Grubbs reaction Intramolecular

There are times that it is important to run the Grubbs reaction under equilibrating conditions. In the course of a synthesis of ophirin 12, Michael Crimmins of the University of North Carolina observed (J. Am. Chem. Soc. 2004,126, 10264) that metathesis of 8 under the usual conditions gave mainly the undesired cyclic dimer. At elevated temperature, the dimer re-entered the equilibrium, leading to the desired 9 as the major (15 1) product. The oxonene ring system of 10 then directed the intramolecular Diels-Alder cycloaddition, leading to 12. 

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). 

Sequential Grubbs metathesis/Diels-Alder strategies can be used to produce tetrahydroquinolines. For example, intramolecular enyne metathesis followed by reaction with alkynes followed by oxidation serves as a useful route to multisubstituted systems (Scheme 78) <2000CC503>. 

Enyne systems are also capable of impressive multiple RRM transformations. For the first such example see Ref. [119]. The reaction of a ruthenium alkyli-dene with an alkyne produces a new vinyl alkylidene, which can participate in further intramolecular or intermolecular metathesis reactions to form fused ring systems. This has led Grubbs to designate alkynes in such systems as relays . In a noteworthy example, Zuercher et al. [ 120] constructed the four fused rings of the steroid backbone 68 in one efficient step using tandem enyne re-... 

Pandit et al. reported in 1996 the first synthesis of the pentacyclic core reminiscent of the ircinal and ircinol structures [86,87]. The tricyclic key intermediate 216 was prepared by intramolecular Diels-Alder reaction of 214, which was in turn prepared from L-serine 210 in 10 steps (Scheme 8.14) [77,88-93]. The second phase of the synthesis involved the construction of the 8- and 13-membered rings, which was realized by sequential RCM on compounds 220 and 224 employing Grubb s catalyst, which therefore completed the first construction of the ABCDE pentacyclic core (Scheme 8.15). The application of the RCM methodology has been... 

Conformationally constrained a-Boc-aminophosphonates (387), (388) (389), (390) and (391) were made via a transition metal catalysed Curtins rearrangement. The conformational constraint involved either a ring-closing metathesis reaction catalysed by the first generation Grubbs catalyst or intramolecular cyclopropanation mediated by Rh2(OAc)4 (Figure 66). ... 

The Grubbs second-generation catalyst will first attack the C=C double bond that delivers the most driving force to the reaction. After the ROM of the cyclohexene ring, the molecule can undergo subsequent intramolecular alkene metathesis reactions. 

As described before, TBS ethers can be cleaved under acidic conditions. Hence, treatment of 34 with 1 M HCl in a mixture of methanol and dichloromethane for six hours at room temperature affords the desired diol 86 in 60 % yield. Then, 86 is subjected to RCM, mediated by Grubbs second-generation catalyst 28, which has already been used for the preparation of lactone 29 In order to have optimal conditions for an intramolecular ring-closing reaction the reaction is performed with a highly diluted solution of 86 in dichloromethane (0.001 M) in the presence of 10 mol-% of catalyst 28 thus providing macrocyle 35 with (8 -configuration in 82 % yield. 

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