RCM Reactions

The following order of initiation rate constants was found by Grubbs et al. for 71a and some precatalysts containing one phosphine ligand 56d< 56k 71a<56h (cf. Scheme 15 for structures of 56d,h,k) [48b, 55]. Thus, 71a shows a rate of initiation comparable to that of 56k but three orders of magnitude higher than that of 56d. Nevertheless, 56d appears to be more reactive in RCM reactions than 71a [56]. Wakamatsu and Blechert were the first to report that the activity of precatalysts related to 71a can be dramatically enhanced by modification of the benzylidene unit [56]. For example, RCM of 75 using 1 mol% of BINOL-derived complex 71b yields the azacyclic product 76 in quantitative yield within 20 min (Eq. 10), whereas with 56d only 4% of 76 was obtained under these conditions [56]. 

Although the number of applications of olefin metathesis to transition metal complexes is small compared to the number of applications in organic synthesis, this field is becoming increasingly important. Spectacular examples are the double RCM reactions of copper phenanthroline complexes as a synthetic route to catenanes [113] or a recently reported approach to steric shielding of rhenium complex terminated sp-carbon chains [114]. 

In recent years, a wealth of information has accumulated on RCM reactions leading to 5-, 6-, and 7-membered carbocycles and heterocycles, so that it is impossible to refer to all the new, natural product-directed work. Therefore, we will concentrate here on a few selected examples that can illustrate (1) the progress made by the advent of the second-generation ruthenium catalysts C-E, (2) the use of RCM in concert with other innovative methodology, and (3) the use of RCM in total syntheses of newly discovered natural products which, due to an outstanding biological profile, have attracted specific interest by the synthetic community. 

A year after the total synthesis of (+)-laurencin [85], Crimmins disclosed the total syntheses of (+)-prelaureatin (169) and (+)-laurallene (168) by applying a similar strategy (Scheme 31) [86]. The critical RCM reaction was undertaken... 

For the previous preparation of a mixed acrolein acetal and its use in an RCM reaction during callystatin A total synthesis, see Crimmins MT, King BW (1998) J Am Chem Soc 120 9084... 

RCM. See Ring-closing metathesis (RCM) Reaction by-products, removing, 83 Reaction extrusion, 204 Reaction index, 237 Reaction injection molding (RIM), 205 Reaction-in-mold (RIM) nylon, 149 Reaction kinetics, 76, 77 Reaction mechanisms, polyesterification, 66-69... 

The most common clinical picture of non-immediate RCM reactions is a macu-lopapular exanthema, which resembles other drug-induced T-cell-mediated hypersensitivity reactions. The reported onset of skin eruptions 2-10 days after the first exposure to a RCM and 1-2 days after re-exposure to the same substance is typical for an allergic drug reaction with a sensitization phase. 

Chromatographic workup enabled the separations of anti and syn isomers and pure anti-24a, syn-2A anda ft -24b where obtained. RCM studies with these pre-catalyst and standard substrates 1, 3, 7 and 9 indicated that an anti arrangement of the naphthyl side chains gave better activity in these RCM reactions. 

As noted above, while stndying the effect of the side chains of the NHC ligands on rntheninm olefin metathesis, it was fonnd that catalysts bearing smaller-sized aryl gronps were more snccessfnl for RCM reactions to form tetrasnbstitnted double bonds [43,45]. However, several attempts dnring the evolution failed, becanse these complexes were either difficnlt to synthesise or nnstable (Fig. 3.13). 

Even more recently, Grisi and co-workers reported two catalysts bearing NHC ligands with syn (43) and anti (44) methyl gronps on the A-heterocyclic backbone [58]. These two catalysts represent the possible configurations of the same NHC ligand nsed as isomeric mixture in catalyst 42b (Fig. 3.16). The catalytic performance of both 43 and 44 was evaluated in the RCM reactions of 1, 3, and 5, with catalyst 29a taken as benchmark system. It was found that iyn-catalyst 43 was more active than the parent pre-catalyst 29a, while anft-catalyst 44 was less active than 29a. 

In 2009, Buchmeiser and co-workers reported the synthesis of a novel ruthenium complex 54 based on a seven-membered NHC ligand [68] (Fig. 3.22). To examine the catalytic activity of complex 54 in the RCM reaction, the authors subjected the complex to a series of typical RCM reactions by using substrates 1, 3, and 5. Pre-catalyst 54 showed only moderate reactivity with 1 and 3 and no reaction occurred with 5. 

Ring Closing Metathesis (RCM) Reactions Used in the Pharmaceutical Industry... 

Natural products are valuable substrates for further transformations, especially if they contain one or more stereogenic centers of defined absolute configuration. One of the most frequently used natural products in this respect is the monoter-pene a-pinene (6/3-43), which has also been restructured using domino processes. Mehta and coworkers [241] have used the alcohols 6/3-44, easily accessible from a-pinene (6/3-43), for a ROM/RCM reaction to give 6/3-45 and 6/3-46, which were... 

The application of the RCM reaction to the construction of nitrogen-containing ring systems, including quinolizidine derivatives, has been reviewed <1999EJ0959>. From that date, this strategy has become more and more common in quinolizidine synthesis, especially in cases where the cyclization takes place by formation of a bond 7 to the heteroatom. Some examples are given below. 

A double RCM reaction of 367 permitted the efficient construction of the fused bicyclic quinolizidine skeleton 368 as the major product, together with a small amount of the other possible double-metathesis product 369 (Scheme 84) <20020L639, 2004CEJ3286>. Similarly, an RCEYM process from substrate 370, carried out in an atmosphere of ethylene, afforded the quinolizine derivative 371 <2004JOC6305>. 

Enantiomerically pure triene 395, whose chirality stems from that of /3-D-ribofuranosc, was transformed into the chiral pyrrolidine 396 by intramolecular iodoamination. A subsequent RCM reaction gave indolizine derivative 397. Treatment of this compound with nucleophiles afforded mixtures of indolizine and quinolizine derivatives in... 

In one example of application of the RCM strategy, summarized in Scheme 107, the key intermediate 454 was obtained from 451 by sequential Wittig methylenation to 452, reductive iV-deprotection to 453, and introduction of an alkenyl chain onto the secondary amine. The RCM reaction of 454 to 455 proceeded in quantitative yield in the presence of the second-generation Grubbs catalyst <20040L965>. 

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