Amino acids chiral purity

It was not the aim of this chapter to describe all chromatographic separations of racemic amino acids accomplished so far, but rather demonstrate applicability of these methods to separation of DL-amino acids. Chiral separations, using TLC, enables rapid and inexpensive testing both of optical enantiomers, their derivatives, peptides, and control of enantiomeric purity. 

William Knowles at the Monsanto Company discovered some years ago that u-amino acids can be prepared enantioselectively by hydrogenation of a Z enam-ido acid with a chiral hydrogenation catalyst. (S)-Phenylalanine, for instance, is prepared in 98.7% purity contaminated by only 1.3% of the (H) enantiomer when a chiral rhodium catalyst is used. For this discovery, Knowles shared the 2001 Nobel Prize in chemistry. 

Pawlowska, M. and Armstrong, D. W. (1994). Evaluation of enantiomeric purity of selected amino acids in honey. Chirality 6, 270-276. 

Ekgorg-Ott, K.H., Armstrong, D.W. (1996). Chirality evaluation of the concentration and enantiomeric purity of selected free amino acids in fermented malt beverages (beers). Chirality 8, 49-57. 

Possible racemisation of imines, derivatives of amino acids and R(—)-myrtenal, has been examined by Dufrasne et al.1 After 72 h, no significant effect on chiral purity was observed. For imines being derivatives of chiral primary amines and the a-substituted 8-keto-aldehydes, no evidence of epimerisation has been indicated by the NMR measurements.3 For a series of imines, being derivatives of amino acids or amino acid esters and (R)-BINOL reagents, Chin et al.5 have tested the possibility of epimerization under experiment conditions. It was shown that R S ratio has changed only slightly, and after 24 h, the difference was lower than 10%. 

The preparation of optically active analogues of the natural amino acids has proven reasonable using the reaction of tris(trimethylsilyl) phosphite with chiral aldimines prepared from optically active amines.225 The asymmetric induction has been observed to be as high as 80%, a significant competitive process compared to the multistep approaches available.226227 An alternative one-step approach involving asymmetric induction upon addition to an aldimine derived from a chiral N-substituted urea provided a product with less desirable optical purity.228... 

Naturally occurring chiral compounds provide an enormous range and diversity of possible starting materials. To be useful in asymmetric synthesis, they should be readily available in high enantiomeric purity. For many applications, the availability of both enantiomers is desirable. Many chiral molecules can be synthesized from natural carbohydrates or amino acids. The syntheses of (+)-exo-brevicomin (66) and negamycin (67) illustrate the application of such naturally occurring materials. 

See Section IV.1 for alternative methods of chiral resolution. Partial chemical hydrolysis of proteins and peptides with hot 6 M HC1, followed by enzymatic hydrolysis with pronase, leucine aminopeptidase and peptidyl D-amino acid hydrolase, avoids racemiza-tion of the amino acids281. The problems arising from optical rotation measurements of chiral purity were reviewed. Important considerations are the nonideal dependence of optical rotation on concentration and the effect of chiral impurities282. 

The chiral purity of amino acids at large enantiomeric excess can be determined automatically by derivatization with 4-fluoro-7-nitro-2,l,3-benzoxadiazole (127b) followed by CE with cyclodextrin chiral selectors and detection of the LIF excitation at 488 nm. Lod 140 ppm of L-phenylalanine in D-phenylalanine324. 

A major advantage that nonenzymic chiral catalysts might have over enzymes, then, is their potential ability to accept substrates of different structures by contrast, an enzyme will select only its substrate from a mixture. Striking examples are the chiral phosphine-rhodium catalysts, which catalyze die hydrogenation of double bonds to produce chiral amino acids (10-12), and the titanium isopropoxide-tartrate complex of Sharpless (11,13,14), which catalyzes the epoxidation of numerous allylic alcohols. Since the enantiomeric purities of the products from these reactions are exceedingly high (>90%), we might conclude... 

Hsu s group in Taiwan have developed a procedure for the synthesis of (Y)-2-amino-4-phenylbutanoic acid, the phenylalanine homologue with one additional methylene group. Hydantoinase and L-A-carbamoylase genes have been cloned from different Bacillus species and overexpressed in E. coli. Both the R- and the 5-enantiomers were cleaved by the hydantoinase, but only the 5-form of the A-carbamoyl amino acid was hydrolyzed by the second enzyme. The reactions could be run in a single pot, with successive addition of the two enzymes, and were successful in the sense of giving a product of high chiral purity. However, the yield was... 

Despite its efficiency in numerous cases optical resolution is by no means a trivial operation. In each case the optimum method has to be found by laborious trial and error procedures the optical purity of the material has to be secured and its absolute configuration has to be established before the compound can be used in a synthetic sequence. These drawbacks of optical resolution led chemists to start their syntheses from optically active natural products (the so-called chiral carbon pool ). A variety of suitable ex-chiral-pool compounds including carbohydrates, amino acids, hydroxy acids, and terpenoids are shown. 

In order to generally categorize the reaction schemes mentioned previously and the following ones in the course of indirect enantioseparation techniques, it has to be emphasized again, that the reciprocity principle should always be applicable. This means that if a chiral acid as the CDA can be used successfully to resolve the enantiomers of a chiral amine, then this optically pure amine as the CDA will equally well separate the enantiomers of the acid by the indirect method. The OPA reaction (see Figure 4) is therefore equally well suited for analyzing the optical purity of thiols, amines or amino acids. 

An example is the intramolecular stereoselective alkylation of (carbonylamino)acetonitrile derived from 1-arylethanamines as chiral inductors. Thus, base-catalyzed cyclization of [alkyl-(chloroacetyl)amino]acetonitriles led to /1-lactams which have been transformed into (R)- or (S)-aspartic acid. Optical purity ranged from 21 to 67%65. 

Due to these limitations Evans et al. focussed on the exploration of imide-derived enolates (165). They expected these systems to react stereoselective in carbon-carbon bond formation and that the derived imides might be readily hydrolized or reduced under the mild conditions required for the construction of complex products, One of the two chiral 2-oxazolidones (175) chosen for study by Evans et al.179) is derived from (S)-valine and was readily prepared from this inexpensive commercially available a-amino acid having an optical purity exceeding 99 %. The preparation of the related imide-derived enolate (165) is shown in the next scheme. Alkylation reactions employing (175) resulted in excellent diastereoface selection, as summarized in Table 4 179). 

A group at the Academy of Sciences in Moscow 197) has synthesized chiral threonine. Derivatives of cyclic imino acids form copper complexes with glacine and carbonyl compounds. Hydroxyethylation with acetaldehyde and decomposition of the resulting complexes produced threonine with an optical purity of up to 97-100% and with threo/allo ratios of up to 19 1 197). The chiral reagents could be recovered and re-used without loss of stereoselectivity. The mechanism of this asymmetric synthesis of amino acids via glacine Schiff base/metal complexes was also discussed 197). 

The [2,3]-sigmatropic rearrangement of (E)-(218a), a derivative of the chiral cyclic a-amino acid (S)-proline, produced the aminonitrile (219) in a stereoselective manner. Saponification of (219) yielded (+)-2-methyl-2-phenyl-3-butenal (220) with an enantiomeric excess of 90%219>. In replacing the benzyloxymethyl moiety in (218a) by a methyl group, the optical purity of the chiral aldehyde (220) obtained in the corresponding reaction sequence decreases considerably 219). 

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