Enantiomer regeneration

Diastereomeric relationships provide the basis on which a number of important processes depend. Resolution is the separation of a mixture containing equal quantities of enantiomers (termed a racemate or racemic mixture) into its components. Separation is ordinarily effected by converting the mixture of enantiomers into a mixture of diastereomers by treatment with an optically active reagent (the resolving agent). Since the diastereomers will have different physical and chemical properties, they can be separated by conventional methods and the enantiomers regenerated in a subsequent step. An example of this method is shown in Scheme 2.2 for the resolution of a racemic carboxylic acid by way of diastereomeric salt formation using an optically active amine. The / -acid-/ -amine and S-acid-/ -amine salts are separated by fractional recrystallization, and the resolved carboxylic acid is freed from its amine salt by acidification. 

Of the methods to prepare single enantiomers, resolution by preparation of the diastereomers from the racemic mixture and then separation of the diastereomers followed by regeneration of the single enantiomer might be the most common. If the racemic mixture has either acidic or basic functionality, this can be accomplished by salt formation. For example, in the synthesis of levothyroxine, used to treat hypothyroidism, the chiral center is resolved at an intermediate stage. The intermediate is a racemic mixture and has a carboxylic acid fimctionality. When the racemic mixture is treated with a chiral amine to form the ammonium carboxylate, two diastereomers are formed. These can be separated and then the carboxylic acid of the single enantiomer regenerated by treatment with acid. 

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... 

Alkaline hydrolysis of the adducts 6 and 7, which is fairly mild in the case of the imide adducts, liberates 3-hydroxycarboxylic acids 8 or ent-8 and simultaneously regenerates the chiral auxiliary reagent. Furthermore, both enantiomers of the 3-hydroxycarboxylic acid are available in almost optically pure form depending on which reagent is chosen as the starting material. 

The TSIL used in this study has an ester moiety in its structure, which enables it to react in enzyme-catalyzed transesterification reaction. In the first part of the cycle, one of the enantiomers of the racemic alcohol is preferentially transformed into an ester of the IL-coupled acid. The other, unreacted enantiomer of the alcohol is then extracted, while the newly formed IL ester is treated with an excess of ethanol in the presence of the same enzyme. This process is accompanied by the regeneration of TSIL in the active form. The main advantage of the presented... 

Enantioenriched alcohols and amines are valuable building blocks for the synthesis of bioactive compounds. While some of them are available from nature s chiral pool , the large majority is accessible only by asymmetric synthesis or resolution of a racemic mixture. Similarly to DMAP, 64b is readily acylated by acetic anhydride to form a positively charged planar chiral acylpyridinium species [64b-Ac] (Fig. 43). The latter preferentially reacts with one enantiomer of a racemic alcohol by acyl-transfer thereby regenerating the free catalyst. For this type of reaction, the CsPhs-derivatives 64b/d have been found superior. 

The silylcuprate conjugate addition reaction has been used for the protection of an enone double bond, which can be regenerated with CuBr2 [22a], and for the strategic introduction of the silyl substituent for stereocontrol and regiocontrol purposes. Enantiopure 5-trimethylsilyl-2-cyclohexenone can be prepared by conjugate addition reaction [44] and the appropriate enantiomer has been converted into a number of natural products (Scheme 3.4) [38]. These synthetic strategies exploit... 

When the resulting mixture of benzoylformic acid and (i )-mandelic acid was treated with a cell free extract of Streptomyces faecalis IFO 12964 in the presence of NADH,the keto acid can be effectively reduced to (i )-mandelic acid (Fig. 1). Fortunately the presence of A. bronchisepticus and its metabolite had no influence on the reduction of the keto acid. The regeneration of NADH was nicely achieved by coupling the reaction with reduction by formic acid with the aid of formate dehydrogenase. As a whole, the total conversion of racemic mandelic acid to the i -enantiomer proceeded with very high chemical and optical yields. The method is very simple and can be performed in a one-pot procedure [6]. 

Spent 2,2,6,6-tetramethyl-l-oxopiperidinium can be regenerated directly at a platinum anode in aqueous acetonitrile and aldehyde products do not undergo further oxidation to the carboxylic acid [37]. Either of the two racemic quinolyl-l-oxyls 4 functions better as catalyst for the oxidation of primaiy and secondary al-kanols, but the chiral forms do not achieve selective oxidation of one enantiomer of... 

An elegant four-enzyme cascade process was described by Nakajima et al. [28] for the deracemization of an a-amino acid (Scheme 6.13). It involved amine oxidase-catalyzed, (i )-selective oxidation of the amino acid to afford the ammonium salt of the a-keto acid and the unreacted (S)-enantiomer of the substrate. The keto acid then undergoes reductive amination, catalyzed by leucine dehydrogenase, to afford the (S)-amino acid. NADH cofactor regeneration is achieved with formate/FDH. The overall process affords the (S)-enantiomer in 95% yield and 99% e.e. from racemic starting material, formate and molecular oxygen, and the help of three enzymes in concert. A fourth enzyme, catalase, is added to decompose the hydrogen peroxide formed in the first step which otherwise would have a detrimental effect on the enzymes. 

In water, the third-generation (16) and fourth-generation dendrimers (17) induced chirality toward the (S)-enantiomer (50% ee for 16 and 98% ee for 17). In THF high enantiomeric excess was achieved only with the third-generation dendrimer (99% (S) ee for 16 and 3% (S) ee for 17). Dendrimer 16 was recovered from the heterogeneous reaction mixture by nanofiltration on a Millipore microporous membrane system. After regeneration of the catalytic activity by treatment with... 

Ketones. The lithio derivative of ( +)-(.S )-. Y,.S -dimethyl-S-phenylsulfoxiinine (16), or its enantiomer, may be used both to resolve racemic ketones164 and to determine absolute configurations of ketones. For example, rac-19 on addition of 16 formed the diastereomeric /j-hydroxy-sulfoximines 17 and 18 which were separated. The configuration of 17 was established by an X-ray analysis. The ketones can be regenerated from the /1-hydroxysulfoximines by thermolysis. Thus, heating of 17 and 18 to 80 °C (for 12 h) furnished 19 [a precursor of (+ )-modhephen] and ent-l9165. 

Optically active halides also can be racemized by an SN2 mechanism. A solution of active 2-chlorobutane in 2-propanone containing dissolved lithium chloride becomes racemic. Displacement of the chloride of the halide by chloride ion inverts configuration at the atom undergoing substitution (see Section 8-5). A second substitution regenerates the original enantiomer. Eventually, this back-and-forth process produces equal numbers of the D and l forms the substance then is racemic ... 

It should be recalled that whereas the enantiomers in the mixture (or racemate) (1) have identical physical properties (except for their action on the plane of polarised light), the diastereoisomers (2) and (3) have physical properties (e.g. solubility, boiling points, chromatographic behaviour, etc.) which are frequently significantly different. Resolution of the mixture (or racemate) can then be achieved provided that one of the diastereoisomers may be obtained in a pure state, and that regeneration from it of the pure enantiomorphous form is not accompanied by any degree of racemisation. 

A racemic form is 50 50 mixture of enantiomers. It is optically inactive. A racemic mixture of configurational isomers cannot be separated (resolved) by ordinary chemical means (distillation, crystallization, chromatography) unless the reagent is chiral. One way to separate a pair of enantiomers is to first convert them to diastereomers by reaction with a chiral reagent, then separate the diastereomers and regenerate the (now separate) enantiomers. 

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