Decarboxylation of a-amino acids

Figure 6.22 (a) Strecker pathway for decarboxylation of a-amino acids (a similar... 

DAKIN WEST Acylation An acylative decarboxylation of a-amino acids or a-thio acids. 

Decarboxylations of a-amino acids are some of the most widely studied enzymatic reactions, and had been, at one time, presumed to be exclusively associated with pyridoxal-dependent catalysis. The reactivity of an enzyme of this type with carbonyl group reagents such as hydrazines, cyanide or hydroxylamine, was therefore consid-... 

Oximes can be converted to their corresponding nitro compounds with Oxone and refluxing acetonitrile (eq 58). They can also be cleaved to their parent carbonyl compounds by Oxone in conjunction with glacial acetic acid, or silica gel/alumina and microwave irradiation (eq 58). Ketoximes and aldoximes are both converted to carbonyl compounds in high yields using the microwave and alumina procedure. Several of the above transformations are highlighted in the oxidative decarboxylation of a-amino acids to form ketones and carboxylic acids. ... 

As the parent substance of animal bases, protein calls for almost exclusive consideration. The biologically active amines of man might be looked upon as derivatives of protein. In a narrower sense they are bases, which arise through decarboxylation of a-amino-acids. This clearly distinguishes them from protein derivatives whose biosynthesis takes place in a different manner, as in the production of betaine, the methylation of amines, the conversion of amino-acids and amines to amides by hydrolysis or other processes. 

The influence of electrostatic effects on pyridoxal 5 -phosphate-dependent enzymic decarboxylation of a-amino acids has been studied using ab initio calculations. " The catalytic ability of molecular receptors on a dibenz[c,/z] acridine skeleton to bind and decarboxylate dibutylmalonic acid has been investigated. ... 

A wide variety of functionality can be incorporated into the substrate acids, such as in the decarboxylation of a-amino acid derivatives which leads to amines (eq Application of this methodology to the appropriate aspartate and glutamate derivatives provides access to the useful radicals (5) which can be trapped in many ways, such as by halides (overall, a Hunsdiecker reaction), as can many other radical species obtained using this chemistry (see below). 

Bach, R.D. and Canepa, C. (1997) Theoretical model for pyruvoyl-dependent enzymatic decarboxylation of a-amino acids. J. Am. Chem. Soc., 119, 11725-11733. 

The synthesis and metabolism of trace amines and monoamine neurotransmitters largely overlap [1]. The trace amines PEA, TYR and TRP are synthesized in neurons by decarboxylation of precursor amino acids through the enzyme aromatic amino acid decarboxylase (AADC). OCT is derived from TYR. by involvement of the enzyme dopamine (3-hydroxylase (Fig. 1 DBH). The catabolism of trace amines occurs in both glia and neurons and is predominantly mediated by monoamine oxidases (MAO-A and -B). While TYR., TRP and OCT show approximately equal affinities toward MAO-A and MAO-B, PEA serves as preferred substrate for MAO-B. The metabolites phenylacetic acid (PEA), hydroxyphenylacetic acid (TYR.), hydroxymandelic acid (OCT), and indole-3-acetic (TRP) are believed to be pharmacologically inactive. 

Histamine is a critical mediator in anaphylactic reactions. It is a diamine produced by decarboxylation of the amino acid histidine in the Golgi apparatus of mast cells and basophils. Once secreted, it is rapidly metabolized by histamine methyltransferase [2]. Plasma histamine levels are elevated in anaphylaxis, reaching a concentration peak at 5 min and declining to baseline by 30-60 min [3]. Therefore, histamine samples for assessing an anaphylactic reaction should be obtained within 15 min of the onset of the reaction. Urinary metabolites of histamine may be found for up to 24 h. 

While a number of drugs, e.g. a-methyl dopa, inhibit the enzyme they have little effect on the levels of brain DA and NA, compared with inhibition of tyrosine hydroxylase and they also affect the decarboxylation of other amino acids. Some compounds, e.g. a-methyl dopa hydrazine (carbidopa) and benserazide, which do not easily enter the CNS have a useful role when given in conjunction with levodopa in the treatment of Parkinsonism (see Chapter 15) since the dopa is then preserved peripherally and so more enters the brain. 

