Racemic mixture resolution


Clearly, there is a need for techniques which provide access to enantiomerically pure compounds. There are a number of methods by which this goal can be achieved . One can start from naturally occurring enantiomerically pure compounds (the chiral pool). Alternatively, racemic mixtures can be separated via kinetic resolutions or via conversion into diastereomers which can be separated by crystallisation. Finally, enantiomerically pure compounds can be obtained through asymmetric synthesis. One possibility is the use of chiral auxiliaries derived from the chiral pool. The most elegant metliod, however, is enantioselective catalysis. In this method only a catalytic quantity of enantiomerically pure material suffices to convert achiral starting materials into, ideally, enantiomerically pure products. This approach has found application in a large number of organic  [c.77]

The separation of a racemic mixture into its enantiomeric components is termed resolution The first resolution that of tartaric acid was carried out by Louis Pasteur m 1848 Tartaric acid IS a byproduct of wine making and is almost always found as its dextrorotatory 2R 3R stereoisomer shown here m a perspective drawing and m a Fischer projection  [c.310]

One approach called enzymatic resolution, involves treating a racemic mixture with an enzyme that catalyzes the reaction of only one of the enantiomers Some of the most commonly used ones are lipases and esterases enzymes that catalyze the hydrol ysis of esters In a typical procedure one enantiomer of the acetate ester of a racemic alcohol undergoes hydrolysis and the other is left unchanged when hydrolyzed m the presence of an esterase from hog liver  [c.312]

Section 7 14 Resolution is the separation of a racemic mixture into its enantiomers It IS normally carried out by converting the mixture of enantiomers to a mixture of diastereomers separating the diastereomers then regenerating the enantiomers  [c.317]

Resolution (Section 7 14) Separation of a racemic mixture into Its enantiomers  [c.1292]

Microorganisms and their enzymes have been used to functionalize nonactivated carbon atoms, to introduce centers of chirahty into optically inactive substrates, and to carry out optical resolutions of racemic mixtures (1,2,37—42). Their utifity results from the abiUty of the microbes to elaborate both constitutive and inducible enzymes that possess broad substrate specificities and also remarkable regio- and stereospecificities.  [c.309]

In many cases only the racemic mixtures of a-amino acids can be obtained through chemical synthesis. Therefore, optical resolution (42) is indispensable to get the optically active L- or D-forms in the production of expensive or uncommon amino acids. The optical resolution of amino acids can be done in two general ways physical or chemical methods which apply the stereospecific properties of amino acids, and biological or enzymatic methods which are based on the characteristic behavior of amino acids in living cells in the presence of enzymes.  [c.278]

Crystallization Method. Such methods as mechanical separation, preferential crystallisation, and substitution crystallisation procedures are included in this category. The preferential crystallisation method is the most popular. The general procedure is to inoculate a saturated solution of the racemic mixture with a seed of the desired enantiomer. Resolutions by this method have been reported for histidine (43), glutamic acid (44), DOPA (45), threonine (46), A/-acetyl phenylalanine (47), and others. In the case of glutamic acid, the method had been used for industrial manufacture (48).  [c.278]

Because the starting materials were optically active, the products were all pure enantiomers. Later, the synthetic scheme shown in Figure 5 was developed (22,45). Resolution of the racemic mixture was accompHshed at the penultimate stage and the optically active D-threo-amine (7) was converted to florfenicol (2). This synthetic process also resulted in the synthesis of thiamphenicol shown in Figure 6 using 1,1,2,3,3,3-hexafluoropropyl diethylamine (FPA) (46). More recently an improved method of synthesis of florfenicol has been developed (17).  [c.517]

The P CD column exhibits excellent selectivity for enantiomers of certain amino acid derivatives. Underivatized amino acids are apparentiy too small to biad tightly to the P CD cavity and show no enantiomeric resolution. When a substituent such as a dansyl group is present on the amino acid, strong iaclusion complexes with P CD are formed and baseline separation is achieved (see Table 2) (10). Either the amino or the carboxylate group of the amino acid can be derivatized to obtain chiral recognition. Derivatization of both groups, however, tends to reduce chiral recognition. It is possible to detect as Httie as 0.2% of one enantiomer ia a racemic mixture as shown ia Figure 2b, thus providing an extremely sensitive test of optical purity (5).  [c.98]

The lipase from Pseudomonas sp. KIO has also been used to cleave the chloroacetate, resulting in resolution of a racemic mixture since only one enantiomer was cleaved.  [c.93]

