Enantiomeric amino acid ester

The hydrolysis of enantiomeric amino-acid ester derivatives catalysed by an optically active bifunctional catalyst containing hydroxamic and imidazole groups shows a pH dependency of stereoselectivity with rate differences between enantiomers of up to 2. ... 

The S-isomer is deacylated faster with an enantiomeric reaction rate ratio of 3 to 1. The binding constants were again found to be the same for both enantiomers so the difference in rates is probably due to AG differences in the transition state for the enantiomeric amino acid ester. The results are presented in Fig. 5.10. 

O Donnell imine 23 with various aldehydes, giving P-hydroxy-a-amino acid esters 44 with high enantiomeric excess,1401 as shown in Scheme 15. 

Extractions of aqueous solutions of racemic amino-acid ester salts with solutions of / -6/s(dinaphthyl)-22-crown-6 [284] in chloroform revealed the dependence of the enantiomeric distribution constant on the structure of the amino acid ester (Table 64). In order to limit the concentrations of complex in the aqueous phase, inorganic salts were added. In the case of tyrosine, serine and alanine no extraction of salt was observed obviously these salts form very hydrophilic complexes. The highest degree of chiral recognition was found with [284] and p-hydroxyphenylglycine methyl ester hexafluorophosphate [A(AG°)... 

Most of the work on chiral recognition has been carried out with amino-acid ester salts. The limited number of available data of similar experiments with amino-acid salts point to an increased enantiomeric differentiation (Table 69 Peacock and Cram, 1976). The reason might be the higher -acidity of the carboxyl group (vide ir fra). In solid-liquid chromatography (see Table 68) the difference between amino-acid salts and amino-acid ester salts is not consistent and not always in favour of the amino-acid salts. However, it should be... 

Chiral discrimination between enantiomeric amino-acid />-nitrophenyl ester hydrobromides in addition to enhanced rate of transacylation were reported by Chao and Cram (1976) for chiral 3,3 -Ws(mercaptomethyl)dinaphthyl-20-crown-6 [323]. Compared with a non-cyclic reference compound (5)-[324] the rates for a series of amino-acid esters are enhanced by factors of 102 to 103, except for L-proline. This once more demonstrates that reaction takes place in... 

Acyl azides (see Section 2.13) The acyl-azide method of coupling is unique for two reasons. First, it is the only case in which the immediate precursor of the activated form of the peptide is not the parent acid. The starting material is the peptide ester that is obtained from the amino acid ester by usual chain assembly (Figure 2.25, path A). Second, it is the only method that just about guarantees production of a peptide that is enantiomerically pure, provided scrupulous attention is paid to details of procedure. There is no danger for loss of chirality during conversion of the ester to the hydrazide and then the azide, but care must be taken to avoid contact of... 

Amino acid derivatives can be examined for enantiomeric purity by the same procedures after removal of the protecting groups. Another approach is to couple them directly with another derivative to give protected dipeptides whose diastereomeric forms are usually easy to separate by HPLC (see Section 4.11). An A-protected amino acid is coupled with an amino acid ester, and vice versa. Use of soluble carbodiimide as reagent (see Section 1.16), followed by aqueous washes, gives clean HPLC profiles. It is understood that the derivative that serves as reagent must have been demonstrated to be enantiomerically pure.43 84-89... 

At that time, as now, the enantiomers of many chiral amines were obtained as natural products or by synthesis from naturally occurring amines, a-amino acids and alkaloids, while others were only prepared by introduction of an amino group by appropriate reactions into substances from the chiral pool carbohydrates, hydroxy acids, terpenes and alkaloids. In this connection, a recent review10 outlines the preparation of chiral aziridines from enantiomerically pure starting materials from natural or synthetic sources and the use of these aziridines in stereoselective transformations. Another report11 gives the use of the enantiomers of the a-amino acid esters for the asymmetric synthesis of nitrogen heterocyclic compounds. 

Chiral crown ethers have been employed extensively (48-53, 56-60, 86, 90, 93-95, 107, no, 116, 117, 128, 143, 144, 152-155, 158-161, 163, 164, 212-227) for enantiomeric recognition of racemic primary alkyl ammonium cations including those associated with amino acid ester salts. Resolutions have been effected employing both bulk and chromatographic procedures. 

Chiral titanium complexes with a, a, a, a -tetraaryl-l,3-dioxolane-4,5-dimethanol (TADDOL) ligands are versatile auxiliaries in the Lewis acid catalyzed alcoholysis of racemic 4-(arylmethyl)-2-phenyl-5(477)-oxazolones 234, providing the corresponding enantiomerically enriched N-protected amino acid esters 235 (Scheme 7.73). The enantioselectivity of the reaction is dependent on the solvent, temperature, and chiral ligand. Selected examples of the alcoholysis of saturated 5(477)-oxazolones are shown in Table 7.21 (Fig. 7.23). 

The aldol reaction of p-nitrobenzaldehyde with acetone is catalyzed by Zn2+ complexes of a-amino acid esters in MeOH, giving the optically active aldol adduct (Scheme 8B1.12) [28]. Although the enantiomeric excesses of the product have not been determined, the extent of asymmetric induction is dependent on the structure of a-substituents in the amino acids. The Zn2+ complexes of amino acid esters bearing an aromatic substituent such as esters of phenylalanine, tyrosine, and tryptophane (Trp) are more effective in terms of both catalytic activity and asymmetric induction. The highest asymmetric induction is observed with Trp-OEt ligand. 

