Racemic carboxylic acids

Although decarboxylation reaction seems to be a simple one-carbon removing reaction, it is demonstrated that this reaction is a unique and useful reaction in the preparation of optically active carboxylic acids. If the starting material is a racemic carboxylic acid, the optically active compound can be obtained via symmetrization by chemical carboxylation followed by asymmetrization via enzymatic reaction. Accordingly, the whole process can be said as chemicoenzymatic deracemization (Fig. 24). 

The coupling of the selone to racemic carboxylic acids with dicyclohexylcarbodiimide in dichloromethane with 4-dimethylaminopyridine at 0°C for 0.5-1 hour affords the acylated derivatives. Similar results are obtained using the acid chloride and triethyl amine. Figure 13 (upper part) shows the selenium spectrum for the diastereomeric. Y-acyl derivatives of the oxazo-lidine-2-selone with (A,A)-5-methylheptanoic acid. Clearly the shift difference of about (5 = 0.1 is sufficient for integration of the two singlets. The lower part of the figure shows the remarkably different 77Se resonances observed for four species derived from partially deuterated phenylacetic acid. The diastereomeric mixture of the monodeuteriated substance is easily detected (AS = 0.07, 5.0 Hz). 

Acidic or basic racemates, such as carboxylic acids or amines, are most easily applicable to this method because of the following reason a racemic carboxylic acid or amine is readily reacted with an optically active amine or carboxylic acid to afford a pair of diastereomeric salts. 

Miyazawa, T. Kurita, S. Shimaoka, M. Ueji, S. Yamada, T. Resolution of racemic carboxylic acids via the lipase-catalyzed irreversible transesterification of vinyl esters. Chirality 1999, 11 554-560. 

The asymmetric synthesis of enantiomerically pure primary amines has received considerable attention in recent years due to applications of the chiral amines, either as chiral auxiliaries for the synthesis of optically active molecules [33] or as a deri-vatizing agent for the resolution of racemic carboxylic acids [34], Hydroboration -amination is also a convenient synthetic route to epimerically clean amine derivatives in a simple one-stage reaction. Interestingly, rrans-2-phenylcyclopentylamine (cypenamine), which is an antidepressant [35], can be obtained as a pure isomer in good yields by the hydroboration of 1-methylcyclopentene [7,10,36] (Scheme 13). 

The classical method to resolve a racemate is to react the mixture of enantiomers with one enantiomer of some other chiral compound. The products are diastereomers and can be separated by using the usual methods, such as recrystallization or chromatography. Then the separated diastereomers are individually converted back to the enantiomers of the original compound. Figure 7.5 shows how a racemic carboxylic acid can be resolved. 

Imagine the reaction between a chiral, but racemic alcohol and a chiral, but racemic carboxylic acid, to give an ester in an ordinary acid-catalysed esterification (Chapter 12). 

Stereoselective Esterifications of Racemic Carboxylic Acids 85 IPG butyrate —IPG... 

Resolving Reagent for Carboxylic Acids and Other Types of Compounds. A large number of carboxylic acids have been resolved via their diastereomeric salts with (S)- or (7 )-a-methylbenzylamine (1). The ready availability of both enantiomers of (1) guarantees access to both enantiomers of the desired acid. Compounds (2)-(6) are representative examples of acids obtained in high enantiomeric purity. " Alternatively, racemic carboxylic acids have been resolved by covalent derivatization with (1) and separation of the resulting diastereomeric amides by physical means such as chromatography (eq 1) or fractional crystallization (eq 2). ... 

Resolution of Carboxylic Acids. The enantiomers of 1-(1-naphthyl)ethylamine are used to resolve racemic carboxylic acids by selective crystallization of diastereomeric salts. For example, crystallization of racemic 3-bromobutyric acid with (R)-(+)-NEA followed by acidification of the diastereomeric salt afforded (S)-(+)-3-bromobutyric acid (eq 1). In the same manner, resolution with (5)-(-)-NEA yielded (R)-(-)-3-bromobutyric acid after liberation of the amine (eq 1). ... 

Variety of racemic carboxylic acids reversed-phase silica gels coated with copper(ll) complexes of... 

IV. Analytical Separation and Optical Resolution of Racemic Carboxylic Acids and Amino Acids... 

The optical resolution of racemates 22a, 25a, and 27a was carried out by chromatographic separation of their (4/ ,5S)-MPOT-amide derivatives 22b, 25b, and 27b. The absolute stereochemistry of each pure diastereoisomer was confirmed by comparing the physical data of its derivative with those of the authentic compound in each case. Thus, (4i ,5S)-MPOT (5) proved to be a satisfactory chiral reagent useful for analytical separation and optical resolution of racemic carboxylic acids and amino acids (85JCS(P1)2361). 

Lipase-catalyzed esterifications of racemic carboxylic acids in SCFs have been studied by several groups. The target in all of these studies was the preparation of optically pure anti-inflammatory drugs ibuprofen and naproxen. Rantakyla and Aaltonen reported the kinetic resolution of racemic ibuprofen by esterification catalyzed by immobilized lipase from Mucor miehei [Eq. (1)] (8,74,75) ... 

Table 11.1-5. Pig liver esterase-catalyzed enantiomer-differentiating hydrolysis of racemic carboxylic acid esters and lactones in aqueous solution (HLE horse liver esterase).

Table 11.1-13. Lipase-catalyzed enantiomer-differentiating hydrolysis of racemic carboxylic acid esters and lactones in aqueous solution (PPL pig pancreas lipase, PSL Pseudomonas sp lipase, PFL Pseudomonasfluorescens lipase, CCL Candida cylindracea lipase, ANL Aspergillus niger lipase, PCL Pseudomonas cepacia lipase, CAL-A Candida antarctica A lipase, CRL Candida rugosa lipase, CAL Candida antarctica lipase, not specified).

---