The separation of a racemic mixture into its enantiomeric components is termed resolution. The first resolution, that of tartaric acid, was carried out by Louis Pasteur in 1848. Tartaric acid is a byproduct of wine making and is almost always found as its dextrorotatory 2R, iR stereoisomer, shown here in a perspective drawing and in a Fischer projection.  [c.310]

One approach, called enzymatic resolution, involves treating a racemic mixture with an enzyme that catalyzes the reaction of only one of the enantiomers. Some of the most commonly used ones are lipases and esterases, enzymes that catalyze the hydrolysis of esters. In a typical procedure, one enantiomer of the acetate ester of a racemic alcohol undergoes hydrolysis and the other is left unchanged when hydrolyzed in the presence of an esterase from hog liver.  [c.312]

Resolution (Section 7.14) Separation of a racemic mixture into its enantiomers.  [c.1292]

The lipase from Pseudomonas sp. KIO has also been used to cleave the chloroacetate, resulting in the resolution of a racemic mixture, since only one enantiomer was cleaved.  [c.162]

Four general methods have been used for obtaining chiral ligands resolution of a racemic mixture, use of a chiral naturally occurring product 33), and asymmetric homogeneous or heterogeneous hydrogenation.  [c.14]

A better solution for preparative columns is the development of separation media with substantially increased selectivities. This approach allows the use of shorter columns with smaller number of theoretical plates. Ultimately, it may even lead to a batch process in which one enantiomer is adsorbed selectively by the sorbent while the other remains in the solution and can be removed by filtration (single plate separation). Higher selectivities also allow overloading of the column. Therefore, much larger quantities of racemic mixtures can be separated in a single run, thus increasing the throughput of the separation unit. Operation under these overload conditions would not be possible on low selectivity columns without total loss of resolution.  [c.61]

The continuing trend to replace racemic drugs, agrochemicals, flavors, fragrances, food additives, pheromones, and some other products with their single enantiomers is driven by their increased efficiency, economic incentive to avoid the waste of the inactive enantiomer, and regulatory action resulting from the awareness that individual enantiomers have different interactions with biological systems. There are several methods to obtain enantiomerically pure compounds. The most important are (i) syntheses based on chiral starting materials from natural sources such as amino acids (ii) enantioselective reactions and (iii) separations of mixtures of enantiomers using methods such as crystallization via diastereoisomers, enzymatic or chemical kinetic resolution, and chromatographic separation [1-3].  [c.55]

Unless a resolution step is included the a ammo acids prepared by the synthetic methods just described are racemic Optically active ammo acids when desired may be obtained by resolving a racemic mixture or by enantioselective synthesis A synthesis IS described as enantioselective if it produces one enantiomer of a chiral compound m an amount greater than its mirror image Recall from Section 7 9 that optically inactive reactants cannot give optically active products Enantioselective syntheses of ammo acids therefore require an enantiomerically enriched chiral reagent or catalyst at some point m the process If the chiral reagent or catalyst is a single enantiomer and if the reaction sequence is completely enantioselective an optically pure ammo acid is obtained Chemists have succeeded m preparing a ammo acids by techniques that are more than 95% enantioselective Although this is an impressive feat we must not lose sight of the fact that the enzyme catalyzed reactions that produce ammo acids m living systems do so with 100% enantioselectivity  [c.1122]

A particular point of interest included in these hehcal complexes concerns the chirality. The heUcates obtained from the achiral strands are a racemic mixture of left- and right-handed double heUces (Fig. 34) (202). This special mode of recognition where homochiral supramolecular entities, as a consequence of homochiral self-recognition, result from racemic components is known as optical self-resolution (203). It appears in certain cases from racemic solutions or melts (spontaneous resolution) and is often quoted as one of the possible sources of optical resolution in the biological world. On the other hand, the more commonly found process of heterochiral self-recognition gives rise to a racemic supramolecular assembly of enantio pairs (204).  [c.194]

Resolution Methods. Chiral pharmaceuticals of high enantiomeric purity may be produced by resolution methodologies, asymmetric synthesis, or the use of commercially available optically pure starting materials (44,45). Resolution refers to the separation of a racemic mixture. Classical resolutions involve the constmction of a diastereomer by reaction of the racemic substrate with an enantiomerically pure compound. The two diastereomers formed possess different physical properties and may be separated by crystallization (qv), chromatography (qv), or distillation (qv). A disadvantage of the use of resolutions is that the best yield obtainable is 50%, which is rarely approached. However, the yield may be improved by repeated racemization of the undesired enantiomer and subsequent resolution of the racemate. Resolutions are commonly used in industrial preparations of homochiral compounds (16). Chiral acids and amines are generally separable by crystallization of the diastereomeric salts formed with an appropriate optically pure amine or acid, respectively (46). Racemic mixtures of mandelic acid (27) are resolved by treatment with optically pure (R)-(+)-methy1henzy1amine (28) and formation of the diastereomeric salts (29) and (30). (R)-(—)-MandeHc acid selectively crystallizes with (R)-(+)-methy1henzylamine (28) and is isolated by simple filtration.  [c.241]

