Ruthenium catalysts dynamic kinetic resolution

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. 

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-... 

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]. 

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). 

J. H. Koh, and J. Park, Dynamic kinetic resolution of allylic alcohols mediated by ruthenium- and lipase-based catalysts,... 

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... 

Rhodium and ruthenium complexes of CHIRAPHOS are also useful for the asymmetric hydrogenation of p-keto esters. Dynamic kinetic resolution of racemic 2-acylamino-3-oxobutyrates was performed by hydrogenation using ((5,5)-CHIRAPHOS)RuBr2 (eq 3). The product yields and enantiomeric excesses were dependent upon solvent, ligand, and the ratio of substrate to catalyst. Under optimum conditions a 97 3 mixture of syn and anti p-hydroxy esters was formed, which was converted to o-threonine (85% ee) and D-allothreonine (99% ee) by hydrolysis and reaction with propylene oxide. 

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. 

Interestingly, dynamic kinetic resolution was observed for substrates with appropriate skeletal or functional perturbation. Such substrates are 3-oxo esters with amido-. carbamato- or ami-domethyl substituents at C-2 (Table 8). In the hydrogenation of these substrates with ruthenium-BIN AP catalysts, extremely high synianti ratios prevailed, with the major products of the L-threonine series being nearly optically pure60. 

Such dynamic kinetic resolutions can also be conducted on cyclic jS-keto esters. Two examples are shown in Equations 15.59 and 15.60. Such cyclic substrates contain a stereocenter at the carbon between the two carbonyl groups. Again, a dynamic kinetic resolution of these substrates by hydrogenation occurs selectively to form predominantly a single stereoisomer. This reaction occurs to form a 99 1 ratio of diaste-reomers and 93% enantioselectivity of the major diastereomer in the presence of a ruthenium-BINAP catalyst. The positions of the keto and ester functionalities can also be reversed. Reduction of the cyclic p-keto ester in Equation 15.60 generates, in this case, the cis diastereomer with high diastereoselectivity and enantioselectivity. ... 

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. 

Today, dynamic kinetic resolution of secondary alcohols by combination of enzymes with transition metal catalysts, originally developed by Williams and Backvall, are perhaps the best developed methods (33-36). Hitherto the most successful catalyst designs have been based on half-sandwich ruthenium complexes, of which the pentaphenylcyclopentadienyl ruthenium complex has been claimed as the currently best racemization catalyst. Racemization is then based on reversible conversion of the alcohol into the corresponding ketone (Fig. 21, A). The dynamic kinetic resolution of 1-phenylethanol with isopropenyl acetate in toluene in the presence of Novozym 435, performed in preparative scale, is a good example of the use of ruthenium complexes (35). Another thoroughly studied racemization method (Fig. 21, B) is based on the use of acidic resins or zeolites. Here the racemization takes place through prochiral sp car-benium ion by simultaneous elimination and addition of water (37). The use of... 

Kejrwords Dynamic kinetic asymmetric transformation (DYKAT) Dynamic kinetic resolution (DKR) Hydrogenation Imine reduction Ketone reduction Mechanism of carbonyl reduction Mechanism of imine reduction Mechanism of dUiydrogen activation Ruthenium catalysis Shvo s catalyst Transfer hydrogenation... 

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. ... 

Maviynsky D, Paivio M, LundeU K, Sillanpaa R, Kanerva LT, Leino R. Dicarbonylchloro(pentabenzylcyclopentadienyl) ruthenium as racemization catalyst in the dynamic kinetic resolution of secondary alcohols. Eur. J. Org. Chem. 2009 1317-1320. 

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