Grubbs’catalysts chiral

Double sequential ene-yne ring-closing metathesis on a series of chiral 3,4-bisallyloxybut-l-ynes using both Grubbs catalysts has been used to generate chiral dioxabicyclo[4.4.0]decanes (Scheme 48) <2003JOC7889>. 

Ru-catalysed enyne metathesis offers a short approach to chiral derivatives of 3-vinyl-5,6-dihydro-2//-pyrans. Some epimerisation can occur at the pyranyl C atom at elevated temperatures (Scheme 3) <02T5627>. The bispropargyloxynorbomene derivative 6 undergoes a cascade of metathesis reactions in the presence of alkenes and Grubbs catalyst incorporating an enyne-RCM that leads to fused cyclic dienes. A dienophile can be added to the reaction mixture, resulting in Diels-Alder reactions and the formation of functionalised polycyclic products <02TL1561>. 

Chiral dioxabicyclic systems are selectively formed from 3,4-bisallyloxybut-1-yne derivatives under an ethylene atmosphere. A single RCM is performed when a RuCl2(PCy3)2(= CHPh) is employed, while the cascade RCM of dienyne is the major reaction with a second generation Grubbs catalyst (Scheme 5). In this case, the substitution of the allyloxy groups can selectively lead to dioxabicyclo[4.4.0]decane or to dioxabicyclo[5.3.0]decane [13]. 

Figure 5.12 Synthesis of chiral second generation Grubbs catalysts from chiral b2-diamines.

The stereodirecting effect of the axially chiral 1,1 -binaphthyl ligand is assisted by the bulky wingtip group of the carbene (Mes) and the additional substituents of the benzylide-nyl ligand that features prominently in the Grubbs catalyst (see Figure 5.12). 

Note The IJ -biphenyl and the 1,1 -binaphthyl scaffolds have the same steric influence on the transition metal (ruthenium) centre of the second generation Grubbs catalyst. Therefore, the improved chiral resolution in the product is likely due to a favourite combination of axial and central chirality. 

CM has also been applied in the immobilization of biologically active molecules. Thus, [230] Reetz and co-workers supported chiral phosphonate as a potential suicide enzyme inhibitor by reacting alkenyl phosphonates with either allyl-modified SIRAN (a porous glass) or allyl-modified TentaGel in the presence of the Grubbs catalyst in CH2CI2 at reflux. 

A simple example is the synthesis of analogues of the antibiotic and antifungal streptazolin by Cossy.40 Enantiomerically pure diene carbamate 188, prepared from the chiral pool (see chapter 23 and the workbook for this chapter) was treated with the Grubbs catalyst to form the six-memberedring 189 required for (-)-4,5-dihydrostreptazolin 190. This metathesis product inevitably contains a Z-alkene. 

The amine 49, made from one enantiomer of propylene oxide by simple reactions, is the source of the chirality. A cross-metathesis with 47, using the Grubbs catalyst 50 gave a surprisingly excellent yield (89%) of the complete carbon skeleton 49 of monomorine. 

The next few stages to produce the metathesis substrate 78 are straightforward and involve the creation of no new chiral centres. The metathesis was very successful with the original Grubbs catalyst 85 and gave the cyclic diene 86. Now the two carbonyl groups and the last two chiral... 

At another GlaxoSmithKline site, in the USA, the development of a drug for osteoporosis and osteoarthritis required a seven-membered heterocycle with two controlled chiral centres. This time the Hoveyda—Grubbs catalyst had to be used but the loading is very low indeed. Notice also that a free OH group does not interfere. 

The pioneering work on enantioselective ruthenium olefin metathesis was carried out by Grubbs and co-workers in 2001 [69] (Fig. 3.23). Catalysts 55a-b and 56a-b were designed and prepared from C -symmetric NHC hgands with a combination of chiral backbone and mono-ortfto-substituted aryl side chains, a motif that was expected to form a chiral environment around the metal centre. 

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