Glycine racemization

Mirror Symmetry Breaking via Autocatalytic Crystallization of the System Glycine/Racemic a-Amino Acids... 

DL-Alanine is the first amino acid which was synthesi2ed chemically (138). Glycine and DL-methionine have also been suppHed by this method (20). However, amino acids formed by the chemical method are racemic, and it is necessary to resolve the mixture to get the L- or D-form amino acid which is usually demanded. 

If, however, the /7-nitrophenyl ester of iV-henzoyl-L-leucine is treated with 1-methyl-piperidine in chloroform for 30 min and then coupled with glycine ethyl ester, the dipeptide isolated is almost completely racemic. Furthermore, treatment of the p-nitrophenyl ester of iV-benzoyl-L-leucine with 1-methylpiperidine alone leads to the formation of a crystalline material, C13H15NO2, having strong IR bands at 1832 and 1664 cm . Explain these observations, and suggest a reasonable stmcture for the crystalline product. 

The importance of chemical syntheses of a-amino acids on industrial scale is limited by the fact that the standard procedure always yields the racemic mixture (except for the achiral glycine H2N-CH2-COOH and the corresponding amino acid from symmetrical ketones R-CO-R). A subsequent separation of the enantiomers then is a major cost factor. Various methods for the asymmetric synthesis of a-amino acids on laboratory scale have been developed, and among these are asymmetric Strecker syntheses as well. ... 

These two selectors terminated with a glycine were then prepared on a larger scale, their carboxyl groups reacted with 3-aminopropyltriethoxysilane, and the conjugate immobilized onto silica. Each CSP was packed into columns and used for the separation of racemic (l-naphthyl)leucine ester 17. Separation factors of 6.9 and 8.0 were determined for the columns with DNB-ala-gly and DNB-leu-gly selector respectively. These were somewhat lower than those found for similar CSPs using the parallel synthesis and attached through a different tether [87]. 

Kcurentjes et al. (1996) have also reported the separation of racemic mixtures. Two liquids are made oppositely chiral by the addition of R- or S-enantiomers of a chiral selector, respectively. These liquids are miscible, but are kept separated by a non-miscible liquid contained in a porous membrane. These authors have used different types of hollow-fibre modules and optimization of shell-side flow distribution was carried out. The liquid membrane should be permeable to the enantiomers to be separated but non-permeable to the chiral selector molecules. Separation of racemic mixtures like norephedrine, ephedrine, phenyl glycine, salbutanol, etc. was attempted and both enantiomers of 99.3 to 99.8% purity were realized. 

Kanegafuchi Chemical Industries produce D-p-hydroxyphenyl glycine, which is a key raw material for the semisynthetic penicillins ampicillin and amoxycillin. Here, an enantioselective hydantoinase is applied to convert the hydantoin to the D-p-hydroxyphenyl glycine. The quantitative conversion of the amide hydrolysis is achieved because of the in situ racemization of the unreacted hydantoins. Under the conditions of enzymatic hydrolysis, the starting material readily racemizes. Therefore, this process enables the stereospecific preparation of various amino acids at a conversion of 100% [38]. 

New analyses of material from the interior of the Orgeuil and Ivona meteorites show the presence of P-alanine, glycine and y-amino-n-butyric acid as the main components (0.6-2.0ppm) traces of other amino acids were also detected. The amino acids were present as racemic mixtures, i.e., d/l = 1, so that an extraterrestrial origin can be assumed (Ehrenfreund et al., 2001). 

Certain classes of compounds are too reactive for the present method. Ethyl mandelate produced a racemic, protected phenyl glycine derivative. Benzylic alcohols with two methoxy groups (directly conjugating in the 2 and 4 positions) gave azide of 50% e.e. 

All amino acids except glycine exist in these two different isomeric forms but only the L isomers of the a-amino acids are found in proteins, although many D amino acids do occur naturally, for example in certain bacterial cell walls and polypeptide antibiotics. It is difficult to differentiate between the D and the L isomers by chemical methods and when it is necessary to resolve a racemic mixture, an isomer-specific enzyme provides a convenient way to degrade the unwanted isomer, leaving the other isomer intact. Similarly in a particular sample, one isomer may be determined in the presence of the other using an enzyme with a specificity for the isomer under investigation. The other isomer present will not act as a substrate for the enzyme and no enzymic activity will be demonstrated. The enzyme L-amino acid oxidase (EC 1.4.3.2), for example, is an enzyme that shows activity only with L amino acids and will not react with the D amino acids. 

According to essentially the same protocol, racemic 2-[2 -(hydroxymethyl)-cyclopropyl] glycine (189) and spiropentylglycine (191) were also prepared in 31 and 25% overall yield, respectively (Scheme 56) [9, 21]. 3-Methylthio-3,4-me-thanoproline (192) has been synthesized along an analogous route as well [20b]. 

Fluoroalanines may be considered a-fluoromethylated glycines. Due to the presence of an acidic hydrogen on the a-carbon, racemization and loss of a fluoride anion are very easy, in contrast to the other a-fluoromethylated amino acids. 

Monofluoroalanine is accessible, as a racemate, by means of either classical methods or fluoromethylation of a masked glycinate anion by a monofluorohalo-genomethane (CH2C1F). ... 

The numerous preparations of mono-, di-, tri-, and hexafluoro derivatives of valine, norvaline, leucine, norleucine, and isoleucine, using classical methods of amino acid chemistry (e.g., amination of an a-bromoacid, " azalactone, Strecker reaction, amidocarbonylation of a trifluoromethyl aldehyde, alkylation of a glycinate anion are not considered here. Pure enantiomers are generally obtained by enzymatic resolution of the racemate, chemical resolution, or asymmetric Strecker reaction. ... 

Racemization is not encountered when 4-unsubstituted-5(477)-oxazolones or 4,4-disubstituted-5(477)-oxazolones are used as reagents. Indeed, 4-unsubstituted-5(47/)-oxazolones function as glycine synthons in the synthesis of A-acylglycyl-a-amino acids. For example, aminolysis of 2-(trifluoromethyl)-5(47/)-oxazolone with a-methylphenylalanine affords A-(trifluoroacetyl)glycyl-a-methylphenylalanine. 4,4-Disubstituted-5(4//)-oxazolones, readily available by alkylation of the monosubstituted derivatives, are very useful intermediates in the synthesis of peptides that incorporate ot,ot-disubstituted amino acids. As an example, 4-(aryl-methyl)-2-phenyl-4-(trifluoromethyl)-5(4//)-oxazolones 260 are key intermediates... 

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