Hoveyda catalyst 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)...

The crucial RCM reaction of the 1,1-disubstituted alkene 92 was accomplished using Hoveyda—Gmbbs second-generation catalyst 4 to provide 93 in 76% yield. This reaction proved to be challenging and slow addition of the catalyst along with the use of benzoquinone (05JACS17160) to quench any in situ formed Ru—H species (04EJOC1865) was key to the success of this reaction. 

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... 

Wang and co-workers [70] at GlaxoSmithKline published several RCM approaches for the preparation of potent eathepsin K inhibitor 144, a eandi-date for the treatment of osteoporosis and osteoarthritis. Aeeordingly, pure diene 142 imderwent RCM reaction with 0.1-0.2 mol% of Hoveyda s second-generation catalyst 124 in toluene at reflux and afibrded cychzed product 143 (71.8 kg, 96% yield), without any byproducts (Scheme 9.38). 

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). 

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,. 

---