Domino metathesis Grubbs catalyst

The main reason for the rapid development of metathesis reactions on a laboratory scale (the reaction itself had been known for quite a long time) has been the development of active and robust second-generation ruthenium catalysts (6/3-14 to 6/3-16), which usually provide better yields than the first-generation Grubbs catalysts (6/3-9 or 6/3-13) (Scheme 6/3.2). This also reflects the huge number of domino processes based on ruthenium-catalyzed metathesis, which is usually followed by a second or even a third metathesis reaction. However, examples also exist where, after a metathesis, a second transition metal-catalyzed transformation or a pericyclic reaction takes place. 

A domino metathesis process using the enyne 6/3-54 and ethylene as substrates was developed by Arjona, Plumet and coworkers (Scheme 6/3.15) [244]. Interestingly, by using catalyst 6/3-15 (Gmbbs II), the pyrrolidone 6/3-55 was obtained in 98% yield as the only product, whereas with catalyst 6/3-13 (Grubbs I), compounds 6/3-56 (60%) and 6/3-57 (25%) were formed. 

Another intramolecular ene-yne metathesis followed by an intermolecular metathesis with an alkene to give a butadiene which is intercepted by a Diels-Alder reaction was used for the synthesis of condensed tricyclic compounds, as described by Lee and coworkers [266]. However, as mentioned above, the dienophile had to be added after the domino metathesis reaction was completed otherwise, the main product was the cycloadduct from the primarily formed diene. Keeping this in mind, the three-component one-pot reaction of ene-yne 6/3-94, alkene 6/3-95 and N-phenylmaleimide 6/3-96 in the presence of the Grubbs II catalyst 6/3-15 gave the tricyclic products 6/3-97 in high yield (Scheme 6/3.28). 

Plumet et al. described domino metathesis of propargyl (2-endo-7-oxanorborn-5-enyl) ethers 62a-62c with allyl acetate in the presence of Grubbs ruthenium catalyst Ic (Scheme 22). The reaction proceeds stereoselectively to produce substituted m-fused bicyclic ethers 63a-63c. In a similar manner, indolizidinone derivative 64 is obtained from compound 62d instead of pyrrolizidine derivative 63d. ... 

The C2-symmetric trienes 7 and 9 readily derived from D-marmitol underwent a symmetrical cleavage via a domino process featuring two ring-dosing metathesis (RCM) events to afford the enantiopure lactones 8 and 10, respectively (Scheme 2.2) [4]. While the second-generation Grubbs catalyst 2 led to an effident conversion of the p,Y-unsaturated diester 9, the more reactive phosphine-ffee catalyst 4 was required for a dean transformation of the a,fi-unsaturated diester 7. 

Similarly, the 18-membered macrocycle 14, which served as a precursor for the synthesis of a bioactive analog of the anticancer agent antimycin Aj, was quickly produced by domino self-metathesis/RCM from the threonine derivative 13 (Scheme 2.4) [5b]. The Zhan catalyst 5 was shown to be more effective for this key step than the Grubbs catalysts 1 or 2. 

The corresponding assembly of the fused 7/7-bicyclic substructure present in 93 by domino dienyne metathesis of silyl ether 92 with Grubbs catalyst 2 was... 

The selective domino dienyne metathesis of 94 with Grubbs catalyst 2 to give the fused 5/9-bicyclic substructure embedded in 95 controlled by olefin substitution was coupled in a sequential manner with a chemoselective ruthenium-catalyzed hydrogenation of the disubstituted alkene of 95 to yield the tricyclic protected amino ketone 96 in a one-pot process (Scheme 2.35) [18h]. Only two further steps were required to convert 96 into the Lycopodium alkaloid (+)-lycoflexine. 

Coupling an ROM event with enyne metathesis opens up further possibilities for RRM. As already discussed for reactions involving only olefins, norbomenes are valuable strained cycloolefins for the ring-opening step [22], Treatment of the norbomene derivative 123 with the first-generation Grubbs catalyst 1 under ethylene atmosphere induced a smooth domino ROM/enyne RCM/diene RCM process with quantitative formation of the tricyclic compound 124 (Scheme 2.45) [22b]. 

A domino RCM/reduction transformation of dienes 147 and 149 to furnish the saturated heterocycles 148 and 150, respectively, was realized by simultaneous treatment of the substrates with Grubbs catalyst 1 and triethylsilane (Scheme 2.52) [29]. Possibly, the hydrogenation step was catalyzed by the metathesis-inactive catalyst after completion of the RCM event. 

Another synthetically useful isomerization that can be combined with a metathesis event in a domino transformation is a metallotropic [l,3]-shift of a transient ruthenium aUdnyl carbene complex [33]. Treatment of the polyunsaturated substrate 162 with Grubbs catalyst 2 afforded the oligoenyne 163 in 86% yield... 

Enyne metathesis/metallotropic [l,3]-shift domino processes are also valuable for natural product synthesis [33c,d]. Reaction of substrate 168 with cis-l,4-diacetoxy-2-butene in the presence of Grubbs catalyst 2 generated the intermediate ruthenium alkinyl carbene through a relay RCM with the hberation of 2,5-dihydrofuran followed by metallotropic [l,3]-shift and terminating (Z)-selective CM with the co-olefin to yield the conjugated enediyne 169 (Scheme 2.58) [33c]. The antitumor active Panax ginseng constituent (3R,9R,10R)-panaxytriol was readily synthesized from 169 in six steps. 

Within this chapter, two sections are devoted to rhodium and ruthenium. The two main procedures using rhodium are first, the formation of 1,3-dipoles from diazocompounds followed by a 1,3-dipolar cycloaddition [10] and second, hy-droformylation [11], The ruthenium-catalyzed domino reactions are mostly based on metathesis [12], with the overwhelming use of Grubbs I and Grubbs 11 catalysts. 

As discussed earlier in detail, metathesis reactions have been used in extensio in domino processes. Almost all published examples employ Grubbs I and II catalysts... 

Next to fused bicyclic systems, the domino dienyne metathesis process can also be applied to the construction of bridged bicyclic dienes. Thus, dienyne 110 bearing differently substituted alkene units to ensure a regiocontrolled cyclization readily afforded the taxosteroid hybrid compound 111 without competing cyclopentene formation in the presence of the Grubbs second-generation catalyst 2 (Scheme 2.40) [19]. 

Different types of olefin metathesis, all proceeding according to the Chauvin mechanism and catalyzed by Schrock-type or Grubbs-type metathesis catalysts. Tandem, domino and cascade metathesis reactions couple several of these reactions (in particular ROMP + ROM). 

Grigg et al. reported a successful four-component domino reaction for the synthesis of functionalized dienes 316 from aryl iodides, allyl amine derivative, allene, and carbon monoxide [110] (Scheme 6.83). Carbon monoxide could insert into the C—Pd bond of arylpalladium(II) iodides to generate a carbonylpalladium species, which is followed by allenylation to form n-allylpalladium species. Finally, the attack of the nitrogen nucleophile produces the product observed. The products of this domino multicomponent reaction could be subjected efficiently to ring-closing metathesis in the presence of Grubbs second-generation catalyst. 

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