Another interesting example is SHMT. This enzyme catalyzes decarboxylation of a-amino-a-methylmalonate with the aid of pyridoxal-5 -phosphate (PLP). This is an unique enzyme in that it promotes various types of reactions of a-amino acids. It promotes aldol/retro-aldol type reactions and transamination reaction in addition to decarboxylation reaction. Although the types of apparent reactions are different, the common point of these reactions is the formation of a complex with PLP. In addition, the initial step of each reaction is the decomposition of the Schiff base formed between the substrate and pyridoxal coenzyme (Fig. 7-3). 

In order to account for the nonvolatility, infusibility, and limited solubility, Leuchs postulated polymerization of the ground type cyclic compound, as indicated by the subscript x in his formula given above. It is now well established that linear polypeptides are produced on decarboxylation of the N-carboxyanhydrides of a-amino acids, and under favorable conditions the chain length may be fairly large. Leuchs favored the view that strained rings, i.e., those of other than five or six... 

The ring-opening of the cyclopropane nitrosourea 233 with silver trifiate followed by stereospecific [4 + 2] cycloaddition yields 234 [129]. (Scheme 93) Oxovanadium(V) compounds, VO(OR)X2, are revealed to be Lewis acids with one-electron oxidation capability. These properties permit versatile oxidative transformations of carbonyl and organosilicon compounds as exemplified by ring-opening oxygenation of cyclic ketones [130], dehydrogenative aroma-tization of 2-eyclohexen-l-ones [131], allylic oxidation of oc,/ -unsaturated carbonyl compounds [132], decarboxylative oxidation of a-amino acids [133], oxidative desilylation of silyl enol ethers [134], allylic silanes, and benzylic silanes [135]. 

Oxidative decarboxylation of a-amino carboxylic acid The electrochemical oxidation of Al-acyl-a-amino acids (96) in MeOH affords N, O-acetals (98) through acyliminium intermediates (97) (Scheme 36) [121]. 

The principal pathways for the biogenesis and metabolism of histamine are well known. Histamine is formed by decarboxylation of the amino acid, L-histidine, a reaction catalyzed by the enzyme, histidine decarboxylase. This decarboxylase is found in both mammalian and non-mammalian species. The mammalian enzyme requires pyridoxal phosphate as a cofactor. The bacterial enzyme has a different pH optimum and utilizes pyruvate as a cofactor (26.27). 

An analogous method was used by Endo and colleagues in a-amination of unreactive carboxylic acids. Treatment of iV-acylhydroxylamine O-carbamates 92 by KHMDS or LDA followed by [3,3]-sigmatropic rearrangement and decarboxylation provided a-amino acid analogues 93 (equation 29). 

Azomethine ylides can be generated in situ from various readily accessible starting materials. One of the easiest approaches to produce 1,3-dipoles involves the decarboxylation of immonium salts derived from condensation of a-amino acids with aldehydes or ketones [3, 204—206]. For example, the azomethine ylide 203, obtained by decarboxylating the condensation product of N-methylglycine and paraformaldehyde in refluxing toluene, reacts with Cjq to give the N-methyl-pyrrolidine derivative 204 in 41% yield (Scheme 4.32) [204]. 

Histamine is an imidazole compound, formed by decarboxylation of the amino acid L-histidine, a reaction catalyzed by the enzyme histidine decarboxylase. 

Histamine is formed by decarboxylation of the amino acid l -histidine, a reaction catalyzed in mammalian tissues by the enzyme histidine decarboxylase. Once formed, histamine is either stored or rapidly inactivated. Very little histamine is excreted unchanged. The major metabolic pathways involve conversion to /V-methylhistamine, methylimidazoleacetic acid, and imidazoleacetic acid (IAA). Certain neoplasms (systemic mastocytosis, urticaria pigmentosa, gastric carcinoid, and occasionally myelogenous leukemia) are associated with increased numbers of mast cells or basophils and with increased excretion of histamine and its metabolites. 

