Ruthenium catalyzed racemization

Scheme 5.11 Dynamic kinetic resolution of alcohol 18 by combination of enzymatic transesterification and ruthenium-catalyzed racemization.

Scheme 1.5 A simplified mechanism for ruthenium-catalyzed racemization of sec-alcohol.

Asymmetric reductive acetylation was also applicable to acetoxyphenyl ketones. In this case the substrate itself acts as an acyl donor. For example, m-acetoxyace-tophenone was transformed to (R)-l-(3-hydroxyphenyl)ethyl acetate under 1 atm H2 in 95% yield [16] (Scheme 1.12). The pathway of this reaction is rather complex. It was confirmed that nine catalytic steps are involved two steps for ruthenium-catalyzed reductions, two steps for ruthenium-catalyzed racemizations, two steps... 

Backvall later demonstrated ruthenium-catalyzed racemization of a range of primary benzyhc amines using Shvd s dimeric catalyst in toluene at 100 °C [15]. 

Dijksman, A. Elzinga, M., J. Li, Yu-Xin, Arends, I., Sheldon, R., A. Efficient ruthenium-catalyzed racemization of secondary alcohols application to dynamic kinetic resolution. Tetrahedron Asymmetry 2002, 13, 879-884. 

Scheme 133 DKR of in situ-foirned (i-hydroxyesters coupling a lipase enantioselective irreversible acylation with ruthenium-catalyzed racemization (R = Ph, p-OMe-Ph, PhCH2-)-...

The ruthenium-catalyzed racemization of a-methylbenzyl alcohol was combined with an enzyme-catalyzed transesterification with lipase. Dinuclear ruthenium complex 64 effectively catalyzes the racemization of a-methylbenzyl alcohol and the combination of 64, p-chlorophenyl acetate, and enzyme N-435 in the reaction of racemic amethylbenzyl alcohol gave enantiomerically pure (R)-a-methylbenzyl acetate in the excellent yield (Eq. 12.26) [29]. 

Scheme 19.5 Dynamic kinetic resolution of a secondary alcohol based on ruthenium-catalyzed racemization and enzymatic acylation.

Larsson, A. L. E., Persson, B. A., and Backvall, J.-E. (1997). Enzymatic resolution of alcohols coupled with ruthenium-catalyzed racemization of the substrate alcohol. Angew. Chem. Int. Ed. Engl., 36,1211-1212. 

Koh, J. H., Jung, H. M., Kim, M.-J., and Park, J. (1999). Enzymatic resolution of secondary alcohols coupled with ruthenium-catalyzed racemization without hydrogen mediator. Tetrahedron Lett., 40,6281-6284. 

Sheldon et al. have combined a KR catalyzed by CALB with a racemization catalyzed by a Ru(II) complex in combination with TEMPO (2,2,6,6-tetramethylpi-peridine 1-oxyl free radical) [28]. They proposed that racemization involved initial ruthenium-catalyzed oxidation of the alcohol to the corresponding ketone, with TEMPO acting as a stoichiometric oxidant. The ketone was then reduced to racemic alcohol by ruthenium hydrides, which were proposed to be formed under the reaction conditions. Under these conditions, they obtained 76% yield of enantiopure 1-phenylethanol acetate at 70° after 48 hours. 

Ursini, C.V., Dias, G.H.M. and Rodrigues, J.A.R., Ruthenium-catalyzed reduction of racemic tricarbonyl( 7 -aryl ketonejchromium complexes using transfer hydrogenation a simple alternative to the resolution of planar chiral organometallics. J. Organomet. Chem., 2005,690, 3176. 

DKR of secondary alcohol is achieved by coupling enzyme-catalyzed resolution with metal-catalyzed racemization. For efficient DKR, these catalyhc reactions must be compatible with each other. In the case of DKR of secondary alcohol with the lipase-ruthenium combinahon, the use of a proper acyl donor (required for enzymatic reaction) is parhcularly crucial because metal catalyst can react with the acyl donor or its deacylated form. Popular vinyl acetate is incompatible with all the ruthenium complexes, while isopropenyl acetate can be used with most monomeric ruthenium complexes. p-Chlorophenyl acetate (PCPA) is the best acyl donor for use with dimeric ruthenium complex 1. On the other hand, reaction temperature is another crucial factor. Many enzymes lose their activities at elevated temperatures. Thus, the racemizahon catalyst should show good catalytic efficiency at room temperature to be combined with these enzymes. One representative example is subtilisin. This enzyme rapidly loses catalytic activities at elevated temperatures and gradually even at ambient temperature. It therefore is compatible with the racemization catalysts 6-9, showing good activities at ambient temperature. In case the racemization catalyst requires an elevated temperature, CALB is the best counterpart. 

