Ruthenium catalysts resolution

The sense of diastereoselectivity in the dynamic kinetic resolution of 2-substi-tuted / -keto esters depends on the structure of the keto ester. The ruthenium catalyst with atropisomeric diphosphine ligands (binap, MeO-biphep, synphos, etc.) induced syn-products in high diastereomeric and enantiomeric selectivity in the dynamic kinetic resolution of / -keto esters with an a-amido or carbamate moiety (Table 21.21) [119-121, 123, 125-127]. In contrast to the above examples of a-amido-/ -keto esters, the TsOH or HC1 salt of /l-keto esters with an a-amino unit were hydrogenated with excellent cwti-selectivity using ruthenium-atropiso-... 

Antimalarials Mefloquine is a major drug for malaria, in particular, for chloroquine-resistant malaria." However, some cases of neuropsychiatric adverse events and the apparition of resistance tend to limit its use. Metabolism into inactive and phototoxic 1 -7/-2-oxoquinoline is blocked by the presence of the CF3 group." Instead of performing the resolution of enantiomers at the end of the synthesis," the asymmetric reduction of the carbonyl group in the presence of ruthenium catalyst and a chiral diphosphine provided mefloquine with an excellent enantiomeric excess (Figure 8.25). °... 

Racemic resolution of a-hydroxy esters was achieved with Pseudomonas cepacia lipase (PCL) and a ruthenium catalyst (for a list, see Figure 18.13) as well as 4-chlorophenyl acetate as an acyl donor in cyclohexane, with high yields and excellent enantiomeric excesses (Huerta, 2000) (Figure 18.14). Combining dynamic kinetic resolution with an aldol reaction yielded jS-hydroxy ester derivatives in very high enantiomeric excesses (< 99% e.e.) in a one-pot synthesis (Huerta, 2001). 

Enzymatic DKRs have also been applied in domino one-pot processes [97]. The combination of a lipase-catalyzed resolution with an intramolecular Diels-Alder reaction led to interesting building blocks for the synthesis of natural products such as compactin [98,99] or forskolin [100-102], A ruthenium catalyst is employed for the racemization of the slow reacting enantiomer of the starting material. The DKR with lipase B from C. antarctica delivered high enantiomeric excesses which could mainly be contained through the Diels-Alder reaction (Fig. 12). 

Ruthenium catalysts that contain Cl-MeO-BIPHEMP have been used in the asymmetric hydrogenation of P-keto esters (99% ee)126 and the dynamic kinetic resolution of substituted P-keto esters (Scheme 12.33).121 The asymmetric hydrogenation of methyl 3,3-dimethyl-2-oxobutyrate to the corresponding a-hydroxy ester has been reported with ruthenium catalyst, RuBr2[(-)-Cl-MeO-BIPHEMP] 2 (Scheme 12.34).121... 

Kinetic resolution of secondary alcohols is performed by asymmetric oxidation using an optically active (nitroso)(salen)ruthenium(II) chloride 12 (Eq. 3.14) [48]. The ruthenium catalyst 12 is also effective for asymmetric imidation of alkyl aryl sulfide [48c]. 

Another ruthenium catalyst was used for the dynamic kinetic resolution of allylic alcohols [reaction (24)] by acylation yielding allylic acetates. Again a redox process should be responsible for the racemization. 

The rate of carbon formation is far less on noble metals than on nickel and this behaviour appears to be related to the difficulty found by noble metals of dissolving carbon in bulk. ° The carbon formed on the surface of noble metals was found to be almost indistinguishable from the catalyst particles. High-resolution TEM images taken from a ruthenium catalyst employed in the SMR reaction revealed a structure in which a few carbon layers were deposited on the surface of the Ru particles. The mechanism by which whiskers grow on the surface of the nickel particles becomes blocked by sulphur poisoning of the catalyst surface. In this specific case, several octopus carbon filaments or whiskers are formed on a given nickel particle. A similar carbon structure has been reported to develop on Ni-Cu alloy catalysts with low nickel contents (20 wt%).ii... 

An elegant combination of monomers with the components of a dynamic kinetic resolution (DKR) permitted the conversion of a racemic diol into a polymer consisting of enantioenriched units that could be recovered by polymer hydrolysis [28]. Diol 5 and achiral diester 6 were combined with a well-known system of lipase and ruthenium catalyst (see Chapters 4 and 5 for more on this). The esterification of the free hydroxyl groups is very selective (for the R) configuration) but as the polymerization proceeds, the (S) stereocentres are racemized. Upon 92% conversion of the hydroxy groups and hydrolysis of the polymer, an enantioenriched sample of the diol was obtained that contained essentially none of the (S,S)-isomer. 

In 2001, Takahashi et al. [204] described the first Ru-catalyzed asymmetric allylic substitutions. The planar-chiral cydopentadienyl-mthenium complexes led to branched aUylation products with enantiosdectivities of up to 97% ee. Some years later, they showed that such complexes serve as effective catalysts for the kinetic resolution of racemic allyhc carbonates such as 200 in AAAs. The absolute configurations of the recovered carbonates and the alkylation products such as 201 were shown to depend on the substituent on the cyclopentadienyl group at the 4-position of the ruthenium catalyst (Scheme 12.98) [205]. 

