Reduction Of Α-keto Esters Research Articles

Microbial Production of Chiral Hydroxy Esters and Their Analogs: Biocatalytic Reduction of Carbonyl Compounds by Actinobacteria, <i>Agromyces</i> and <i>Gordonia</i> Strains

We screened 15 Agromyces strains from the Microbacteriaceae family and 16 Gordonia strains from the Gordoniaceae family to investigate their biocatalytic ability to reduce carbonyl compounds. Two Agromyces strains (A. soli NBRC109063 and A. humatus NBRC109085) and two Gordonia strains (G. hydrophobica NBRC16057 and G. malaquae NBRC108250) grew well in 230 medium. The stereoselective reduction of various carbonyl compounds using these four strains was investigated. We discovered that these strains can reduce aliphatic and aromatic α-keto esters and an aromatic α-keto amide. On the basis of the conversion rate and stereoselectivity of the alcohols produced, G. hydrophobica NBRC16057 is a potential biocatalyst for the stereoselective reduction of α-keto esters and an aromatic α-keto amide to the corresponding chiral alcohols. Our results also suggest that the reduction of ethyl 2-methylacetoacetate by wet G. hydrophobica NBRC16057 cells in the presence of L-glutamate is useful for the production of chiral ethyl 3-hydroxy-2-methylbutanoate.

Synthesis of Complex Glycolates by Enantioconvergent Addition Reactions.

The unique role that stereochemistry plays in molecular recognition events continues to provide a driving force for synthesizing organic compounds in enantioenriched form. The tendency of enantioenriched organic compounds to revert to an entropically favored racemic state in the presence of viable racemization pathways (e.g., the enolization of stereogenic carbonyl derivatives) can sometimes interfere with this objective; however, beginning with Noyori's foundational disclosure of a dynamic kinetic transfer hydrogenation, the ability to channel racemic, configurationally labile starting materials through stereoconvergent reaction pathways has been recognized as a powerful strategy in asymmetric synthesis. Proton transfer, retro-aldol, retro-Michael, reversible redox events, and other processes that can be deleterious to asymmetric synthesis are exploitable in enantioconvergent reactions using chiral small molecules and enzymes as asymmetric catalysts. Enantioselective reduction of configurationally labile carbonyl derivatives bearing a C-H acidic chiral center are particularly common. Because facile racemization is vital to stereocontrol in these transformations, hydrogenations of β-dicarbonyls are commonplace, while less activated substrates have been used less commonly. Our entry into enantioconvergent catalysis evolved from a long-standing interest in the synthesis of complex glycolates and began with the development of a general Noyori-type transfer hydrogenation of α-keto esters. Key innovations in this work include the identification of a new terphenylsulfonamide-Ru(II) complex, which displays unusual preference toward reduction of α-keto esters, and the observation that α-keto esters racemize under mildly basic conditions. This work was extended to the dynamic kinetic hydrogenation of racemic acyl phosphonates. Moreover, the recent recognition that the mechanistic paradigm underlying enantioconvergent hydrogenation chemistry can be extended to diverse carbon-centered nucleophiles has led to advances in the art. Our lab has developed a number of enantioconvergent tertiary alcohol syntheses. In the context of carbon-centered nucleophiles, we have focused on the use of α-keto esters; however, in the latter part of this Account, we will briefly describe our nascent efforts to develop dynamic kinetic additions of carbon-centered nucleophiles to β-oxo acid derivatives. While the enantioconvergent hydrogenation of β-keto acid derivatives is carried out on 100-ton scale annually, non-hydrogenative transformations of these compounds constitute an underexplored subclass of enantioconvergent reactions. With regard to future prospects, a trend toward transformations that afford increasing levels of molecular complexity is apparent. It can be expected that the burgeoning field of asymmetric 1,2-addition chemistry will further drive this chemistry to encompass a wider array of enantioconvergent additions. Additionally, the continued exploration of these chemistries in the context of less conventional electrophiles, as well as identifying novel or overlooked modes of racemization, holds considerable potential.

