Aminomalonic acid

A. G. Ogston in 1948 explained the dilemma of how an enzyme can enan-tiospecifically produce a chiral product from a prochiral molecule such as citric acid or 2-aminomalonic acid. He pointed out two requirements three-point contact at three active sites (a, b, and c ) and catalytic dissimilarity between the two active sites (a and b ) associated with the pro-R and pro-5 groups (a and b) of the prochiral molecule as shown in Fig. 3.2. 

The synthesis of 3-carboxyalkyl oxadiazoles, starting from acyl-aminomalonic acid monoesters has been described p. 8l6 33a). 

Cultures of Streptomyces rimosus var paromomycinus characteristically develop UV absorption at 240 and 278 nm due to formation of malonomicin (22), a compound that shows antiprotozoal activity towards Trypanosoma congolense, the causative agent of sleping sickness in cattle [42]. Malonomicin contains an unique aminomalonic acid unit that, on brief heating in water, undergoes decarboxylation and results in a compound devoid of biological activity [43]. Hydrolysis of the compound yielded L-serine and racemic aspartic acid. The structure was elucidated by chemical and spectroscopic methods [43,44] and was confirmed by total synthesis [45]. 

There is no asymmetric carbon atom in aminomalonic acid molecule. When both of the carboxylic acids are substituted by esterification with different alcohols, optical isomers are generated. It is known that aminomalonic acid derivatives readily racemize in solution under ordinary conditions. L-Asp-Ama(OFn)-... 

OMe was found by Fujino et al.(11) to be 22000 33000 times sweeter than sucrose. It is not exactly known whether the sweettasting isomer has the L-L(or S-R) or the L-D(or S-S) configuration because of ready racemization. From the examination of its projection formula, it could be predicted that the L-L(or S-R) isomer (42), in which aminomalonic acid diester takes an L(or R)-configuration, would be sweet. This prediction agreed with that reported in the literature (14). 

In Ama-L-Phe-OMe (47) (14, 15), it is also not known whether the sweet-tasting isomer has the L-L(or S-S) or the D-L(or R-S) configuration. In the case of aspartyl dipeptide esters, the L-L isomer was sweet. By analogy, other researchers deduced that the L-L(or S-S) isomer ((47b) in Figure 4) would be sweet. However, it seemed to us that the D(or i )-configuration would be preferred for the aminomalonic acid because the D-L(or R-S) isomer ((47a) in Figure 4) was compatible with the sweet formula and could also fit the spatial barrier model (13), whereas the L-L(or S-S) isomer could neither fit the receptor model nor meet the sweet formula. 

Other abbreviations used Prw, n-propyl Pr , i-propyl Bun, n-butyl Bft, i-butyroyl Fe, fenchyl Cap, capryline=or-amino-octanoic acid aThr, aWothreonine HyNle, (3-hydroxynorleucine MPA, methylphenethyl-amine, HMPA, hydroxymethylphenethylamine Ama, aminomalonic acid. 

We also studied the pyridoxal-dependent decarboxylation of an aminomalonic acid, a process providing an a-amino acid as the product. Our interest was to induce stereoselectivity in the process. Therefore, we synthesized catalysts 42 and 43, which rigidly held chirally mounted groups [42]. With the basic 42 we obtained 42% ee favoring l-phenylalanine in the decarboxylation of 2-amino-2-benzyl-malonic acid, while with non-basic 43 the ee was too low to detect. We proposed that the basic side chain delivered a proton to the decarboxylation intermediate in a stereoselective fashion. 

A -Acylated amino acids are anodically oxidized in methanol or acetic acid solution under decarboxylative methoxylation or acetoxylation via the intermediate A-acyliminium ion in the course of a Non-Kolbe reaction (Hofer-Moest reaction) according to Scheme 8, path b. This type of reaction has been used intensively for amidoalkylation reactions by Mori, Seebach, and Steckhan. These reactions were based on the results of Iwasaki applying N-acyl aminomalonic acid half esters [Eq. (46)] [239]. 

Anodic decarboxylative methoxylation has also been used to generate an efficient electrophilic chiral glycine equivalent. This is produced from the cyclic dipeptide of L-proline and aminomalonic acid diester. Anodic decarboxylation of the remaining carboxylic function leads to the chiral iV,<9-acetal, which can undergo nucleophilic substitution followed by hydrolysis to give back L-proline and the nonproteinogenic new enantiopure i)-amino acid [Eq. (49)] [201]. 

Side-chain CH2 may be hydroxylated, e.g. hydroxylysine, hydroxyprolines (trans-4-hydroxyproline in particular), or carboxylated, e.g. to give ot-aminomalonic acid, (3-carboxyaspartic acid, y-carboxyglutamic acid, (3-hydroxyaspartic acid, etc. 

Formation of chiral a-amino acids from aminomalonic acids via decarboxylative protonation is readily accomplished in the presence of thiourea 1 (ex quinidine)/ The diaster-eomeric 2 (ex quinine) has been employed to generate monomethyl esters in chiral form by methanolysis meso-cydic anhydrides ... 

The way in which an enzyme, by three-point attachment, can discriminate between chemically-equivalent groups is illustrated in Figure 12.5 for the case of aminomalonic acid. This acid has two —COOH groups which are equivalent in the ordinary... 

The enzyme aspartate decarboxylase (EC 4.1.1.11) will decarboxylate aminomalonic acid in H20 to yield (25)-[2- HJglycine and will also transaminate glyoxylic acid in H20 to yield (2K)-[2- H]]glycine (78). The chirality of the product was assayed using the pro-S specific D-amino acid oxidase (EC 1.4.3.3). 

Aminomalonic acid is a substrate for aspartate /5-decarboxylase (EC 4.1.1.12). When (3R)- and (3S)-[3- C]aminomalonates were prepared from [3- C]-and [l- C]serines, respectively, and incubated with this enzyme, the 3-pro-R carboxyl group was lost (346). Since the decarboxylation had been shown to incorporate label into the 2-pro-S hydrogen of glycine (78), the decarboxylation was deemed to have occurred with retention of configuration. 

N. Berova, J. Breinholt, G. W. Jensen, A. Kjcer, L.-C. Lo, K. Nakanishi, R. I. Nielsen, C. E. Olsen, C. Pedersen, and C. E. Stidsen, Malonofungin an antifungal aminomalonic acid from Phaeoramularia fusimaculans, Acta Chem. Scand., 48 (1994) 240-251. 

M.p. 113° decbmp. Sol. EtOH, EtgO. NHj in MeOH —aminomalonic acid. 

Lactams from aminomalonic acid esters and y-Lactams... 

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