Pahnans et al. prepared 5 by the reaction of [RuCl2(p-cymene)]2 and 2-phenyl-2-aminopropionamide in the presence of potassium carbonate. They used 5 in an iterative tandem catalysis for the synthesis of chiral oligoesters. The enzymatic ring opening of 6-methyl-e-caprolactone was combined with ruthenium-catalyzed alcohol racemization to produce optically active oligomers of 6-methyl-e-capro-lactone [23] (Scheme 1.17). 

As described in the previous section, the ruthenium-catalyzed propargylic alkylation of propargylic alcohols with acetone afforded the corresponding alkylated products in high yields with complete selectivity [27]. When an optically active 1 -phenyl-2 -propyn-1 -ol was treated with acetone at room temperature in the presence of la as catalyst, only a racemic alkylated product was obtained [27]. This result... 

In 2001, Takahashi and his co-workers developed the first asymmetric ruthenium-catalyzed allylic alkylation of allylic carbonates with sodium malonates which gave the corresponding alkylated compounds with an excellent enantioselectivity (Equation (Sy)). Use of planar-chiral cyclopentadienylruthenium complexes 143 with an anchor phosphine moiety is essential to promote this asymmetric allylic alkylation efficiently. The substituents at the 4-position of the cyclopentadienyl ring play a crucial role in controlling the stereochemistry. A kinetic resolution of racemic allylic carbonates has been achieved in the same reaction system (up to 99% ee). ... 

In order to reduce the time needed to perform a complete kinetic resolution Lindner et al53 reported the use of the allylic alcohol 30 in enantiomerically enriched form rather than a racemic mixture in kinetic resolution. Thus, the kinetic resolution of 30 was performed starting from the enantiomerically enriched alcohol (R) or (S)-30 (45%) ee obtained by the ruthenium-catalyzed asymmetric reduction of 32 with the aim to reach 100 % ee in a consecutive approach. Several lipases were screened in resolving the enantiomerically enriched 30 either in the enantioselective transesterification of (<5)-30 (45% ee) using isopropenyl acetate as an acyl donor in toluene in non-aqueous medium or in the enantioselective hydrolysis of the corresponding acetate (R)-31, (45% ee) using a phosphate buffer (pH = 6) in aqueous medium. An E value of 300 was observed and the reaction was terminated after 3 h yielding (<5)-30 > 99% ee and the ester (R)-31 was recovered with 86% ee determined by capillary GC after 50 % conversion. 

Grant and Krische have described a racemic protocol for the synthesis of allcarbon C3 quaternary centers from 3-hydroxy-3-tert-prenyloxindole 76 that was accessed via ruthenium catalyzed addition of 1,1-dimethylallene 75 to isatin 74 [45]. As outlined in Scheme 21, 76 was converted to the electrophilic 3-chloro derivative, which was trapped with indole under basic conditions to afford 78 in 60% yield. A mechanism has been proposed for the C-C bond-forming event that involved first-order irmizatirHi of chloride irm assisted by delocaUzatiOTi of oxindole... 

After screening a range of metal complexes based on iridium, aluminum, rhodium, or ruthenium toward their suitability to racemize (S)-l-phenylethanol, Williams and Harris et al. [12] demonstrated a proofof concept for the combination of such a metal-catalyzed racemization of 1-phenylethanol with an in situ enzymatic acylation of preferentially one enantiomer, although some Hmitations appeared such as limited conversion and the need for a range of additives. A representative example for this type of DKR is shown in Scheme 19.4 with the successful synthesis of the ester (R)-IO with enantioselectivity of 98% ee at 60% conversion. 

For a long time, metal-catalyzed racemization in such chemoenzymatic DKRs has been preferentially carried out with ruthenium and palladium and related heavy metal catalysts. An interesting alternative for this process was reported by the Berkessel group [24], who developed an efficient DKR based on an aluminum catalyst for racemization. Compared to heavy metals, aluminum represents an economically attractive and readily available metal, and thus an interesting metal component for a racemization catalyst (Scheme 19.8). The aluminum complexes that turned out to be most successful in these studies were prepared starting from... 

Historically, this term was applied for the first time by Noyori [2], in the case of a ruthenium-catalyzed hydrogenation of a-substituted-P-keto esters. According to Noyori and his coworkers, even when the racemization constant k ac is the same as the rate constant of the fast reacting enantiomer, good enantioselectivities and quantitative conversions can be obtained [3]. An efficient DKR process can also be obtained when krac is higher than the rate constant of the reduction of the slow reacting enantiomer (krac > fesiow)-... 

Dynamic Kinetic Resolution (DKR) under Hydrogenation Conditions Ruthenium-catalyzed asymmetric hydrogenation of racemic a-substituted ketones via-dynamic kinetic resolution (DKR) is one of the elegant and powerful methods for the synthesis of chiral alcohols that simultaneously control two adjacent stereogenic centers with high levels of selectivity in a single chemical operation. This method was first reported... 

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