Preparation of Chiral Hydroxy Esters Using Actinobacteria: Biocatalyst Activity of Marine-Derived <i>Micromonospora</i> and <i>Streptomyces</i> Strains

To research the potential ability of marine-derived actinomycetes to act as biocatalysts, 8 Micromonospora strains and 5 Streptomyces strains were screened. Two recommended media (227 and 1076 media) and 2 modified media (1076-25% and P-1076-25% media) for liquid culture of these marine-derived actinomycetes were tested. As a result, 2 Micromonospora strains (Micromonospora sp. NBRC107096 and 107097) cultured with the 1076-25% medium and 2 Streptomyces strains (Streptomyces tateyamensis NBRC105048 and Streptomyces sp. NBRC105896) cultured with P-1076-25% medium showed a good growth. The stereoselective reduction of α-keto esters using these 4 actinomycetes was tested. As a result, it was found that these strains had a reducing activity toward various α-keto esters. The introduction of L-glutamate or sucrose as an additive remarkably increased the conversion ratios in the reduction of substrates by the Micromonospora strain. Furthermore, in the presence of L-alanine, Streptomyces tateyamensis NBRC105048 reduced ethyl pyruvate, ethyl 2-oxobutanoate, ethyl 2-oxopentanoate, ethyl 2-oxohexanoate, and ethyl 3-methyl-2-oxobutyrate to the corresponding α-hydroxy ester with a high conversion ratio and with excellent enantiomeric excess. Thus, we found that these marine-derived actinomycetes have great potential to be used as biocatalysts for stereoselective reduction of carbonyl compounds.

The Ability of Edible Mushrooms to Act as Biocatalysts: Preparation of Chiral Alcohols Using Basidiomycete Strains

To examine the potential ability of edible mushrooms to act as biocatalysts, 19 basidiomycete strains were screened. Modified media (PG, O, and PGO medium) for liquid cultivation of these basidiomycete strains were designed and tested. Wet cells (>10 g) of 4 basidiomycete strains (Pleurotus salmoneostramineus H7, P. salmoneostramineus H13, Ganoderma lucidum NBRC31863, Flammulina velutipes NBRC31862) were harvested from PGO medium for 7 days. The stereoselective reduction of α-keto esters using the 4 strains was tested. It was found that each of these strains had a reducing activity toward 6 aliphatic α-keto esters. In the presence of L-alanine as an additive, the reduction of ethyl 2-oxobutanoate and ethyl 2-oxopentanoete by P. salmoneostramineus H7 produced the corresponding alcohol with a high conversion ratio and with excellent enantiomeric excess (>99% e.e. (R)). Furthermore, ethyl pyruvate, ethyl 2-oxobutanoate, and ethyl 2-oxopentanoate were predominantly reduced to the corresponding (R)-hydroxy ester (>99% e.e.) by G. lucidum. Thus, we found that these edible mushrooms have great potential to be used as biocatalysts for the stereoselective reduction of carbonyl compounds.

ChemInform Abstract: Diastereoselective Reduction of α-Keto Esters Bearing chiro- Inositol Derivatives as Chiral Auxiliaries.

Abstract The reduction of α-keto esters derived from (1 l )-1,2;5,6-biscyclohexylidene-3- tert -butyldimethysilyl- chiro -inositol with Selectride ® proceeded with high diastereoselectivity to afford the corresponding α-hydroxy esters. Addition of 18-Crown-6 led to dramatic changeover in diastereofacial selectivity.

Enantiocomplementary preparation of ( S)- and ( R)-mandelic acid derivatives via α-hydroxylation of 2-arylacetic acid derivatives and reduction of α-ketoester using microbial whole cells

Forty one microorganisms belonging to different taxonomical groups were used to carry out the enantioselective reduction of methyl benzoylformate to afford the corresponding ( R)-methyl mandelate, with moderate to high ee. In contrast, the monooxygenase enzyme in Helminthosporium sp. CIOC3.3316 catalyzed the hydroxylation of methyl 2-phenylacetate to ( S)-methyl mandelate. This combination of oxidation and reduction biotransformations thus provides a method for preparing the enantiomers of chiral α-hydroxy acid derivatives.

Microbial enantioselective reduction of ethyl-2-oxo-4-phenyl-butanoate

Different microorganisms (MOs) were used to carry out the enantioselective reduction of ethyl-2-oxo-4-phenylbutanoate to ( S)-(+)-2-hydroxy-4-phenylbutanoate or ( R)-(+)-2-hydroxy-4-phenylbutanoate. Commercially available Saccharomyces cerevisiae and Dekera sp. led to over 92% ee of ( S)-(+)-2-hydroxy-4-phenylbutanoate. Kluyveromyces marxianus gave the opposite isomer with 32% ee ( R). All reactions, except those with Hansenula sp., proceeded to greater than 90% conversion. This the first report on the use of Dekera sp., Hansenula sp. and K. marxianus in the reduction of α-ketoesters.