Optically active thiiranes have been obtained by resolution of racemic mixtures by chiral tri-o-thymotide. The dextrorotatory thymotide prefers the (5,5)-enantiomer of 2,3-dimethylthiirane which forms a 2 1 host guest complex. A 30% enantiomeric excess of (5,5)-(—)-2,3-dimethylthiirane is obtained (80JA1157).  [c.182]

Because diastereoisomers have different physical and chemical properties, they can be separated by a range of chemical and physical methods. The process of resolution is the sqjaration of a racemic mixture. Separation is frequently effected by converting the enantiomers into a mixture of diastereomers by reaction with a pure enantiomer of a second reagent, the resolving agentP Because the two resulting products will be diastereomeric, they can be separated. The separated diastereomers can then be reconverted to the pure enantiomers by reversing the initial chemical transformation. An example of this method is shown in Scheme 2.4 for the resolution of a racemic carboxylic acid by way of a diastereomeric salt resulting from reaction with an enantiomerically pure amine. The / -acid, / -amine and S-acid, / -amine salts are separated by fractional recrystallization. The resolved acids are regenerated by reaction with a strong acid, which liberates the carboxylic acid from the amine salt.  [c.88]

Synthetic chiral adsorbents are usually prepared by tethering a chiral molecule to a silica surface. The attachment to the silica is through alkylsiloxy bonds. A study which demonstrates the technique reports the resolution of a number of aromatic compoimds on a 1- to 8-g scale. The adsorbent is a silica that has been derivatized with a chiral reagent. Specifically, hydroxyl groups on the silica surface are covalently boimd to a derivative of f -phenylglycine. A medium-pressure chromatography apparatus is used. The racemic mixture is passed through the column, and, when resolution is successful, the separated enantiomers are isolated as completely resolved fiactions. Scheme 2.5 shows some other examples of chiral stationary phases.  [c.89]

Section 7.14 Resolution is the separation of a racemic mixture into its enantiomers. It is nor-rnally canied out by converting the mixture of enantiomers to a mixture of diastereomers, separating the diastereomers, then regenerating the enantiomers.  [c.317]

Unless a resolution step is included, the a-anino acids prepared by the synthetic methods just described are racemic. Optically active amino acids, when desired, may be obtained by resolving a racemic mixture or by enantioselective synthesis. A synthesis is described as enantioselective if it produces one enantiomer of a chiral compound in an amount greater than its minor image. Recall from Section 7.9 that optically inactive reactants cannot give optically active products. Enantioselective syntheses of amino acids therefore require an enantiomerically enriched chiral reagent or catalyst at some point in the process. If the chiral reagent or catalyst is a single enantiomer and if the reaction sequence is completely enantioselective, an optically pure amino acid is obtained. Chemists have succeeded in preparing a-anino acids by techniques that are more than 95% enantioselective. Although this is an impressive feat, we must not lose sight of the fact that the enzyme catalyzed reactions that produce amino acids in living systems do so with 100% enantioselectivity.  [c.1122]

The nature of enantioselective solid membranes can be very diverse. Chiral synthetic and semisynthetic polymers have been applied directly for this purpose, but other chiral molecules have also proved to be useful after immobilization on a nonchiral porous membrane. Polysaccharide derivatives, especially cellulose carbamates [156-159], acrylic polymers, poly (a-amino acids) [160-162] and poly acetylene-derived polymers are some of the polymeric selectors that have been successful in the resolution of racemic mixtures by this method. The high loadability of these compounds, already demonstrated in HPLC and other classical applications, makes them very attractive in continuous processes. Moreover, the filmogenic properties of some of them, such as the polysaccharide derivatives, are interesting characteristics when the formation of a membrane is envisaged. More recently, the introduction of molecular imprinted polymers (MIPs) to membrane technologies has been described as a promising alternative [163-166]. Among the chiral molecules immobilized on a nonchiral rigid support membrane to perform an enantioselective separation are amino acids and proteins, such as BSA [167-169]. The main limitation in the case of solid membranes is the silting that occurs when all recognition sites have been occupied and there is no real transport through the membrane. An ingenious system has been described [159] to take advantage of this phenomenon for the separation of enantiomers.  [c.14]