Chiral phosphonous acid diester induces the kinetic resolution of racemic a-substituted y-unsaturated carboxylic acids through asymmetric protolac-tonization (Scheme 53) (130L2838). Dinamic kinetic resolution with Candida antartica lipase B and the ruthenium catalyst [RuCl(CO)2(T -C5Ph5)] of several homoallylic alcohols is applied in the key step to the synthesis of enantiomericaUy pure 5,6-dihydro-2ff-pyran-2-ones ( [13CEJ13859]). 

This result is explained by the fact that the noble metals do not dissolve carbon [304] (a more likely explanation is discussed in Section 6.2). The carbon formed on the noble metals was observed to be of a stmcture that was difficult to distinguish from the catalyst structure [304]. On a ruthenium catalyst, high-resolution electron microscopy revealed a structure which looked like a few atomic layers of carbon covering most of the surface. 

In 2007, the same authors reported the deracemisation of secondary ben lic alcohols on the basis of a two-step process with the combination of two different chiral ruthenium catalysts (Scheme 3.12). The initial step of this sequential process was a kinetic resolution of the starting secondary alcohol by the selective oxidation of the S-alcohol to the corresponding ketone catalysed by a first chiral ruthenium complex. This ketone intermediate was then selectively reduced to the I -alcohol by the second chiral ruthenium catalyst. As compared with kinetic resolution, this two chiral ruthenium system provided a convenient and efficient approach for the synthesis of chiral alcohols in high yields and excellent enantioselectivities of up to 92% ee, as shown in Scheme 3.12. 

Asymmetric transfer hydrogenation (ATH) reactions of 2-substituted a-alko gr-p-ketophosphonates (602) driven by dynamic kinetic resolution, afforded the corresponding 2-substituted a-alko gr-p-hydroxyphos-phonates (603) with excellent levels of diastereo- and enantioselectivity (Scheme 175). The reactions have been promoted by using chiral ruthenium catalyst (604) and a 0.2 1 mixture of formic acid and triethylamine as the hydrogen source and solvent. ... 

However, not only CALB but also other lipases have been fruitfully coupled in the deracemization of a wide variety of substrates, such as diols [26] a- [27], p- [28], and 8-hydroxyesters [29] benzoins [30] hydroxynitriles [31] haloalcohols [32] hydroxyalkanephosphonates [33] y-hydroxyamides [34] hydroxyacids and hydroxy-aldehydes protected with bulky groups [35] or cyclic allylic alcohols [36]. From those pioneer examples, many efforts have been attempted in order to design other ruthenium catalysts, which could decrease the reaction time and temperature, and improve the reaction conditions, to extend the applicability of this strategy to the resolution of other substrates. Some of those ruthenium catalysts that have led to relevant results are shown in Figure 14.5. 

Eustache F, Dalko PI, Cossy J. Enantioselective monoreduction of 2-alkyl-1,3-diketones mediated by chiral ruthenium catalysts, dynamic kinetic resolution. Org. Lett. 2002 4 1263-1265. 

Kim and co-workers recently reported an excellent example of dynamic kinetic resolution (DKR) using lipase-ruthenium combo catalyst in an IE solvent system (Fig. 7). Applied to this protocol, the authors succeeded in preparing (R)-ester or (5 )-ester using lipase PS or subtilisin, respectively. An IE solvent system is truly appropriate for DKR because racemizafion takes place easily in a highly polar solvent. 

Kinetic resolution results of ketone and imine derivatives are indicated in Table 21.19. In the kinetic resolution of cyclic ketones or keto esters, ruthenium atrop-isomeric diphosphine catalysts 25 induced high enantiomer-discriminating ability, and high enantiopurity is realized at near 50% conversion [116, 117]. In the case of a bicyclic keto ester, the presence of hydrogen chloride in methanol served to raise the enantiomer-discriminating ability of the Ru-binap catalyst (entry 1) [116]. 

Dynamic kinetic resolution is possible for a-alkyl or a-alkoxy cyclic ketones in the presence of KOH, which causes mutation of the stereogenic center syn-alco-hols were obtained selectively with high enantioselectivity using ruthenium-3,5-xyl-binap. Dynamic kinetic resolution of 2-arylcycloalkanones also proceeded with extremely high syn-selectivity and with high enantioselectivity using ruthenium-binap-diamine as catalyst (Table 21.23) [12, 139, 140]. 

The design of in situ atomic-resolution environmental cell TEM under controlled reaction conditions pioneered by Gai and Boyes (87,89) has been adopted by commercial TEM manufacturers, and latter versions of this in situ instrument have been installed in a number of laboratories. In situ atomic resolution-ETEM data demonstrated by Gai et al. (85-90) have now been reproduced by researchers in laboratories using commercial instruments examples include investigations of promoted ruthenium and copper catalysts in various gas environments (93) and detailed investigations of Ziegler-Natta catalysts (94). 

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. 

Kinetic resolutions, such as the ones discussed above, are limited to a 50% yield. Consequently, the undesired enantiomer needs to be recovered, racemized, and recycled, which makes the process more complex and leads to an increased solvent use. The obvious solution is to racemize the slow-reacting enantiomer in situ. With chiral alcohols, the racemization catalysts of choice are based on ruthenium (Figure 10.17). 

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