Keto esters dynamic kinetic resolution

Dynamic kinetic resolution of racemic ketones proceeds through asymmetric reduction when the substrate does racemize and the product does not under the applied experimental conditions. Dynamic kinetic resolution of a-alkyl P-keto ester has been performed through enzymatic reduction. One isomer, out of the four possible products for the unselective reduction (Figure 8.38), can be selectively synthesized using biocatalyst, and by changing the biocatalyst or conditions, all of the isomers can be selectively synthesized [29]. 

Dynamic kinetic resolution of a-alkyl-P-keto ester was conducted successfully using biocatalysts. For example, baker s yeast gave selectively syn(2R, 3S)-product [29a] and the selectivity was enhanced by using selective inhibitor [29b] or heat treatment of the yeast [29c]. Organic solvent was used for stereochemical control of G. candidum [29d]. Plant cell cultures were used for reduction of 2-methyl-3-oxobu-tanoate and afforded antialcohol with Marchantia [29e,f] and syn-isomer with Glycine max [29f]. 

Scheme 21.9 Dynamic kinetic resolution of /7-keto ester.

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-... 

Fig. 32.26 Hydrogenation of acyclic a-substituted yfi-keto esters via dynamic kinetic resolution.

The enzyme-catalyzed regio- and enantioselective reduction of a- and/or y-alkyl-substituted p,5-diketo ester derivatives would enable the simultaneous introduction of up to four stereogenic centers into the molecule by two consecutive reduction steps through dynamic kinetic resolution with a theoretical maximum yield of 100%. Although the dynamic kinetic resolution of a-substituted P-keto esters by chemical [14] or biocatalytic [15] reduction has proven broad applicability in stereoselective synthesis, the corresponding dynamic kinetic resolution of 2-substituted 1,3-diketones is rarely found in the literature [16]. 

SCHEME 62. Dynamic kinetic resolution of a-substituted /3-keto esters. 

Highly stereoselective hydrogenation of racemic a-substituted P-keto esters via dynamic kinetic resolution [14,17] has been reported. Hydrogenation of a racemic a-amidomethyl substrate with the (-)-DTBM-SEGPHOS/Ru catalyst resulted in the 2S,3R alcohol in 99.4% ee (syn anti=99.3 0.7) (Scheme 22) [36]. The product was a key compound for an industrial synthesis of carbapenem antibi-... 

Dynamic kinetic resolution of a-alkyl- 3-keto ester was conducted successfully using biocatalysts (Figure 28(b)). 290 For the reduction of ethyl... 

Carbapenem antibiotics (29) can be manufactured from intermediates obtained by Ru(BINAP)-catalyzed reduction of a-substituted P-keto esters by a dynamic kinetic resolution (Scheme 12.8). 4-Acetoxy azetidinone (30) is prepared by a regioselective RuCl3-catalyzed acetoxylation reaction of 31 with peracetic acid 46 This process has been successful in the industrial preparation of the azetidinone 30 in a scale of 120 tons per year.47 The current process has changed ligands to 3,5-Xyl-BINAP (3c), and 31 is obtained in 98% ee and >94% de (substrate-to-catalyst ratio, or S/C ratio = 1,000).23... 

Dynamic kinetic resolution can occur for a-substituted P-keto esters with epimerizable substituents provided that racemization of the antipodes 32 and 33 is rapid with respect to the Ru(BINAP)-catalyzed reduction, thereby potentially allowing the formation of a single diastereo-isomer (Scheme 12.9). Deuterium labeling experiments have confirmed the rapid equilibrium of... 

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. 

Transfer hydrogenation of aryl ketones in the presence of 159B has been reported. Catalysts catering to reduction of chloromethyl aryl ketones and a-amino ketones are 180 and 18l/ respectively, besides their other uses. An analogue of 180 assists reduction of cyclic (3-keto esters to cis-(3-hydroxy esters by HCOOH-Et3N via dynamic kinetic resolution. 

Scheme 7.8. Asymmetric reduction of chiral P-keto esters may be used in an asymmetric transformation of the first kind (dynamic kinetic resolution) [78],...

Scheme 7.70 NHC-catalyzed dynamic kinetic resolution with p-keto esters reported by Scheidt and Cheong.

This type of dynamic kinetic resolution has been conducted on a production scale by the Takasago Company. - [Ru(cymene)yj, in combination with Tol-BINAP, generates a catalyst for the hydrogenation of a p-keto ester containing an amidomethyl group on the central carbon (Equation 15.58). The product of this reaction is used for the synthesis of carbapanen antibiotics. This hydrogenation has been reported to be conducted on the scale of 50-120 tons per year. 

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. ... 

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