Racemization processes

Jere et al. also reported on the stereoretentive C-H bond activation in aqueous phase catalytic hydrogenation of alanine (19). They demonstrated that hydrogenation of the carboxylic functionality is a stereo retentive process. Racemization occurs through a distinct process. 

Figure 7.11 Acylase process with racemization (May, 2002). Conventional process racemization at pH 3, 80-100 °C novel process racemization with enzyme (NAAR), pH 7-8, 25 10 °C.

L-6-Hydroxynorleucine, a different key chiral intermediate used for synthesis of the vasopeptidase inhibitor Omapatrilat (Vanlev ), was prepared in 89% yield and > 99% optical purity by reductive amination of 2-keto-6-hydroxyhexanoic acid using glutamate dehydrogenase from beefliver (Hanson, 1999) (Figure 13.22). In an alternative process, racemic 6-hydroxynorleucine produced by hydrolysis of 5-(4-hydroxybutyl)hydantoin was treated with D-amino acid oxidase to prepare a mixture containing 2-keto-6-hydroxyhexanoic acid and L-6-hydroxynorleucine followed by the reductive amination procedure to convert the mixture entirely to L-6-hydroxynorleucine, with yields of 91-97% and optical purities of > 99%. 

The starting material for the acylase process is a racemic mixture of N-acetyl-amino acids 20 which are chemically synthesized by acetylation of D, L-amino acids with acetyl chloride or acetic anhydride in alkaU via the Schotten-Baumann reaction. The kinetic resolution of N-acetyl-D, L-amino acids is achieved by a specific L-acylase from Aspergillus oryzae, which only hydrolyzes the L-enantiomer and produces a mixture of the corresponding L-amino acid, acetate, and N-acetyl-D-amino acid. After separation of the L-amino acid by a crystallization step, the remaining N-acetyl-D-amino acid is recycled by thermal racemization under drastic conditions (Scheme 13.18) [47]. In a similar process racemic amino acid amides are resolved with an L-spedfic amidase and the remaining enantiomer is racemized separately. Although the final yields of the L-form are beyond 50% of the starting material in these multistep processes, the effidency of the whole transformation is much lower than a DKR process with in situ racemization. On the other hand, the structural requirements for the free carboxylate do not allow the identification of derivatives racemizable in situ therefore, the racemization requires... 

During the same period, eontinuous process improvements on the resolution route to S -naproxen have achieved dramatic cost reductions. The breakthrough comes from in-process racemization and recycle of the R-naproxen byproduct and the recovery of the resolving agent (Figure 2). In this novel and efficient resolution process, the racemic naproxen is reacted with half an equiva-... 

The dynamic kinetic resolution (DKR) of secondary alcohols and amines (Scheme 11.11) is a prominent, industrially relevant, example of chemo-enzymatic chemistry in which a racemic mixture is converted into one enantiomer in essentially 100% yield and in high ee. This is in sharp contrast to enzyme-catalyzed kinetic resolutions that afford the desired end-product in a yield of at most 50%, while 50% of the starting material remains unreacted. In DKR processes, hydrolases are typically employed as the enantioselective acylation catalyst (which can be either R or S selective) while a concurrent racemization process racemizes the remaining substrate via an optically inactive intermediate. This ensures that all starting material is converted into the desired end-product. The importance of optically pure secondary alcohols and amines for the pharmaceutical industry triggered the development of a number of approaches that enable the racemization of sec-alcohols and amines via their corresponding ketones and imines, respectively [42],... 

When a quaternary carbon atom is produced in the acylation process, racemization is not possible and the stereochemical outcome can be affected by the presence of an adjacent stereocenter. Treatment of the chiral lactone (168) with LDA and acetyl cyanide gave the diastereomeric products (169) and (170) in the ratio 60 1 (equation 44). ... 

As part of an ongoing program focused on chirality in supramolecular systems [8, 39], it was noted that stereochemical aspects of H-bonding information may also be used to direct self-assembly processes. Racemic 12 produces a pleated ribbon comprised of doubly H-bonded components of alternating chirality, motif A. In contrast, optically pure 12 is predicted to form the cyclic hexamer B, provided the available H-bonding capacity is fully used... 

Scheme 5.11 Coordination polyhedra of the eight enantiomers of Ln [DTPA-bis(amide)] complexes, assuming that the geometry is a tricapped trigonal prism. Interconversions between the two columns (mirror image) correspond to the wagging process (racemization at N3), while the interconversions between rows in a column result in racem-ization at N1 and N3. Adapted with permission from H. hammers et al, Inorg. Chem. 36, 2527 (1997) [180]. Copyright (1997) American Chemical Society.