Since fluorescamine reacts only with primary amino groups, secondary amino acids do not give a fluorescent product with this reaction. A method for converting secondary amino acids into primary amines has been described for analysis using fluorescamine [87], and is based on treatment of the amino acid with N-chlorosuccinimide. The reaction involves an oxidative decarboxylation of the amino acids. This method has been incorporated into the automatic analysis of amino acids with fluorescamine [88]. The fluorescence spectra and the sensitivities are similar to those of the derivatives of the primary amino acids. 

Oxidation of oxalic acid with dimethyl-V,V-dichlorohydantoin and dichloroisocya-nuric acid is of first order with respect to the oxidant. The order with respect to the reductant is fractional. The reactions are catalysed by Mn(II). Suitable mechanisms are proposed.129 A mechanism involving synchronous oxidative decarboxylation has been suggested for the oxidation of a-amino acids with l,3-dichloro-5,5-dimethylhydantoin.130 Kinetic parameters have been determined and a mechanism has been proposed for the oxidation of thiadiazole and oxadiazole with trichloroiso-cyanuric acid.131 Oxidation of two phenoxazine dyes, Nile Blue and Meldola Blue, with acidic chlorite and hypochlorous acid is of first order with respect to each of the reductant and chlorite anion. The rate constants and activation parameters for the oxidation have been determined.132... 

The oxidation of co-ordinated cysteine ligands may also give a variety of products. The most usually encountered reactions involve the formation of sulfenate or sulfinate as above however, in some cases disulfide formation occurs in preference to oxygen transfer. In the example shown in Fig. 9-39, the formation of the disulfide is accompanied by decarboxylation of the amino acid ... 

Azomethine ylides are organic 1,3-dipoles possessing a carbanion next to an im-monium ion [ 12]. Cycloadditions to dipolarophiles provide access to pyrrolidine derivatives, useful intermediates in organic synthesis with stereo- and regiochem-ical control. Azomethine ylides can be readily produced upon decarboxylation of immonium salts derived from the condensation of a-amino acids with aldehydes or ketones. When they are added to C60, a fulleropyrrolidine monoadduct is formed in which a pyrrolidine ring is fused to the junction between two six-memberedrings of afullerene [13-15].Very importantly,functionalized aldehydes lead to the formation of 2-substituted fulleropyrrolidines, whereas reaction with AT-substituted glycines leads to AT-substituted fulleropyrrolidines (Scheme 1). 

Decarboxylation of an amino acid is an important reaction, catalyzed by a pyridoxal-dependent decarboxylase, that affords an amine as product (Scheme 2.6). It is very attractive to learn how to mimic this process to generate various amines from a-amino acids. Unfortunately, our previous studies established that treatment of a-alkyl amino acids with pyridoxal afforded only ketone and pyridoxamine as products, by a transamination-dependent oxidative decarboxylation process (pathway b in Scheme 2.5) [41]. Consequently, non-oxidative decarboxylation, using pyridoxals to generate amines, remains elusive. 

This vitamin acts as a coenzyme in the metabolism of carbohydrates and is present in all living tissues. It acts in the form of thiamin diphosphate in the decarboxylation of a-keto acids and is referred to as cocarboxylase. Thiamin is available in the form of its chloride or nitrate, and its structural formula is shown in Figure 9-12. The molecule contains two basic nitrogen atoms one is in the primary amino group, the other in the quater-... 

The concept of inhibition via p elimination of fluoride ion has now been extended to the irreversible inhibition of a-amino acid decarboxylases. Ornithine decarboxylase (ODC), which catalyzes the decarboxylation of ornithine to putrescine is irreversibly inhibited by a-difluoromethylornithine (IX Fig. 9) (28). In this case, the carbanion formation which precedes P elimination is generated by loss of CO2, and not by proton abstraction (Fig. 9). Similarly, aromatic amino acid decarboxylase is irreversibly inhibited by C-difluoromethyl-3,4-dihydroxyphenylalanine (29) while histidine decarboxylase, ornithine decarboxylase and aromatic amino acid decarboxylase have been inhibited by the corresponding <=d-monof luoromethylanri.no acids, respectively (29). 

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