Unnatural D-amino acids

There have also been reports [36, 37] that racemization of amino acids occurs more rapidly using MW heating than conventional heating at the same temperature. Chen et al. [36] observed that racemization of amino acids in acetic acid the presence of benzaldehyde was accelerated by MW heating. Lubec et al. [37] reported that some D-proline and ris-4-hydroxy-D-proline were found in samples of infant milk formula when they were heated in a MW oven. On the other hand, conventionally heated samples did not contain these unnatural D-amino acids. This report caused concern, and received media attention because D-proline is neurotoxic and suggested that MW heating of some foods could have deleterious effects on their nutritional value and the health of the consumer. 

Incorporation of unnatural D-amino acids (e.g. D-Ala instead of Gly2)... 

Ever since Fischer, many chemists have focused their attention on the taste of amino acids. Generally, natural L-amino acids exert either no taste or a bitter taste while unnatural D-amino acids elicit a sweet taste almost without exception. Proteinogenic L-amino acids that exhibit a bitter taste include Trp (0.133%), Phe (0.069%), Tyr (0.017%), Leu (0.011%), Arg, Val, lie, and Pro, and the remaining amino acids exert either no taste or a sour taste. The values in parentheses show the caffeine concentration that provides the same bitterness as a 0.3% amino acid solution.165 However, different authors have reported different values for the strength of their... 

The reason bacteria use these unnatural D-amino acids in their cell walls is to protect them againstthe enzymes in animals and plants, which cannotdigest proteins containing D-amino acids. 

Much work has been done therefore, to try and stabilize this bond towards hydrolysis. It is possible to replace the amino acid glycine with an unnatural D-amino acid such as D-alanine. Since D-amino acids are not naturally occurring, peptidases do not recognize the structure and the peptide bond is not attacked. The alternative tactic of replacing L-tyrosine with D-tyrosine is not possible, since this completely alters the relative orientation of the tyrosine aromatic ring with respect to the rest of the molecule. As a result, the analogue is unable to bind to the analgesic receptor and is inactive. 

The scarcity of unnatural D-amino acids makes these compounds attractive synthetic targets, especially when one considers the disparity of price relative to their naturally occurring partners. If the hydroxyl group of an L-lactate could be displaced by a nitrogen nucleophile with inversion of configuration, this would allow easy access to D-alanine derivatives. Such a transformation can be realized by the reaction of 2 with diphenyl phosphorylazide and DBU to produce the (R)-azidoester 96 (98% ee) [33]. The initial step of the reaction is the formation of phosphonate 95. The resulting liberated azide then completely displaces the phosphonate group, with nearly total inversion of the stereo center. 

The replacement of the natural L-amIno acids with unnatural D-amino acids can make the peptides resistant to the actions of several peptidases that generally rapidly degrade the... 

For the chemical stabilization of peptides, different methods are known, such as the incorporation of unnatural D-amino acids that are not recognized by peptide-digesting proteases. Also, in the case of PDP2, the incorporation of an unnatural amino acid (benzoyl phenylalanine, peptide PDP3) (Figures 4.1 and 4.2) led to enhanced cellular stability [16]. 

For example, n-p-hydroxyphenylglydne, a key intermediate in the synthesis of semisynthetic cephalosporins and penicillins, is currently manufactured on a multi-thousand ton scale. The hydantoinase-catalysed reaction is also suitable for the production of unnatural D-amino acids, although the in situ racemization of the remaining substrate via keto-enol tautomerization is generally slow. To facilitate the stereoinversion, base or hydantoin racemase of Pseudomonas and Arthrobacter strains is often used. 

Two aPNAs were used in this study, L-CTCCT(b2) as well as its antipode D-CTCCT(b2) made up of unnaturally configured amino acids. A control peptide lacking nucleobases, Ac-Trp-Cys " -Lys-Ser-(Ala2-Lys-Ser)4-Gly-Lys-NH2, was also... 