One example is the optically active amino acid derivative (S)-20n which contains a bipyridyl substituent (Scheme 3.14). The alkylation reaction in the presence of the cinchona alkaloid catalyst 33 proceeds with 53% ee (83% yield of (S)-20n) and gave the desired enantiomerically pure a-amino acid ester (S)-20n in >99% ee after re-crystallization [43]. Subsequent hydrolysis of the optically pure (S)-20n furnished the desired unprotected a-amino acid 35. A different purification method, subsequent enzymatic resolution, reported by Bowler et al., furnished the a-amino acid product 35 with enantioselectivity of 95% ee [44],... 

This process relies on rapid base-induced racemization of the azlactone and rate-limiting ring opening by the alcohol nucleophile. In this process the DMAP derivative 79a acts as both Bronsted-basic and as nucleophilic catalyst. With 2-propanol as reagent enantiomeric excesses up to 78% were achieved for the product amino acid esters [87]. 

Sawada, M. et al., Determination of enantiomeric excess for amino acid ester salts using FAB mass spectrometry. Chem. Commun. 1569-1570 (1998)... 

Glycosylamines were shown efficient stereodifferentiating templates in the synthesis of enantiomerically pure P-amino acids. They react with silylketene acetals and zinc(II) chloride as the promoting Lewis acid via a Mannich-type pathway to give P-amino acid esters 12 in high yields and high diastereoselectivity [26], (Scheme 9). 

To recognize a chiral ammonium guest, binaphthyl hinge crowns were designed and proved the enantiomeric separation of protonated amino acid ester racemates [21]. A series of chiral azophenol acerands incorporating one or two optically active hydrobenzoin unit, 51-58, has been synthesized to study the title theme, enantiomer selective coloration with chiral amines. 

Further great advancements in the field of asymmetric alkylation reactions have been made by several groups for the chiral phase transfer-catalyzed alkylation of glycinates. This type of reaction offers attractive access to enantiomerically pure, particularly nonproteinogenic a-amino acids. A pioneer in this field is the O Donnell group (O Donnell et al. 1989 for an excellent recent review, see O Donnell 2001) who developed the first a-amino acid ester synthesis by means of this methodology. Notably, this group also reported a first scale up of the synthesis in... 

Indeed, this concept proved successful and after optimization of the catalyst structure and of the reaction conditions, a number of azlactones 6 could be transformed to highly enantiomerically enriched N-acyl amino acid esters 9 of high enantiomeric purity (Berkessel et al. 2005, 2006). Some of the results are summarized in Scheme 5. 

It was mentioned in the beginning that azlactones and oxazinones are activated amino acid derivatives. In the KR discussed here, the remaining oxazinone enantiomer can be reacted further, in the crude reaction mixture, with nucleophiles. For example, treatment with resin-bound and N-terminally nonprotected peptides results in coupling with a P-amino acid. Heating of the homogeneous crude reaction mixture (typically toluene as solvent) with dilute aqueous hydrochloric acid results in hydrolysis of the unreacted oxazinone enantiomer and precipitation of the corresponding N-acyl P-amino acid. The latter can be isolated in excellent enantiomeric purity by simple filtration. The filtrate contains the P-amino acid ester of opposite configuration (Berkessel et al. 2005). 

D/L enantiomeric ratios for alanine, valine, glutamic acid, leucine, proline, and phenylalanine in the remaining half of the desalted amino acid fraction were obtained by gas chromatography (15). Hie N-trifluoroacetyl-L-prolyl-DL-amino acid esters were synthesized, then separated on a Hewlett-Packard Model 5711A Gas Chromatograph with flame ionization detector and a 12 foot colunn of Chromasorb W-AW-DMCS solid support coated with 8% SP 2250. 

Similarly, reversed-phase HPLC can be used as an Eilternative to the racemization test for amino acids as developed by Manning and Moore (115). Rivier and Burgus (109) have suggested the use of L-phenylalanine, coupled via the N-carboxyanhydride method to a hydrolysate, to monitor racemization during synthesis, although other hydrophobic L-amino acids should also prove equally effective. The use of /eri-butyloxycarbonyl-L-amino acid-Af-hydroxysuccinimide esters in the separation of enantiomeric amino acids and diastereoisomeric peptides has been described (110). Ultimately, these methods may not prove as versatile as the use of chiral stationary phases made by stereoselective control of the bonding process or, alternatively, with surface-active reagents similar to the D-... 

Recently, the enantiomeric excess of a-amino acid ester hydrochlorides has been determined directly by using FAB (fast atom bombardment) mass spectrometry without chromatographic separation of the enantiomers. ... 

Enantioselectiveprotonation. French chemists have reported a new method for obtaining optically active a-amino acids A racemic a-amino acid ester is converted into the racemic Schiff base 2. This is deprotonated with LDA to the anion 3, which is then protonated with an optically active acid such as 1. The optically active Schiff base 2 is formed with an enantiomeric ratio as high as 80 20. The enantiomeric ratios are dependent largely on the structure of the diacyltartarlc acid. 

The catalytic hydrogenation of the benzoylformic acid amides of optically active amino acid esters was carried out. When the (5)-amino acid ester was used, the resulting mandelic acid had the (R)-con-figuration. When pyruvic acid amides of optically active benzylic amines were hydrogenated over palladium, optically active lactic acid was obtained in relatively high enantiomeric excess (ee 60%). The... 

A convenient preparation of a new class of 1-L-a-amino acid derivatives of 2-phospholene oxides (405) involves amination of ( ) l-chloro-2-phospho-lene oxides (406) with enantiomerically pure L-a-amino acid esters (407) (Figure 71). ... 

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