Amides, of aspartic acid

Asparagine, the amide of aspartic acid, was first isolated by Robi-quet and Vauquelin, in 1806, from the juice of Asparagus officinalis hence its name. Not only is asparagine found in asparagus, but also in the seedlings of lupines, peas, vetches, etc., from which it is best and most easily prepared. 

A therapeutically useful amino acid-related reaction is the amidation of aspartic acid to produce asparagine. 

Asparagine is obviously related to aspartic acid, since it is the mono-amide of aspartic acid. When asparagine (5.29) was first converted to the N,N-dibenzyl... 

Asparagine and glutamine (page 37) are the acid amides of aspartic acid and glutamic acid. 

Also belonging to the group of amino acids with non-ionizable side chains are asparagine and glutamine, the acid amides of aspartic acid and glutamic acid respectively. Owing to the amide... 

The carboxamidomethyl ester was prepared for use in peptide synthesis. It is formed from the cesium salt of an A-protected amino acid and o -chloroacet-amide (60-85% yield). It is cleaved with 0.5 M NaOH or NaHC03 in DMF/H2O. It is stable to the conditions required to remove BOC, Cbz, Fmoc, and t-butyl esters. It cannot be selectively cleaved in the presence of a benzyl ester of aspartic acid. ... 

Its composition, C H7N04, was established in 1833 by Boutron-Charlard and Pelouze, and confirmed by Liebig. In 1848 Piria showed that aspartic acid was converted into malic acid by the action of nitrous acid, and he regarded aspartic acid and asparagine as the two amides of malic acid... 

This idea of their constitution was proved to be erroneous by Kolbe in 1862, who showed that aspartic acid did not give off ammonia when boiled with dilute caustic alkali, and that asparagine only lost half of its nitrogen when thus treated. Aspartic acid was therefore not the amide of malic acid, but amino-succinic acid, and asparagine the amide of this compound. 

Alanine and aspartate are synthesized from pyruvate and oxaloacetate, respectively, by transamination from glutamate. Asparagine is synthesized by amidation of aspartate, with glutamine donating the NH4. These are nonessential amino acids, and their simple biosynthetic pathways occur in all organisms. 

Only three new amino acids were found (by automatic amino acid analysis) in poly-D,L-alanine after irradiation in 0.1% solution in the absence of O2 with doses to 5 Mrads. All were in yields less than G = 0.02. The first was eluted before aspartic acid and was therefore acidic the second was eluted in the position of aspartic acid, and the third in the position of glycine. We have not been able to confirm the identities of these products by TLC because of the low yields. The products found by amino acid analysis could not account for the discrepancy between amide-like ammonia formed (G = 0.66) and alanine destroyed (G = 1.9). Aspartic acid is formed when alanine is irradiated in solution 26), and it is likely that the carboxylation reaction proposed by these authors also accounts for the observed aspartic acid formation in PDLA. 

The presence of O2 during irradiation of PDLA (0.1% solution, 1 atm. O2), increased the amino acid destruction G = —1.9 in N2 and 2.1 in O2) and the formation of amide-like ammonia (G = 0.66 in N2, 2.0 in O2). The acidic amino acid formed in N2 was not found in samples irradiated in O2, but the amount of aspartic acid was increased. It is possible that O2 converted the precursor of the unknown acidic amino acid into aspartic acid. The small amount of glycine apparently was not affected. 

Fig. 6.21. In situ activation of a carboxylic acid—i.e., the side chain carboxyl group of protected L-aspartic acid—as the mixed anhydride (B) and its aminolysis to a Weinreb amide. How this Weinreb amide acylates an organolithium compound is shown in Figure 6.44. The acylation of an H nucleophile by a second Weinreb amide is presented in Figure 6.42 and the acylation of a di(ketone enolate) by a third Weinreb amide in Figure 13.64. Figure 6.50 also shows how Weinreb amides of carboxylic acids can be obtained by C,C bond formation.

There are 5 residues of glutamic acid and 2 of aspartic acid. Either one or two of them may be present as amides. 

The cyclization of aspartic acid residues to form aspartimide is the most likely side-reaction observed in routine SPPS (Fig. 10). This is a sequence-dependent side-reaction that occurs either during chain elongation or during final TFA cleavage when Asp(OtBu)-AA sequence (AA = Ala, Gly, Ser, Asn(Trt)) is present in the peptide. Hydrolysis of the aspartimide ring leads to a mixture of both a- and P-peptides. Its reaction with piperidine used for Fmoc removal also leads to the formation of a- and p-piperidides. Normally, in Fmoc-based SPPS, Asp (OtBu) provides sufficient protection. However, for particular sequences such as Asp(OtBu)-Asn(Trt) particularly sensitive to aspartimide formation, addition of HOBt to the piperidine solution or protection of the aspartyl amide bond with the 2-hydroxy-4-methoxybenzyl (Hmb) group should be considered (36). 

Cyclization of aspartic acid and asparagine to form aspartimides, and to a lesser extent of glutamic acid and glutamine to form glutarimide is an acid- and base-catalyzed common side reaction in peptide synthesis (see also Section 2.2.2). In SPPS it is particularly troublesome when Asp-Gly, Asp-Ala, and Asp-Ser sequences are present,but also with Asp-Asn.P P Piperidine-catalyzed aspartimide formation can be very rapid,and in this context DBU is even worse than piperidine.P The formation of aspartimide is reduced by the addition of HOBt or 2,4-dinitrophenol, but more efficiently it is reduced by protecting the aspartyl amide bond with the 2-hydroxy-4-methoxybenzyl (Hmb) group (see Section 2.3.2).P 1... 

Cycloalkyl esters for the side-chain protection of aspartic acid in SPPS have been developed to increase resistance to aspartimide formation. Based on mechanistic studies of this side reaction, these protection groups should fulfill the following criteria provide steric hindrance to intramolecular aminolytic attack of the ester by the amide nitrogen in acidic and basic media, provide increased stability toward repetitive TFA treatments but quantitative cleavage by HE, as well as stabilization of the carbenium ion produced by cleavage of the protecting group to prevent recapture by the peptide. The secondary cycloalkyl esters are more acid stable and more sterically hindered if compared to the primary benzyl esters. In Scheme 7, different cycloalkyl esters are shown. 

Following oral administration 7-22% of alitame is unabsorbed and excreted in the feces. The remaining amount is hydrolyzed to aspartic acid and alanine amide. The aspartic acid is metabolized normally and the alanine amide excreted in the urine as a sulfoxide isomer, as the sulfone, or conjugated with glucuronic acid. 

This vitamin is synthe.sized by most green plants and microorganisms. The precursors are y-ketoisovaleric acid and /S-alanine. The latter originates from the decarboxylation of aspartic acid. y-KetoLsovalcric acid is converted to keto-pantoic acid by Ar.W" -methyIenetetrahydrofolic acid then, on reduction, pantoic acid is formed. Finally, pantoic acid and alanine react by amide formation to form pantothenic acid. 

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