Amino acids optical activity

Another method for the preparation of 3-aryl-4//-l,2,4-oxadiazin-6(5.H )-oncs 4 is the reaction of aromatic nitrile oxides with ethyl esters of x-amino acids, which is thought to proceed via the esters of the A-(carboxymethyl)amide oximes discussed above. The nitrile oxides are generated from hydroxiinoyl chlorides7 and react in situ with the esters. If the esters are derived from optically active amino acids, optically active oxadiazinones are obtained.13... 

One of the important conclusions of the early attempts was that it is fruitful to place the functionality near an optically active support. Already in 1958, Isoda and coworkers reported for the first time the enantioselective hydrogenation with a Raney nickel catalyst modified with optically pure amino acids. Optical yields reported at that time were from low (2.5%) to moderate (36%) values (for references see [12]). Subsequently, in 1963, Izumi and coworkers [100] initiated an extended study of the modified Raney nickel system with TA. As a result of their initial researches, this system was the first heterogeneous chiral catalyst to give high enantioselectivities in the hydrogenation of / -ketoesters (95%) [101,102],... 

Asymmetric synthesis of amino aeUs. Optically active amino acids can be prepared by addition of hydrogen cyanide to SchifT bases prepared from aliphatic aldehydes (representing the R group) and optically active benzylic amines (representing the... 

The Kabachnik Fields reaction, which involves the hydrophosphonylation of phos phites with imines generated in situ from carbonyl compounds and amines, is an attractive method for the preparation of a amino phosphonates. Optically active a amino phosphonic acids and their phosphonate esters are an attractive class of compounds due to their potent biological activities as nonproteinogenic analogues of a amino acids. Therefore, considerable attention has been given to their enantio selective synthesis by hydrophosphonylation of preformed imines, using either metal based catalysts or organocatalysis [107]. 

Optical isomerism of phenoxycarboxylic acids also plays a decisive role in their activity. Of the amino acid derivatives of 2,4-dichlorophenoxyacetic acid and 2,4-dichlorophenoxypropionic acid only the derivatives of the dl- and L-amino acids are active, while the respective D-amino acid derivatives are completely inactive. This can be attributed to the fact that plants are unable to hydrolyse the peptide bond of the D-derivatives (Wood and Fontaine, 1952 Krewson et al., 1956). 

Although transformation of optically active a-amino acid into active intermediates without any loss of optical purity is useful for synthesis of optically active nitrogen-containing compounds, intermediary iminium ion which is a typical sp cation, might lose the original chirality to afford racemic product (Scheme 2). 

In the presence of an amino acid-derived boronate (e.g. 2) or a diamine-tin(II), complex,as Lewis acids, optically active aldol products are obtained in good yields (eq 8). In the addition of KSAs to iminies, a diphosphonium ditriflate (eq 9) or an acidic montmorillonite clay has been claimed to give better results than the originally reported Lewis acids (titanium(IV) chloride and trimethylsilyl trifluoromethanesulfonate ). The products of this reaction are valuable intermediates for the synthesis of p-lactams. Two excellent reviews covering this area have recently appeared. ... 

Note that the amino-acids, because of their salt-like nature, usually decompose on heating, and therefore seldom have sharp melting-points. Furthermore, all naturally occurring amino-acids are a-amino-acids, and consequently, with the exception of glycine, can exist in optically active forms. 

All the amino-acids of physiological importance are a-amino-acids, e.g. (in addition to the above compounds), alanine or a-amino-propionk acid, CHaCH(NH,)COOH, and leucine or a-amino-Y-dimethyl-rt-butyric acid, (CH,)aCHCH,CH(NHa)COOH, and naturally occurring samples (except glycine) are therefore optically active. 

Optically active thiazoline-5-ones (203) can be obtained when cycliza-tion of an optically active N-thiobenzoyl amino acid is brought about by the use of dicyclohexyl carbodiimide in pure chloroform, dich-loromethane (455), or tetrahydrofuran (453. 456) (Scheme 104). 

Hydrolysis of the following compound in concentrated hydrochlonc acid for several hours at 100°C gives one of the amino acids in Table 27 1 Which one" Is it optically active" ... 

