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Rozdzielenie mieszanin racemicznych za pomocą krystalizacji. Część 2, Rozdzielenie racematów z utworzeniem diastereoizomerycznych soli

Kołodziejska R., Studzińska R., Kopkowska E., Karczmarska-Wódzka A., Augustyńska B.

Wiadomości Chemiczne

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2015

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[Z] 69, 1-2

89--110

EN

The enantioseparation of a racemate through diastereomeric salt formation with a resolving agent is one of the most attractive methods for obtaining an enantiopure compound, with advantages such as its simplicity in operation, recyclability of the chiral source, and applicability on an industrial scale. In this method the enantiomers are converted into a diastereomeric salt pair by reaction with a single enantiomer of resolving agent. The diastereomers are then separated by crystallization taking advantage of the different solubility of the two compounds [1–3]. The formation of diastereomers, to be separated afterward, usually consists of salt formation with a resolving agent of opposite acide-base character (Scheme 1, 9). In this process, the molecules of opposite character (amine and acid) recognize each other by various interactions on the basis of their molecular structures and functional groups [3]. Using this method can be obtained a series of enantiomerically pure amines (Scheme 2–8) [4–26] and acids (Scheme 10–17) [27–41] which may be valuable substrates for asymmetric synthesis. The conditions for enantioseparation play an important role. On the efficiency of the enantioseparation has an effect the resolving agent, nature of the solvent or just its dielectric constant and the character and amount of some supplementary additives.

2

Rozdzielenie mieszanin racemicznych za pomocą krystalizacji. Część 1, Optymalizacja warunków rozdziału

Kołodziejska R., Kopkowska E., Studzińska R., Karczmarska-Wódzka A., Augustyńska B.

Wiadomości Chemiczne

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2015

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[Z] 69, 1-2

65--88

EN

Methods for obtaining optically active compounds in enantiopure form are commonly classified into three categories: utilization of chiral pool starting materials (stereoselective multistep synthesis), creation of chirality from achiral precursors (asymmetric synthesis) and separation of racemates into their enantiomer constituents (crystallization, chromatography on chiral phases, kinetic resolution). The most important method for the separation of enantiomers is the crystallization. The crystallization can be carried out in the variants: direct crystallization of enantiomer mixtures (homo- and heterochiral aggregates – Scheme 2, 3) and separation of diastereoisomer mixtures (classical resolution) (Scheme 1) [1–5]. The most widely used method for the separation of enantiomers rests on the crystallization of diastereoisomers formed from a racemate and an enantiopure reagent – resolving agent (resolution via salt-formation and complex-formation). The pair of diastereoisomers exhibit different physicochemical properties (e.g., solubility, melting point, boiling point, adsorbtion, phase distribution). For this reason, the crystalline material can be separated from the residue by filtration (Scheme 22) [4, 27], distillation (Scheme 23, 24) [28, 29], sublimation (Scheme 25) [4, 30], or extraction (Scheme 26) [2, 31]. The composition of crystalline diastereoisomers is influenced by resolving agent (structure (Scheme 4) [4] and amount of resolving agent (Scheme 5) [4]), structure of racemates (Scheme 10) [2, 15], the character and amount of supplementary additives (Scheme 6–9) [4, 12–15], nature of the solvent (crystallization with solvent) – Scheme 11–18 [2, 4, 16–23] and time of crystaillzation (Scheme 19–21) [4, 14, 25, 26].

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Enancjoselektywna enzymatyczna desymetryzacja katalizowana oksydoreduktazami. Reakcje utleniania. Część 2

Karczmarska-Wódzka A., Kołodziejska R., Tafelska-Kaczmarek A., Studzińska R., Wróblewski M., Augustyńska B.

Wiadomości Chemiczne

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2015

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[Z] 69, 1-2

53--64

EN

In continuation of our work, we herein describe next enzyme classes applied for oxidation reaction. Dioxygenases, oxidases, and peroxidases are successfully used in the synthesis of desymmetrization products with high yields and enantiomeric excesses. Aromatic dioxygenases, such as toluene dioxygenase (TDO), naphthalene dioxygenase (NDO), and biphenyl dioxygenase (BPDO) found in the prokaryotic microorganisms are enzymes belonging to the dioxygenase class and are the most commonly used in organic synthesis. The α-oxidation of various fatty acids in the presence of an α-oxidase from germinating peas is one of the few examples of oxidases application in asymmetric organic synthesis. The intermediary α-hydroxyperoxyacids can undergo two competing reactions: decarboxylation of the corresponding aldehydes or reduction to the (R)-2-hydroxy acids. In order to eliminate the competitive decarboxylation reaction tin(II) chloride is used as an in situ reducing agent. Peroxidases are the redox enzymes found in various sources such as animals, plants, and microorganisms. Due to the fact that, in contrast to monooxygenases, no additional cofactors are required, peroxidases are highly attractive for the preparative biotransformation. Oxidation reactions catalyzed by (halo)peroxydases are also often used in organic synthesis. N-Oxidation of amines, for instance, leads to the formation of the corresponding aliphatic N-oxides, aromatic nitro-, or nitrosocompounds. From a preparative synthesis standpoint, however, sulfoxidation of thioether is important since it was proven to proceed in a highly stereo- and enantioselective manner. Furthermore, depending on the source of haloperoxidase, chiral sulfoxides of opposite configurations can be obtained.

