Hoveyda-Grubbs’ second-generation

Fig. 3 Olefin metathesis catalysts Schrock tungsten (Cl) and molybdenum (C2) alkylidene complexes, Grubbs first- (C3) and second-generation (C4) catalysts, Hoveyda-Grubbs second-generation catalyst (C5), and Grubbs third-generation catalyst (C6)...

Scheme 1.7 Synthesis of natural product-like molecules with unprecedented scaffold diversity. Initially, building blocks were added iteratively to a fluorous-tagged linker, with intermediates purified by fluorous-solid phase extraction. Metathesis cascades were used to reprogramme the scaffolds and to release final products from the fluorous-tagged linker. Reagents and conditions. (1) Grubbs first-generation catalyst, 21a 23% 21b 56% (2) fluorous-tagged Hoveyda-Grubbs second-generation eatalyst, 21c 33%.

HGII Hoveyda-Grubbs second generation catalyst... 

With regards to the initiation of ROMP kinetics using DCPD as the monomer, the Hoveyda-Grubbs second-generation catalyst proved to be significantly more reactive with over 60% of DCPD conversion observed within the first 5 minutes. The second-generation Grubbs catalyst exhibited the slowest reaction kinetics in bulk polymerization, an observation which is in contrast with the performance observed for similar reactions performed in solution (25,40). 

Cinnamyl bromide 24 and the iodocarbohydrate 23 are combined in a zinc-mediated fragmentation/allylation reaction to afford a highly functionalized 1,7-diene, which is then treated with Hoveyda-Grubbs second-generation catalyst to produce a mixture of diastereomeric cyclohexenes 25 (35% yield) and 26 (32% yield). From the major isomer 25, subsequent Overman rearrangement, dihydroxylation, and deprotection afford the natural product pancrastistatin (28) (Scheme 3.10). 

In the articles on metathesis reactions, ruthenium compounds of organometallic intramolecular-coordination five-membered ring compounds are used for what are generally referred to as Hoveyda-Grubbs first-generation 12 and second-generation 1.3 catalysts (Fig. 1.1) [68, 69]. 

Figure 2 Metathesis catalysts Grubbs first-generation catalyst (5), Grubbs second-generation catalyst (6), Hoveyda—Grubbs catalyst (7), and Grubbs—Nolan catalyst (8).

It is noteworthy that these five syntheses used four different metathesis catalysts in the key alkene forming step. For the cyclization of 7, the use of the Grubbs first generation catalyst Gl, that couples terminal alkenes but tends not to interact with internal alkenes, was probably critical to success. The Hoveyda catalyst H2 is more expensive than the Grubbs second generation catalyst G2, but can often be effective in appHcations in which G2 is sluggish. The Schrock Mo catalyst is less user fiiendly than the (relatively) air and moisture stable Ru catalysts, but is very reactive. 

The most widely used catalysts for RCM are Grubbs ruthenium catalyst 9 and its second generation analogue 10, as well as first and second generation Hoveyda-Grubbs catalysts 11 and 12 (Fig. 6) [38]. The latter have superior stability and reactivity, expanding the applicability of the method considerably. Schrock molybdenum catalyst 13 has also been described for macrocy-clization [38]. 

The use of the second-generation Grubbs catalyst or the Grubbs-Hoveyda catalyst (cat. Gr. H.) (Scheme 37) enables the synthesis of benzo-fused lactams 148 (09TA1154), 149 (05JOC5519), and a-amino-a, -unsaturated lactam 150a (08TL5141). 

The most straightforward application of the Grubbs reaction is to effect homologation of a terminal vinyl group. One concern with the use of the second generation Grubbs catalyst 3 is the cost, about 100/mmol. In conjunction with a total synthesis of the macrolide RK-397, Frank McDonald of Emory reported (J. Am. Chem. Soc. 126 2495, 2004) that the conversion of 1 to 2 required 10 mol % of 3, but that it proceeded efficiently with just 2 mol % of the Hoveyda Ru catalyst 4 (J. Am. Chem. Soc. 122 8168,2002). The alkene so prepared was cleanly trans. An advantage of 4 is that it avoids the use of the expensive PCy,. 

Isoxazolo[2,3-a]pyridin-7-ones were prepared by domino metathesis of the strained nitroso Diels-Alder adduct 87 and a terminal alkene in the presence of a catalytic amount of second generation Grubbs carbene or Hoveyda-Grabbs carbene complex. For example, 88 was obtained as the major product along with minor amounts of 89 starting from 87 and but-3-en-l-ol <07OL1485>. 

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