Synthetic utility of stereoselective alkylations in natural product chemistry is exemplified by the preparation of optically active 2-arylglycine esters (38). Chirally specific a-amino acids with methoxyaryl groups attached to the a-carbon were prepared by reaction of the dimethyl ether of a chiral bis-lactam derivative with methoxy arenes. Using SnCl as the Lewis acid, enantioselectivities ranging from 65 to 95% were obtained. 

The reaction can be used ia the large-scale production of the optically active amino acid detivatives. The chiraUty of the a-carbon is substantially retained and resolution of the product is avoided. 

The asterisk signifies an asymmetric carbon. AH of the amino acids, except glycine, have two optically active isomers designated D- or L-. Isoleucine and threonine also have centers of asymmetry at their P-carbon atoms (1,10). Protein amino acids are of the L-a-form (1,10) as illustrated in Table 1. 

In many cases only the racemic mixtures of a-amino acids can be obtained through chemical synthesis. Therefore, optical resolution (42) is indispensable to get the optically active L- or D-forms in the production of expensive or uncommon amino acids. The optical resolution of amino acids can be done in two general ways physical or chemical methods which apply the stereospecific properties of amino acids, and biological or enzymatic methods which are based on the characteristic behavior of amino acids in living cells in the presence of enzymes. 

Asymmetric synthesis is a method for direct synthesis of optically active amino acids and finding efficient catalysts is a great target for researchers. Many exceUent reviews have been pubHshed (72). Asymmetric syntheses are classified as either enantioselective or diastereoselective reactions. Asymmetric hydrogenation has been appHed for practical manufacturing of l-DOPA and t-phenylalanine, but conventional methods have not been exceeded because of the short life of catalysts. An example of an enantio selective reaction, asymmetric hydrogenation of a-acetamidoacryHc acid derivatives, eg, Z-2-acetamidocinnamic acid [55065-02-6] (6), is shown below and in Table 4 (73). 

The configuration of the amine was retained, except in the case of amino acid derivatives, which racemized at the stage of the pyridinium salt product. Control experiments showed that, while the starting amino acid was configurationally stable under the reaction conditions, the pyridinium salt readily underwent deuterium exchange at the rz-position in D2O. In another early example, optically active amino alcohol 73 and amino acetate 74 provided chiral 1,4-dihydronicotinamide precursors 75 and 76, respectively, upon reaction with Zincke salt 8 (Scheme 8.4.24). The 1,4-dihydro forms of 75 and 76 were used in studies on the asymmetric reduction of rz,>S-unsaturated iminium salts. 

A recent report describes the conversion of A-formyl- and N-acetyl-L-leucine into optically active azlactones with dicyclohexyl-carbodiimide (DCC) [Eq. (29)]. Other cyclization reagents, e.g. acetic anhydride, POCI3, SOCI2, and polyphosphoric acid, cause racemiza-tion. These azlactones react with optically active amino acid esters to give esters of dipeptides with retention of activity. 

Scheeren et al. reported the first enantioselective metal-catalyzed 1,3-dipolar cycloaddition reaction of nitrones with alkenes in 1994 [26]. Their approach involved C,N-diphenylnitrone la and ketene acetals 2, in the presence of the amino acid-derived oxazaborolidinones 3 as the catalyst (Scheme 6.8). This type of boron catalyst has been used successfully for asymmetric Diels-Alder reactions [27, 28]. In this reaction the nitrone is activated, according to the inverse electron-demand, for a 1,3-dipolar cycloaddition with the electron-rich alkene. The reaction is thus controlled by the LUMO inone-HOMOaikene interaction. They found that coordination of the nitrone to the boron Lewis acid strongly accelerated the 1,3-dipolar cycloaddition reaction with ketene acetals. The reactions of la with 2a,b, catalyzed by 20 mol% of oxazaborolidinones such as 3a,b were carried out at -78 °C. In some reactions fair enantioselectivities were induced by the catalysts, thus, 4a was obtained with an optical purity of 74% ee, however, in a low yield. The reaction involving 2b gave the C-3, C-4-cis isomer 4b as the only diastereomer of the product with 62% ee. 

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