4

Enancjoselektywna enzymatyczna desymetryzacja katalizowana oksydoreduktazami. Reakcje utleniania. Część 1

Karczmarska-Wódzka A., Kołodziejska R., Tafelska-Kaczmarek A., Studzińska R., Wróblewski M., Augustyńska B.

Wiadomości Chemiczne

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2015

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[Z] 69, 1-2

35--51

EN

The main advantage of biotransformation involving enzymes, compared to chemical processes, is a highly selective formation of products with precise configuration. Herein we describe enzymes participating in the oxidation processes, especially dehydrogenases and monooxygenases. Dehydrogenases are not only able to catalyze the enantioselective reduction of prochiral ketones, but they can also desymmetrize meso and prochiral diols through the enantioselective oxidation. As a result of this processes, optically active hydroxyketones, hydroxycarboxylic acids, and their derivatives are obtained. Cytochrome P450 monooxygenases (CYPs) constitute a family of heme-containing enzymes which exhibits a variety of catalytic activities. They catalyze different reactions, such as hydroxylation, epoxidation, oxidative deamination, or N- and (S)-oxidation. In the oxidation reaction with monooxygenases, the whole cells are commonly used as catalysts. The use of monooxygenases in the oxidation reaction of prochiral alkanes provides the optically active alcohols. It is very significant that these transformations are still difficult to carry out by chemical methods. Baeyer-Villiger monooxygenases (BVMO EC 1.14.13.X) effectively catalyze the nucleophilic and electrophilic oxidation reactions of various functional groups. BVMO are highly regio- and stereoselective enzymes, and their catalytic potential is used in the synthesis of optically pure lactones and esters. Keywords:

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Enancjoselektywna enzymatyczna desymetryzacja katalizowana oksydoreduktazami. Dehydrogenazy w reakcji redukcji. Część I

Kołodziejska R., Karczmarska-Wódzka A., Tafelska-Kaczmarek A., Studzińska R., Wróblewski M., Augustyńska B.

Wiadomości Chemiczne

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2014

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[Z] 68, 9-10

763--782

EN

Enzymes act as biocatalysts whether are also mediating in all anabolic and catabolic pathways, playing an extremely important role in the cells of all life forms. Catalytic potential of oxidoreductases is most commonly used in reduction reactions. Dehydrogenases and reductases catalyze the reversible desymmetrization reactions of meso and prochiral carbonyl compounds and alkenes. The oxidoreductase- catalyzed reactions require cofactors to initiate catalysis. In most cases, it is nicotinamide adenine dinucleotide (NADH) or its phosphorylated derivative (NADPH), which acts as a hydride donor. The necessity of employing expensive cofactors was, for the long time, one of the main limitations to the use of dehydrogenases. This problem was solved by developing a regeneration system of a cofactor in the reaction environment. Various systems are used for the cofactor recycling. In the case of a carbonyl compound reduction, an irreversible oxidation of formic acid to carbon dioxide is most frequently used. In this paper, selected examples of whole-cell and isolated enzymes applications in the carbonyl compound reduction are discussed. The application of baker’s yeast, microorganisms and dehydrogenases in enantioselective enzymatic desymmetrization (EED) of prochiral ketones leads to a broad spectrum of chiral alcohols used as intermediates in the syntheses of many pharmaceuticals and compounds presenting a potential biological activity.

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Enancjoselektywna enzymatyczna desymetryzacja katalizowana oksydoreduktazami. Reakcje redukcji. Część 2

Kołodziejska R., Karczmarska-Wódzka A., Tafelska-Kaczmarek A., Studzińska R., Wróblewski M., Augustyńska B.

Wiadomości Chemiczne

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2014

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[Z] 68, 11-12

1009--1030

EN

Biotransformation reactions of many organic compounds under the influence of enzymes take place with the high selectivity, rarely achieved by other methods. Ketoesters represent an extensive group of selectively bioreduced compounds. Chiral hydroxyesters and, subsequently, hydroxyacids are valuable intermediates in the syntheses of various biologically active compounds. Acyclic α- and β-ketoesters are transformed to the corresponding (R)- and (S)-hydroxyesters by using a specific dehydrogenases. The whole-cells enzymes, e.g. baker’s yeast, may exhibit a different catalytic activity depending on the substrate structure. Baker’s yeast enzymes selectively reduce the cyclic β-ketoesters providing mainly anti diastereomers due to the lack of rotation around the single α,β carbon-carbon bond. The enzymatic reduction of the esters, cyclopentanone, and cyclohexanone derivatives gave the optically active anti-alcohol enantiomers. The reductive EED of prochiral α-ketoesters, as well as β-ketoesters is an interesting transformation in organic chemistry due to the importance of the resulting chiral α-hydroxy acids and their derivatives used as building blocks. Baker’s yeast-catalyzed reduction of alkyl esters derived from pyruvate and benzoylformate allows the preparation of the (R)-alcohols. Polyketones can also be subjected to the reductive EED to give different compounds bearing the quaternary stereogenic centers which are broadly applied in asymmetric synthesis. In asymmetric synthesis, similarly to carbon-oxygen double bonds, carbon-carbon double bonds of prochiral alkanes can be reduced to obtain the optically active saturated compounds. The reduction of alkenes is catalyzed by both, the whole cells (microorganisms, plant cells) as well as isolated enzymes belonging to the oxydoreductases, so-called ene-reductases. The whole-cell catalysts are suitable, most frequently, for the preparative scale syntheses, but they are less chemoselective in comparison to the isolated reductases. In the case of polyfunctionalized alkenes, microorganisms can cause the additional side reaction reducing the desired product yield.