Many of the amino acids originally tested by Krebs were racemic mixtures. When naturally occurring L-amino acids became available the oxidase was found to be sterically restricted to the unnatural, D series. [D-serine occurs in worms free and as D-phosphoryl lombricine (Ennor, 1959)]. It could not therefore be the enzyme used in the liver to release NH3 in amino acid metabolism. D-amino acid oxidase was shown by Warburg and Christian (1938) to be a flavoprotein with FAD as its prosthetic group. A few years later Green found an L-amino acid oxidase in liver. It was however limited in its specificity for amino acid substrates and not very active—characteristics which again precluded its central role in deamination. 

Design and development of unnatural peptides based on D-amino acids, /1-amino acids, artificial amino acids, etc. 

Although fermentation processes to unnatural amino acids, such as D-amino acids as in this example, are not generally possible, interesting exceptions exist. For instance the Tanabe Seiyaku Co. have developed a fermentation process for D-alanine. This depends on the formation of L-alanine from pyravate, followed by... 

Thus, the need has arisen for larger amounts of unnatural amino acids—those that contain unusual side chains or are in the D-series. Because a-amino acids contain an epimerizable center, D-amino acids are usually accessible through epimerization of the natural isomer, followed by a resolution. Of course, the racemic mixture can also be accessed by synthesis. Because resolution can be either wasteful—if the undesired isomer is discarded—or clumsy—when the other isomer is recycled through an epimerization protocol—many large-scale methods now rely on a dynamic resolution, where all of the starting material is converted to the desired isomer (vide infra, Chapters 6 and 7). With the advent of asymmetric reactions that can be performed at large scale, a substrate can now be converted to the required stereoisomer without the need for any extra steps associated with a resolution approach. 

The favorable effect of the enamide function on asymmetric induction is indicated not only by the result with compound I, but also by later results summarized in Table I, where optical purities in the range of 70 to 80% were generally obtained for various derivatives of alanine, phenylalanine, tyrosine, and 3,4-dihydroxyphenylalanine (DOPA). The Paris group found that the Rh-(-)-DIOP catalyst yielded the unnatural R or d -amino acid derivatives, whereas l-amino acid derivatives could be obtained with a (+)-DIOP catalyst. Since the optical purity of the IV-acylamino acids can often be considerably increased by a single recrystallization (fractionation of pure enantiomer from racemate) and the IV-acetyl group can be removed by acid hydrolysis, this scheme provides an excellent asymmetric synthesis route to several amino acids. 

Nutritional and Physiological Effects of Alkali-Treated Proteins. The first effect of the alkaline treatment of food proteins is a reduction in the nutritive value of the protein due to the decrease in (a) the availability of the essential amino acids chemically modified (cystine, lysine, isoleucine) and in (b) the digestibility of the protein because of the presence of cross-links (lysinoalanine, lanthionine, and ornithinoalanine) and of unnatural amino acids (ornithine, alloisoleucine, / -aminoalanine, and D-amino acids). The racemization reaction occurring during alkaline treatments has an effect on the nitrogen digestibility and the use of the amino acids involved. 

Sometimes chemists need the unnatural D enantiomer of an amino acid, often as part of a drug or an insecticide. Most L-amino acids are isolated from proteins, but the D-amino acids are rarely found in natural proteins. D-amino acids can be synthesized from the corresponding L-amino acids. The following synthetic scheme is one of the possible methods. 

When medicinal chemists are looking for ways to attack bacteria, one approach is to interfere with chemistry carried out by prokaryotes but not by us. The most famous of these attacks is aimed at the construction of the cell walls of some bacteria that contain unnatural (R) (or D-) amino acids. Bacterial cell walls are made from glycopeptides of an unusual kind. Polysaccharide chains are cross-linked with short peptides containing (J )-alanine (D-Ala). Before they are linked up, one chain ends with a glycine molecule and the other with D-Ala-D-AJa, In the final step in the cell wall synthesis, the glycine attacks the D-Ala-D-Ala sequence to form a new peptide bond by displacing one D-Ala residue. 

The use of D-amino acids, or of exotic L- or D-amino acids such as 2.4, does not significantly change the SPS procedure however, the availability of suitable A -Fmoc-protected exotic a-amino acids may be limited thus a method called solid-phase unnatural peptide synthesis (SP-UPS) has been reported. This method, which entails the SPS of unnatural a-amino acids by alkylation of Fmoc-Gly under mild conditions, has been integrated with traditional SP peptide chemistry (28). 

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