Grubbs’s catalysts

Until now, the most efficient approach to synthesize Freidinger lactams 147 started from a resin-bound cinnamylamine 144. A Fukuyama-Mitsunobu reaction to 145 followed by sulfonamide cleavage and a consecutive appropriate acylation built up the diene 146, which underwent ring-closing metathesis involving Grubb s catalyst 123 to generate the desired lactams 147 (Scheme 27, Table 5) [35d]. 

Witulski introduced a novel protocol for crossed alkyne cyclotrimerizations of systems such as 87 mediated by Grubb s catalyst to produce 4,6-disubstituted indolines 88 <00CC1965>. Interestingly, use of Wilkinson s catalyst [RhCl(PPhj)3] allows for the regioselective synthesis of the corresponding 4,5-substituted isomers. 

Diels-AIder reactions were utilized to prepare isoquinoline derivatives. Various tetrahydroisoquinoline-3-carboxylic acid derivatives were prepared by an enyne metathesis followed by a Diels-AIder reaction. For example the enyne 71 was treated with Grubb s catalyst to afford diene 72 in 65% yield. Subsequent Diels-AIder reaction and oxidation gave tetrahydroisoquinoline 73 in 93% yield <0OCC5O3>. Dihydrosoquinoline 75 was prepared... 

The mechanism involves a [2 + 2] cycloaddition reaction between an alkene and a transition metal carbene (Scheme 10.13). In the absence of a transition metal carbene catalyst, the reaction between two alkenes is symmetry forbidden and only takes place photochemically. However, the d-orbitals on the metal catalyst (typically Grubbs s catalyst as shown in Scheme 10.13), break the symmetry and the reaction is facile. 

Ring closure of the diene in [Ru(phen)2(217)] using Grubb s catalyst generates a macrocyclic complex, the photochemical behavior of which has been studied in MeCN solution. Irradiation at >300 nm leads to the expulsion of [Ru(phen)2(MeCN)2], and quantitative regeneration of the macrocyclic complex can be achieved by heating in ethylene glycol. " ... 

Polyhydroxylated piperidines such as are of interest as glucosidase inhibitors. Antoni Riera, also of the University of Barcelona, has developed (J. Org. Chem. 2005, 70,2325) a route to 16 from the readily-available enantiomerically-pure epoxide 11. Condensation with ally isocyanate 12 followed by cyclization gave 13, which was further cyclized by a Grubb s catalyst (unspecified) to 14. Protection set the stage for face-selective dihydroxylation, to give 15. Several other piperidines having other polyhydroxylation patterns were also prepared from 14. 

With 17 now readily available, we proceeded to the key RCM reaction. Our first results, using Grubbs s catalyst [Ru]-b (see Scheme 6) were not encouraging as cyclization products were obtained in only 11 % yield along with unidentified material. Addition of Ti(OiPr)4 (to disrupt the potential stable ruthenium chelate) (Figure 3) did not improve the yield and led to the formation of decomposition products. 

In an effort to improve the yield of the RCM, we tried using the "2nd generation" Grubbs s catalyst [Ru]-c, which had just become commercially available. We found that the catalyst was not compatible with Ti(OiPr)4. When the Lewis acid was omitted we observed a rapid disappearance of the starting material with formation of unidentified polymeric material. 

The first representative 57 of pyrido[2,l-/]-3,l-benzoxazine ring system was synthesized by the ring-closing methathesis of perhydro-3,l-benzox-azine 113 in the presence of the second generation of Grubb s catalyst (06TL3815). 

The Ru-catalysts used tolerate a variety of functional groups, but normally the molecule must have polar side chains that are able to build a template for the catalyst. The modern Second Generation Grubb s Catalysts are more versatile. 

In 2005, Rowan, Nolte, and coworkers described an efficient and templated synthesis of porphyrin boxes using DCC and reversible metathesis reaction [54]. Cyclic tetramers were successfully prepared in good yields (62%) from an olefin-functionalized zinc porphyrin in the presence of first generation Grubb s catalyst and upon addition of a tetrapyridyl porphyrin (TPyP) serving as a template. While a mixture of linear and cyclic oligomers was obtained in the absence of template, addition of TPyP resulted in a reorganization of the DCL to favor the formation of the desired tetrameric box (Fig. 7a). 

The cyclization of 8c to 9c created a trisubsti-tuted double bond, thus preparing new ground for the application of RCM in complex systems. Actually the substrate failed to cyclize with the ruthenium-based Grubb s catalyst, but 20 mol% of a molybdenum-based catalyst described by Schrock led to the cyclized product 9c in 86 % yield (benzene, 55 "C), unfortunately again with a 1.0 1.0 ratio of Z to isomers [11]. 

The formation of 8- and 15-membered rings was achieved by sequential RCM on compounds 184 and 187 utilizing Grubb s catalyst, which provided bislactam 188. Reduction of bislactam 188 with Red-Al completed the total synthesis of ( )-nakadomarin A. 

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... 

A semibiomimetic synthesis of keramaphidin B was also reported utilizing RCM methods (Scheme 8.18) [133]. The keramaphidin B precursor 240 (prepared from dihydropyridinium salt 239 [134,135]) was treated vhth Grubb s catalyst to give the monocyclized 241 and keramaphidin B. 

Scheme 7.17. Ring closing metathesis reaction to obtain (+)-anatoxin-a. (a) second generation Grubb s catalyst 69, CHjCI, 87%. (b) OsO, EtNj, THF, -78°C to rt, then aq. NaHS03, A, 76%. (c) NalO, THF/H O, rt, 95%. (d) TMSI, CHjCN, -10°C, 99%.

Jeon et al. have recently reported on ring-opening metathesis copolymerizations of cyclooctene and the PGSS-norbornylene monomer performed with Grubbs s catalyst. Random copolymers were then formed and fully charac-... 

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