P-keto ester reduction

Figure 1. Presumed transition state for reduction of p-keto ester 21. Only one C-21 epimer is shown for clarity.

Baker s yeast has been widely used for the reduction of ketones. The substrate specificity and enantioselectivity of the carbonyl reductase from baker s yeast, which is known to catalyze the reduction of P-keto ester to L-hydroxyester (L2-enzyme) [15], was investigated, and the enzyme was found to reduce chloro-, acetoxy ketones with high enantioselectivity (Figure 8.32) [24aj. 

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]. 

Figure 8.38 Possible products for the reduction of a-methyl p-keto ester.

In the case of mono-ester substituted pyrroles (e.g., 68) wherein relatively unstable dianions likely to deprotonate ammonia might be produced, the authors instead utilized an excess of (MeOCH2CH2)2NH as a substitute for ammonia. It was felt that upon in situ formation of (MeOCH2CH2)2NLi, this base would be unable to protonate the dianion <00TL1331>. Remarkably, quenching the reduction reactions with benzoyl chloride affords P-keto esters (e.g., 69, R = COPh), a reaction that does not occur when conducted in liquid ammonia. 

Diastereoselective reduction of p-keto esters.1 Reduction of p-keto esters (3) of the chiral a-naphthylborneol (2)2 is stereoselective because one face of the carbonyl group is blocked by the naphthyl group. Chelation of the keto ester with... 

Despite the lack of diastereoselectivity and the moderate yields, the present procedure complements other syntheses of 1,3-diols such as hydride reductions of p-diketones,9 p-hydroxy ketones10 and p-keto esters,11 or the opening of 2,3-epoxy alcohols12 and 3,4-epoxy alcohols13 with Lipshutz cuprates. 

Treatment of the /3-keto ester 220 with sodium ethoxide at elevated temperature triggered off an epoxide ring opening by / -elimination that was followed by the desired Knoevenagel condensation to afford the tricyclic product 206 (Scheme 34). The enone moiety in the intermediate 221 did not show a propensity for deprotonation and, therefore, the ketone carbonyl function of the enone moiety was available for a Knoevenagel condensation. The reduction of the p-keto ester (206) to the corresponding diol was the next objective. Treatment of the TES-protected -keto ester (TES-206) with DIBAH afforded the diastereomeric diols 222 and 223 in a moderate diastereoselec-tivity in favour of the undesired diastereomer 222. The diastereomers were separated and the undesired diastereomer 222 was epimerized to 223 by a sequence that consists of Mitsunobu inversion and benzoate ester reduction [98, 99]. 

Figure 4.11. Examples of redox-initiated radical reactions. Samarium diiodide reduction of the bromide gives a radical that cyclizes faster than the second reduction reaction. Manganese triacetate oxidation of the P-keto ester gives an enol radical that is not further oxidized by the manganese reagent. The IBX oxidizes anilides to the corresponding radicals. Hexamethylphosphoramide = HMPA and Tetrahydrofuran = THE.

Expecting that the introduction of 1,2-dimethyl substituents to ( )-cycIoalkenes should increase non-bonding interaction across the ring, Marshall and coworkers 29) prepared (—)-( )-l,2-dimethylcyclodecene (27a) and showed that this compound is optically quite stable. In their synthetic approach to 27a, they started from the p-keto ester 24 which was converted into (+)-25 through a sequence of reactions involving condensation with 3-buten-2-one, LiAlH reduction, and resolution via the camphor-... 

The enzyme recLBADH is the first catalyst that has been found to allow the highly regio- and enantioselective synthesis of 5-hydroxy-P-keto esters by reduction of the respective diketo esters. This enzymatic reaction is of enormous preparative value. The substrates are readily available by acylation of P-keto ester bisenolates and the reaction only requires a simple batch technique which is easy to scale up. Reduction of the chlorinated compound la has been performed routinely on a 75 g scale in our laboratory (8 L fed batch), yielding (S)-2a in an isolated yield of 84% [10]. 

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]. 

Enolization is an acid-base reaction (2-24) in which a proton is transferred from the a carbon to the Grignard reagent. The carbonyl compound is converted to its enolate ion form, which, on hydrolysis, gives the original ketone or aldehyde. Enolization is important not only for hindered ketones but also for those that have a relatively high percentage of enol form, e.g., p-keto esters, etc. In reduction, the carbonyl compound is reduced to an alcohol (6-25)... 

Patel RN, McNamee CG et al (1992) Stereoselective reduction of P-keto esters by Geotrichum candidum. Enzyme Microb Technol 14 731-738... 

Glucose-grown cells of G. candidum SC 5469 have also catalyzed the stereoselective reduction of ethyl-, isopropyl-, and tertiary-butyl esters of 4-chloro-3-oxobutanoic acid and methyl and ethyl esters of 4-bromo-3-oxobutanoic acid. A reaction yield of >85% and e.e. of >94% were obtained. NAD+-depen-dent oxido-reductase responsible for the stereoselective reduction of P-keto esters of 4-chloro- and 4-bromo-3-oxobutanoic acid was purified 100-fold. The molecular weight of purified enzyme is 950,000. The purified oxido-reductase was immobilized on Eupergit C and used to catalyze the reduction of (39) to S-( - )-(40). The cofactor NAD+ required for the reduction reaction was regenerated by glucose dehydrogenase. 

Although a wide range of [3-hydroxy acids is available by reduction of the corresponding P-keto ester or acid (vide supra), and a number of schemes have been proposed to commercially important compounds, such as captopril, this methodology and class of compounds still have to wait for a new opportunity to show their versatility.49-50... 

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... 

Asymmetric hydrogenation of proprietary P-keto esters with [RuCl2(BINAP)]n in 98-99% ee had been performed by NSC Technologies (Scheme 12.13). Substrate-to-catalyst loadings of 10,000-20,000 have been achieved. These reductions have been performed at small-scale production to ton scale.23 Phoenix Chemicals, whose specialty is in continuous processes, has developed methodology and equipment that can perform this type of transformation up to -100 tons/year for a proprietary P-hydro ester with enantioselectivities of 98-99% ee (see Chapter 31).6768... 

Rhodium and palladium catalysts that contain 4 display high enantioselectivities for the asymmetric hydrogenation of enamides, itaconates, P-keto esters, asymmetric hydroboration, and asymmetric allylic alkylation,80 82 but this ligand system distinguishes itself from other chiral bisphos-phines in the asymmetric reduction of tetrahydropyrazines and tetrasubstituted olefins (see also Chapter 15). The reduction of tetrahydropyrazines produces the piperazine-2-carboxylate core,... 

The transformations that use asymmetric heterogeneous catalysis will be highlighted P-keto esters and diketone reductions by Raney nickel catalyst modified with R,R-tartaric acid and NaBr. a-Keto acid reductions with cinchona modified Pt catalysts are discussed in Chapter 18. 

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