Dynamic kinetic resolution, keto

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]. 

An efficient dynamic kinetic resolution is observed when an a-bromo- or a-acetylamino-/3-keto phosphate is subjected to the hydrogenation with an Ru-BINAP catalyst under suitable conditions. With RuC12[(A)-BINAP](DMF) (0.18 mM) as the catalyst, a racemic a-bromo-/3-keto phosphonate is hydrogenated at 25 °G under... 

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 stereoselective hydrogenation of a-substituted / -keto carboxylates and phosphonates via dynamic kinetic resolution catalyzed by a BINAP-Ru com-... 

Fig. 32.27 Hydrogenation of a-substituted /i-keto phospho-nates 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]. 

The synthesis of jS-hydoxy-a-amino acids is important since these compounds are incorporated into the backbone of a wide range of antibiotics and cyclopeptides such as vancomycins. These highly functional compounds are also subject to dynamic kinetic resolution (DKR) processes, as the stereocenter already present in the substrate epimerizes under the reaction conditions and hence total conversions into single enantiomers are possible. These transformations can be iy -selective ° for N-protected derivatives as shown in Figure 1.27 when using a mthenium-BlNAP catalyzed system and anfi-selective when the jS-keto-a-amino acid hydrochloride salts are reduced by the iridium-MeOBlPHEP catalyst as shown in Figure 1.28. One drawback is that both these reductions use 100 atm hydrogen pressure. 

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-... 

The stereoselective hydrogenation of a-monosubstituted (3-keto carboxylates and phosphonates through dynamic kinetic resolution has been applied to the synthesis of a wide variety of useful bioactive compounds as well as some chiral diphosphines (Figure 1.16) [lc,20,162b,c,179,243,246,250,252], The stereogenic center determined by the BINAP-Ru... 

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. 

Substituted aliphatic and aromatic a-keto ethers (see Figure 2.7) are also amenable to enantioselective hydrogenation catalyzed by cinchona-modified Pt catalysts [34], However, as opposed to the achiral ketones discussed above, kinetic resolution is observed for these chiral substrates. At conversions of 20-42%, ee values of 91-98% were obtained when starting with a racemic substrate. While the very high initial ee values were impressive, it was also dear that this method with yields of less than 50% and gradually decreasing ee values is of little preparative value. The obvious solution was to attempt dynamic kinetic resolution in the presence of a base. Indeed, with OH -activated Amberlites dynamic kinetic resolution was observed. Both (R,S)-2-methoxy cyclohexanol and (R,S)-2-methoxy-l,2-diphenyl ethanol can be obtained... 

Figure 2.7 (Dynamic) kinetic resolution of a-keto ethers.

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],...

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