In another alternate enzymatic process, racemic amino add 82 was first treated with (R)-amino acid oxidase for 4 h to convert 82 to a mixture of (S)-amino add 82a and keto add 83. Subsequently, an amino add dehydrogenase NADP and glucose dehydrogenase were added to the same reaction mixture to convert 83 to (S)-amino acid 82a, providing this product in 54% isolated yield and 99% ee. 

There are also chemical processes that allow a small imbalance in enantiomers to be amplified. The best known is the Soai asymmetric amplification, where the chiral product of a process catalyzes the formation of material with higher enantiomer excess in the next cycle, and this has achieved 85 % enantiomer excesses from material initially enriched by only 0.1 %. In another process, racemic glyceraldehyde (2,3-dihydroxypropanal, vide infra) and 2-aminooxazole (7.48) react in the presence of 1 % enriched proline to give almost enantiopure RNA precursors such as 7.49. ... 

Under these conditions, the a position can be deprotonated, giving a dianion (resonance-stabilized). This dianion can be protonated by water (at the a position), thereby regenerating the carboxylate ion. In the process, racemization occurs at the a position because the a position is sp hybridized (trigonal planar) in the dianion intermediate. Protonation of the dianion can occur on either face of the plane (with equal likelihood), giving a racemic mixture. 

The mechanisms by which sulfonate esters undergo nucleophilic substitution are the same as those of alkyl halides Inversion of configuration is observed m 8 2 reac tions of alkyl sulfonates and predominant inversion accompanied by racemization m 8 1 processes... 

A novel technique for dating archaeological samples called ammo acid racemiza tion (AAR) IS based on the stereochemistry of ammo acids Over time the configuration at the a carbon atom of a protein s ammo acids is lost m a reaction that follows first order kinetics When the a carbon is the only chirality center this process corresponds to racemization For an ammo acid with two chirality centers changing the configuration of the a carbon from L to D gives a diastereomer In the case of isoleucme for example the diastereomer is an ammo acid not normally present m proteins called alloisoleucme... 

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). 

The racemic acid is not a primary product of plant processes but is formed readily from the dextrorotatory acid by heating alone or with strong alkaU or strong acid. The methods by which such racemic compounds can be separated into the optically active modifications were devised by Pasteur and were apphed first to the racemic acid. Racemic acid crystallizes as the dihydrate triclinic prisms. It becomes anhydrous on drying at 110°C... 

R, R -Tartaric acid also can be produced by racemization of (R-R, R -tartaric acid in the presence of y j O-tartaric acid (85). In this process, formation of y j O-tartaric acid during racemization does not occur. 

Enzymatic hydrolysis is also used for the preparation of L-amino acids. Racemic D- and L-amino acids and their acyl-derivatives obtained chemically can be resolved enzymatically to yield their natural L-forms. Aminoacylases such as that from Pispergillus OTj e specifically hydrolyze L-enantiomers of acyl-DL-amino acids. The resulting L-amino acid can be separated readily from the unchanged acyl-D form which is racemized and subjected to further hydrolysis. Several L-amino acids, eg, methionine [63-68-3], phenylalanine [63-91-2], tryptophan [73-22-3], and valine [72-18-4] have been manufactured by this process in Japan and production costs have been reduced by 40% through the appHcation of immobilized cell technology (75). Cyclohexane chloride, which is a by-product in nylon manufacture, is chemically converted to DL-amino-S-caprolactam [105-60-2] (23) which is resolved and/or racemized to (24)... 

This procedure is restricted mainly to aminodicarboxyhc acids or diaminocarboxyhc acids. In the case of neutral amino acids, the amino group or carboxyl group must be protected, eg, by A/-acylation, esterification, or amidation. This protection of the racemic amino acid and deprotection of the separated enantiomers add stages to the overall process. Furthermore, this procedure requires a stoichiometric quantity of the resolving agent, which is then difficult to recover efficiendy. Practical examples of resolution by this method have been pubUshed (50,51). 

Enzymatic Method. L-Amino acids can be produced by the enzymatic hydrolysis of chemically synthesized DL-amino acids or derivatives such as esters, hydantoins, carbamates, amides, and acylates (24). The enzyme which hydrolyzes the L-isomer specifically has been found in microbial sources. The resulting L-amino acid is isolated through routine chemical or physical processes. The D-isomer which remains unchanged is racemized chemically or enzymatically and the process is recycled. Conversely, enzymes which act specifically on D-isomers have been found. Thus various D-amino acids have been... 

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). 

Optical resolution is another method of producing (—)-mentho1 from racemic materials. (A)-Menthol is treated with optically active resolving agents to separate the (—)-mentho1 from the (+)-menthol, which is further processed by racemization over a nickel catalyst and recycled (156). 

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