Most of the chiral membrane-assisted applications can be considered as a modality of liquid-liquid extraction, and will be discussed in the next section. However, it is worth mentioning here a device developed by Keurentjes et al., in which two miscible chiral liquids with opposing enantiomers of the chiral selector flow counter-currently through a column, separated by a nonmiscible liquid membrane [179]. In this case the selector molecules are located out of the liquid membrane and both enantiomers are needed. The system allows recovery of the two enantiomers of the racemic mixture to be separated. Thus, using dihexyltartrate and poly(lactic acid), the authors described the resolution of different drugs, such as norephedrine, salbu-tamol, terbutaline, ibuprofen or propranolol.  [c.15]

The 9 — 15 fragment was prepared by a similar route. Once again Sharpless kinetic resolution method was applied, but in the opposite sense, i.e., at 29% conversion a mixture of the racemic olefin educt with the virtually pure epoxide stereoisomer was obtained. On acid-catalysed epoxide opening and lactonization the stereocentre C-12 was inverted, and the pure dihydroxy lactone was isolated. This was methylated, protected as the acetonide, reduced to the lactol, protected by Wittig olefination and silylation, and finally ozonolysed to give the desired aldehyde.  [c.322]

The primary disadvantage of the conjugate addition approach is the necessity of performing two chiral operations (resolution or asymmetric synthesis) ia order to obtain exclusively the stereochemicaHy desired end product. However, the advent of enzymatic resolutions and stereoselective reduciag agents has resulted ia new methods to efficiently produce chiral enones and CO-chain synthons, respectively (see Enzymes, industrial Enzymes in ORGANIC synthesis). Eor example, treatment of the racemic hydroxy enone (70) with commercially available porciae pancreatic Hpase (PPL) ia vinyl acetate gave a separable mixture of (5)-hydroxyenone (71) and (R)-acetate (72) with enantiomeric excess (ee) of 90% or better (204).  [c.162]

However, it was not until the beginning of 1994 that a rapid (<1.5 h) total resolution of two pairs of racemic amino acid derivatives with a CPC device was published [124]. The chiral selector was A-dodecanoyl-L-proline-3,5-dimethylanilide (1) and the system of solvents used was constituted by a mixture of heptane/ethyl acetate/methanol/water (3 1 3 1). Although the amounts of sample resolved were small (2 ml of a 10 inM solution of the amino acid derivatives), this separation demonstrated the feasibility and the potential of the technique for chiral separations. Thus, a number of publications appeared subsequently. Firstly, the same chiral selector was utilized for the resolution of 1 g of ( )-A-(3,5-dinitrobenzoyl)leucine with a modified system of solvents, where the substitution of water by an acidified solution  [c.10]

Since the proline residue in peptides facilitates the cyclization, 3 sublibraries each containing 324 compounds were prepared with proline in each randomized position. Resolutions of 1.05 and 2.06 were observed for the CE separation of racemic DNP-glutamic acid using peptides with proline located on the first and second random position, while the peptide mixture with proline preceding the (i-alamine residue did not exhibit any enantioselectivity. Since the c(Arg-Lys-0-Pro-0-(i-Ala) library afforded the best separation, the next deconvolution was aimed at defining the best amino acid at position 3. A rigorous deconvolution process would have required the preparation of 18 libraries with each amino acid residue at this position.  [c.64]

Our strategy consisted of the following steps A mixture of potential chiral selectors is immobilized on a solid support and packed to afford a complete-library column , which is tested in the resolution of targeted racemic compounds. If some separation is achieved, the column should be deconvoluted to identify the selector possessing the highest selectivity. The deconvolution consisted in the stepwise preparation of a series of sublibrary columns of lower diversity, each of which constitute a CSP with a reduced number of library members.  [c.85]

Several synthetic strategies are possible and demand that different types of information be provided. In cases where the starting material, whether a racemate or enantiomer, already contains the required chiral center, full characterization of that substance is required, including stereochemical purity and validation of chiral analytical procedures. Where a racemate or other intended enantiomeric mixture is required, evidence should be provided that these are the result unless obvious from the synthetic route employed. Where the preferred enantiomer is obtained by isolation, the resolution step is considered part of the overall manufacturing process and the usual details of the procedure should be given together with the number of cycles used. If a nonequimolar mixture of enantiomers is needed, then the manufacturing process must be validated to ensure consistent composition of the active ingredient.  [c.324]


See pages that mention the term Racemic mixture resolution : [c.286]    [c.140]    [c.58]   
Carey organic chemistry (0) -- [ c.310 , c.311 , c.317 ]

Organic chemistry (0) -- [ c.310 , c.311 , c.317 ]