Stereochemical control in microbial reduction. Part 31: Reduction of alkyl 2-oxo-4-arylbutyrates by baker's yeast under selected reaction conditions

Treatment of baker's yeast with phenacyl chloride in an aqueous–organic solvent has been proven to be an effective method of inhibiting the enzymes that afford ( S)-enantiomers of α-hydroxy esters in the reduction of α-keto esters. The procedure is effective for the whole-cell system to produce the ( R)-product with high chemical yield and high enantiomeric excess.

Purification and Characterization ofα-Keto Ester Reductases from Bakers’ Yeast

Three α-keto ester reductases (yeast keto ester reductase, YKER-II, -IV, -V) were purified from bakers’ yeast. YKER-II, -IV, and -V are dimeric, monomeric, and dimeric enzymes, respectively, and molecular masses are estimated to be 58, 31–39, and 83kDa, respectively, based on gel filtration and SDS- polyacrylamide electrophoresis. Kinetic parameters and stereoselectivities in reduction of α-keto esters have been measured. YKER-IV contributes mainly to reduction by bakers’ yeast at low substrate concentrations, and is useful for synthetic purposes.

Reduction by bakers' yeast in benzene

Reduction of α-keto esters by non-immobilized bakers' yeast in an organic solvent is reported. When benzene is employed as the solvent, the reduction tends to afford the corresponding R)-hydroxy ester predominantly.

Diastereoselective reduction of α-keto esters bearing chiro-inositol derivatives as chiral auxiliaries

Abstract The reduction of α-keto esters derived from (1 l )-1,2;5,6-biscyclohexylidene-3- tert -butyldimethysilyl- chiro -inositol with Selectride ® proceeded with high diastereoselectivity to afford the corresponding α-hydroxy esters. Addition of 18-Crown-6 led to dramatic changeover in diastereofacial selectivity.

NAD(P)+‐NADPH Models. 60. Induction of Double Asymmetry in the Reduction of α‐Keto Esters

AbstractUsing a chiral 1,4‐dihydronicotinamide derivative, N‐α‐methylbenzyl‐1‐propyl‐2,4‐dimethyl‐1,4‐dihydronicotinamide (Me2PNPH), we have studied the reduction of various α‐keto esters that have a chiral center in the acid‐moiety. All of the four possible diastereomers of the corresponding α‐hydroxy esters were afforded. A detailed investigation into the diastereomeric composition of the product has revealed that the molecular arrangement and the conformations of the substrate at the transition state of the reduction are controlled by the polarity and/or the polarizability of the substituents. The 2R,3R‐isomer is the most predominant product when 4R,9R‐Me2PNPH is employed as the reductant.

Chromium complexed carbinols as highly effective auxiliaries for use in asymmetric induction : reduction of α-ketoesters

High percentages of asymmetric induction are obtained during reduction of pyruvate and phenylglyoxylate esters of chromium complexed carbinol 1a : 75% with NaBH 4 and 85% to 90% with L-selectride.

Reduction by a Model of NAD(P)H. XIV. Mechanistic Consideration on the Role of Metal Ion

Abstract The driving force for the catalytic activity of metal ions on the reduction of α-keto esters with an NAD(P)H-model compound has been discussed. The scope of the reaction and spectroscopic investigations as well as molecular orbital consideration have revealed that the transition state of the reaction consists of a ternary complex in analogy with a coenzyme–enzye–substrate complex in an enzymic system. It is concluded that, at the transition state, one electron migrates from a model compound to a substrate through a metal ion, which is followed by the transfer of a proton.

Asymmetric reduction of α-ketoesters with Hantzsch esters (dialkoxycarbonyldihydropyridines)

Single and double asymmetric inductions were achieved by the reduction of pyruvates and benzoylformates with 2,6-dimethyl-3,5-dialkoxycarbonyl-1,4-dihydropyridine in the presence of a mono-ionised zinc species; differentiation is made between enantiotopic faces of the substrate carbonyl by diastereotopic hydrogen, and between diastereotopic faces by equivalent and diastereotopic hydrogen.

Electrolyses of some α-keto-carboxylic acids

The Kolbe reaction is largely suppressed when α-oxobutyric and α-oxovaleric acids are electrolysed in methanol with sodium added, by formation of a mixture of three methyl esters: (1) of unsubstituted acid with one carbon atom less than the electrolysed acid, (2) of electrolysed α-keto-acid, (3) of α-hydroxy-acid with the same carbon chain as the electrolysed α-keto-acid. Evidence is provided that α-hydroxy-esters are formed by reduction of α-ketoesters and that the hydrogen comes from the hydroxy-group of methanol. The reduction does not occur when the keto-group is further removed from the ester group or when the methyl group is attached to the carbonyl group of the α-keto-ester.