can be used to control the site of initiation of an RCM reaction in a polyene substrate (Scheme 9) [20]. Thus, dienyne 25 reacts with the catalyst regioselectively at the least substituted site the evolving ruthenium carbene 26 undergoes a subsequent enyne metathesis leading to a new carbene 27, which is finally trapped by the disubsti-tuted olefin to afford the bicyclo[4.4.0]decadiene product 28. By simply reversing the substitution pattern of the double bonds, the complementary bicyclo [5.3.0] compound 32 is formed exclusively, because the cyclization cascade is then triggered at the other end of the substrate. Note that in both examples tri-substituted olefins are obtained by means of a ruthenium based metathesis catalyst [20] ... 

Ru-catalysed enyne metathesis offers a short approach to chiral derivatives of 3-vinyl-5,6-dihydro-2//-pyrans. Some epimerisation can occur at the pyranyl C atom at elevated temperatures (Scheme 3) <02T5627>. The bispropargyloxynorbomene derivative 6 undergoes a cascade of metathesis reactions in the presence of alkenes and Grubbs catalyst incorporating an enyne-RCM that leads to fused cyclic dienes. A dienophile can be added to the reaction mixture, resulting in Diels-Alder reactions and the formation of functionalised polycyclic products <02TL1561>. 

The intermolecular enyne cross metathesis, and consecutive RCM, between a terminal alkyne and 1,5-hexadiene produces cyclohexadienes, by cascade CM-RCM reaction, and trienes, formed during the sole CM step. Studies of various parameters of the reaction conditions did not show any improvement of the ratio of desired cyclohexadiene product [25] (Scheme 12). The reaction with cyclopentene instead of hexadiene as the alkene leads to 2-substituted-l,3-cycloheptadienes [26]. After the first cyclopentene ROM, the enyne metathesis is favored rather than ROMP by an appropriate balance between cycloalkene ring strain and reactivity of the alkyne. 

Diynes are also used to perform intermolecular enyne metathesis. With the objective of producing functionalized hetero- and carbocycles, a cascade diyne-alkene cross metathesis leading to five-membered cyclic products has recently been proposed [27] (Scheme 13). 

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... 

R] Although not focused on true tandem/cascade processes, for a review of the synthesis of polycyclics by a combination of enyne metathesis and the Diels-Alder reaction, see Kotha, S. Meshram, M. Tiwari, A. Chem. Soc. Rev. 2009,38,2065-2092. 

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